刘玄石, 李巍^,儿科重大疾病研究教育部重点实验室,北京 100045

Mining and characterization of preterm birth related genes

Xuanshi Liu, Wei Li^,Genetics and Birth Defects Control Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing 100045, China

通讯作者: 李巍,博士,教授,博士生导师,研究方向：医学生物化学,医学遗传,细胞生物学,产前诊断以及遗传咨询。E-mail: liwei@bch.com.cn

编委: 方向东
收稿日期:2019-03-21修回日期:2019-05-8网络出版日期:2019-05-20

Received:2019-03-21Revised:2019-05-8Online:2019-05-20
作者简介 About authors
刘玄石,博士研究生,助理研究员,专业方向：生物信息学E-mail:liuxs2017bioinf@163.com。




摘要
早产(preterm birth, PTB)指胎儿在完成37周妊娠前出生,是新生儿死亡的主要原因,与多种新生儿疾病和成年发生的慢性病相关。据双生子和家系研究报道,遗传因素约占早产风险的15%~35%,然而早产的分子流行病学机制目前尚不明确。本研究通过挖掘文献数据库和疾病数据库中与早产相关的文献,并结合两重过滤的方法,筛选出355个与早产相关基因。富集分析发现早产相关基因主要分子功能包括：受体配体活性、细胞因子受体结合、细胞因子活性和生长因子活性等;主要通路包括KEGG中富集的糖尿病并发症中的AGE-RAGE信号通路、Chagas病和IL-17信号通路和TNF信号通路等,以及Reactome中富集的多个与免疫相关的通路。早产相关基因与基因组其他基因相比较,转录本数量有差异(α = 0.1, P = 0.06),但在GC含量和基因长度上没有明显差异。本研究结果提示早产基因大多集中在免疫相关通路,具备与免疫过程密切相关的分子功能,为早产的遗传机制研究提供了重要资源。
关键词： 早产;数据挖掘;富集分析;基因特征;转录本数量

Abstract
Preterm birth (PTB) refers to birth before 37 completed gestational weeks. PTB is the leading cause of neonatal deaths and is associated with various neonatal complications and adult-onset chronic diseases. According to twin and family studies, genetic variants account for about 15% to 35% of the incidence of PTB. However, the molecular epidemiology of PTB is still unclear. By mining the PTB-related researches in the literature database and the disease databases, and combining two filtering methods, 355 PTB-related genes were selected. The enrichment analyses of molecular function revealed that the main functions of PTB-related genes include: receptor ligand activity, cytokine receptor binding, cytokine activity, growth factor activity, etc.; the main pathways from KEGG enrichment were the AGE-RAGE signaling pathway in diabetic complications, Chagas disease, and the IL-17 signaling pathway, the TNF signaling pathway, etc, as well as several immune-related pathways from Reactome enrichment. There were differences in the number of transcripts between PTB-related genes and other genes in the genome (α = 0.1, P = 0.06), but there was no significant difference in GC content and gene lengths. The results suggest that PTB-related genes are mostly in immune-related pathways, and have molecular functions closely related to immunity. Our work provides an important resource for the study of the genetical mechanisms of PTB.
Keywords：preterm birth;data mining;enrichment analysis;gene features;transcript number


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本文引用格式
刘玄石, 李巍. 早产相关基因的挖掘与特征分析[J]. 遗传, 2019, 41(5): 413-421 doi:10.16288/j.yczz.19-078
Xuanshi Liu, Wei Li. Mining and characterization of preterm birth related genes[J]. Hereditas(Beijing), 2019, 41(5): 413-421 doi:10.16288/j.yczz.19-078


早产是指胎儿在完成37周妊娠前出生。2010年,世界卫生组织等国际组织对全世界184个国家的调查发现,新生儿的早产率大致是5%~ 18%^[1],中国的早产率大约是7%,每年约有120万早产婴儿,全球排名第二,仅低于印度^[2]。除死亡风险外,早产还可能伴有脑瘫、肺部疾病、听觉和视觉缺陷等风险^[1,2],甚至有研究发现早产与成年后发生的一些慢性疾病相关,如心血管疾病和糖尿病等^[3]。目前,早产的发生机制尚不明确。根据双生子及家系研究的估算,遗传因素对早产风险的影响大约占15%~35%^[4,5,6]。早期对早产遗传机制的研究,通常根据早产病理学特点,选择可能相关的基因展开研究。例如,与新生儿出生体重和月经期有关的PON2^[7],参与炎症反应的TNF、IL10^[8]和TLR2^[9],与血管生成有关的VEGF^[10,11]等。近年来,采用高通量测序技术对早产遗传因素的研究,发现了大量相关的位点和基因,包括采用全基因组关联分析找到的与自发早产相关的3个位点(rs17053026、rs17527054和rs3777722)^[12],以及位于EBF1、EEFSEC和AGTR2基因上的与早产相关的位点^[13];利用全外显子测序发现与早产最显著相关的位点落在CR1基因外显子上^[14];全基因组、转录组和甲基化数据的结果提示RAB31和RBPJ基因与早产相关^[15]等。虽然针对早产遗传因素的研究已经积累了大量数据,然而由于早产的遗传机制相当复杂,现有研究结果也缺乏较好的归纳和整合,如Database for Preterm Birth (dbPTB)最后一次更新是2014年,这使得后续采用生物信息学手段对早产遗传信息的挖掘和早产遗传模型的构建变得困难^[16]。因此,本研究利用生物信息学方法,通过挖掘文献数据库以及疾病基因数据库中报道的早产相关基因信息,整合并分析早产相关基因的特征,为早产的遗传研究提供重要资源。

1 材料与方法

1.1 数据库和软件

(1)文献数据库：美国国家医学图书馆(PubMed, https://www.ncbi.nlm.nih.gov/pubmed/);(2)疾病数据库：人类孟德尔遗传数据库(OMIM, https://www.omim.org/,下载时间：2019年1月18日)、人类基因组变异数据库(ClinVar, https://www.ncbi.nlm.nih.gov/clinvar/,下载时间：2019年2月11日)以及毒物基因组学数据库(CTD, http://ctdbase.org/,下载时间2019年2月6日);(3)基因特征数据通过Ensembl 数据库收集(http://grch37.ensembl.org/biomart/martview/b3df3ce0609b9d96d3347ff1d09e4348,数据下载时间：2019年3月10日)。基因数据均统一使用人类参考基因组GRCh37/hg19;(4)统计应用软件R,版本号3.5.1。R包ClusterProfiler (版本3.10.1)用于富集分析^[17];(5)网页版文本挖掘工具SciMiner (http://hurlab.med.und.edu/SciMiner/,使用时间：2019年3月10日)^[18]。

1.2 文献数据库的信息挖掘

2019年3月8日,通过计算机检索PubMed数据库,采用关键词检索式“preterm birth”AND“gene”,检索年限为建库至2019年3月。整理出所有文献的PMID,输入文本挖掘工具SciMiner。SciMiner软件通过关键字“preterm birth”,以及软件内置的正则表达规则和基因字典,挖掘文献中与早产相关基因。为避免过度匹配,对SciMiner挖掘结果设置阈值和人工审核的两层过滤方式。首先根据设置的阙值,删除了仅在2篇及以下文献中出现的基因。其次通过人工核查摘要,删除摘要中没有直接提及早产的基因。最后筛选出用于后续分析的基因列表。

1.3 疾病数据库的信息挖掘

通过Shell脚本程序,搜索疾病数据库OMIM,ClinVar和CTD,查找与“preterm birth”或其同义词匹配的记录,提取记录下的基因信息,并合并进文献数据库筛选出的基因列表。

1.4 基因富集分析

采用R软件包ClusterProfiler对筛选出的基因,进行了基因功能(Gene Ontology, GO)和KEGG通路(京都基因与基因组大百科全书数据库,Kyoto Encyclopedia of Genes and Genomes)以及Reactome通路^[19]的富集分析,对结果进行多重检验后,获得显著的功能和通路,以FDR<0.05 (false discovery rate)作为显著性的阈值。

1.5 基因特征的收集

采用Ensembl的BioMart,收集了20320个基因的长度,转录本数量,GC含量特征(人基因组版本GRCh37.p13/hg19)。根据筛选出的基因列表,采用Shell脚本程序,从BioMart数据中提取了所需基因的特征信息。

2 结果与分析

2.1 早产相关基因数据库挖掘结果

通过计算机检索PubMed数据库获得来源于800种杂志的2264篇相关文献的摘要,并通过PMID和SciMiner软件挖掘出了文献中与早产可能相关的2149个基因。其中,文献数量居前5%的杂志多数是临床专业期刊(附表1)。经过阈值和人工审核的两层过滤,筛选出在1274篇文献里出现的355个基因(附表2),表1列出了在文献数量中排名前5%的基因。

Supplementary Table 1
附表1
附表1 PubMed检索结果中居前5%的杂志
Supplementary Table 1 Top 5% Journals from PubMed

排序	期刊	用于过滤的文献数量	排序	期刊	用于过滤的文献数量
1	PLoS One	109	11	Mol Hum Reprod	25
2	Pediatr Res	75	12	Sci Rep	22
3	Am J Obstet Gynecol	71	13	Endocrinology	22
4	J Matern Fetal Neonatal Med	36	14	Hum Mol Genet	20
5	Reprod Sci	35	15	Am J Physiol Lung Cell Mol Physiol	20
6	Placenta	30	16	J Perinatol	19
7	Am J Reprod Immunol	29	17	Neonatology	18
8	Am J Med Genet A	29	18	Am J Pathol	18
9	Proc Natl Acad Sci U S A	28	19	J Reprod Immunol	17
10	Biol Reprod	26	20	Pediatrics	16

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Supplementary Table 2
附表2
附表2 早产相关基因
Supplementary Table 2 Preterm birth related genes

基因名称	基因ID	基因全称	有基因记录的文献数
TNF	11892	tumor necrosis factor (TNF superfamily, member 2)	156
IL6	6018	interleukin 6 (interferon, beta 2)	155
IL1B	5992	interleukin 1, beta	140
IL8	6025	interleukin 8	85
NFKB1	7794	nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (p105)	68
COL1A1	2197	collagen, type I, alpha 1	68
PTGS2	9605	prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase)	63
TLR4	11850	toll-like receptor 4	57
VEGFA	12680	vascular endothelial growth factor A	57
IL10	5962	interleukin 10	53
MT-RNR2	7471	mitochondrially encoded 16S RNA	51
INS	6081	insulin	46
PGR	8910	progesterone receptor	42
IGF1	5464	insulin-like growth factor 1 (somatomedin C)	39
TGFB1	11766	transforming growth factor, beta 1	39
SFTPD	10803	surfactant, pulmonary-associated protein D	38
MMP9	7176	matrix metallopeptidase 9 (gelatinase B, 92kDa gelatinase, 92kDa type IV collagenase)	36
NR3C1	7978	nuclear receptor subfamily 3, group C, member 1 (glucocorticoid receptor)	35
SFTPA2B	23441	surfactant, pulmonary-associated protein A2B	34
IL1A	5991	interleukin 1, alpha	33
SFTPA1	10798	surfactant, pulmonary-associated protein A1	32
基因名称	基因ID	基因全称	有基因记录的文献数
CCL2	10618	chemokine (C-C motif) ligand 2	29
F2	3535	coagulation factor II (thrombin)	26
IL4	6014	interleukin 4	25
TLR2	11848	toll-like receptor 2	25
SFTPB	10801	surfactant, pulmonary-associated protein B	24
IFNG	5438	interferon, gamma	24
IL1RN	6000	interleukin 1 receptor antagonist	24
MBL2	6922	mannose-binding lectin (protein C) 2, soluble (opsonic defect)	23
SFTPC	10802	surfactant, pulmonary-associated protein C	23
OXTR	8529	oxytocin receptor	23
MTHFR	7436	5,10-methylenetetrahydrofolate reductase (NADPH)	23
MAPK1	6871	mitogen-activated protein kinase 1	23
NOS2A	7873	nitric oxide synthase 2A (inducible, hepatocytes)	22
ACE	2707	angiotensin I converting enzyme (peptidyl-dipeptidase A) 1	21
REN	9958	renin	21
CRH	2355	corticotropin releasing hormone	20
ALB	399	albumin	20
CYP1A1	2595	cytochrome P450, family 1, subfamily A, polypeptide 1	18
MMP1	7155	matrix metallopeptidase 1 (interstitial collagenase)	18
GSTT1	4641	glutathione S-transferase theta 1	17
GJA1	4274	gap junction protein, alpha 1, 43kDa	17
CD14	1628	CD14 molecule	17
CASP3	1504	caspase 3, apoptosis-related cysteine peptidase	17
APOE	613	apolipoprotein E	16
NOS3	7876	nitric oxide synthase 3 (endothelial cell)	16
F5	3542	coagulation factor V (proaccelerin, labile factor)	16
JUN	6204	jun oncogene	15
IGF2	5466	insulin-like growth factor 2 (somatomedin A)	15
LEP	6553	leptin	15
BCL2	990	B-cell CLL/lymphoma 2	15
GAPDH	4141	glyceraldehyde-3-phosphate dehydrogenase	15
FOS	3796	v-fos FBJ murine osteosarcoma viral oncogene homolog	15
MMP2	7166	matrix metallopeptidase 2 (gelatinase A, 72kDa gelatinase, 72kDa type IV collagenase)	15
SERPINH1	1546	serpin peptidase inhibitor, clade H (heat shock protein 47), member 1, (collagen binding protein 1)	14
FLT1	3763	fms-related tyrosine kinase 1 (vascular endothelial growth factor/vascular permeability factor receptor)	14
NFKBIA	7797	nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha	14
GSTM1	4632	glutathione S-transferase M1	13
SERPINE1	8583	serpin peptidase inhibitor, clade E (nexin, plasminogen activator inhibitor type 1), member 1	13
基因名称	基因ID	基因全称	有基因记录的文献数
IL6R	6019	interleukin 6 receptor	13
TP53	11998	tumor protein p53	13
TWIST1	12428	twist homolog 1 (acrocephalosyndactyly 3; Saethre-Chotzen syndrome) (Drosophila)	13
SOD1	11179	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	13
IL2	6001	interleukin 2	13
CD4	1678	CD4 molecule	13
AGT	333	angiotensinogen (serpin peptidase inhibitor, clade A, member 8)	12
PPARG	9236	peroxisome proliferator-activated receptor gamma	12
CAT	1516	catalase	12
CYP2B6	2615	cytochrome P450, family 2, subfamily B, polypeptide 6	12
PGF	8893	placental growth factor	11
S100A9	10499	S100 calcium binding protein A9	11
GSTA1	4626	glutathione S-transferase A1	11
KDR	6307	kinase insert domain receptor (a type III receptor tyrosine kinase)	11
PRKCA	9393	protein kinase C, alpha	11
STAT1	11362	signal transducer and activator of transcription 1, 91kDa	10
MBP	6925	myelin basic protein	10
IL13	5973	interleukin 13	10
EDN1	3176	endothelin 1	10
LTA	6709	lymphotoxin alpha (TNF superfamily, member 1)	10
TFAP2A	11742	transcription factor AP-2 alpha (activating enhancer binding protein 2 alpha)	10
TLR5	11851	toll-like receptor 5	10
TBXAS1	11609	thromboxane A synthase 1 (platelet, cytochrome P450, family 5, subfamily A)	10
IL1R1	5993	interleukin 1 receptor, type I	10
CYP3A5	2638	cytochrome P450, family 3, subfamily A, polypeptide 5	9
IGFBP1	5469	insulin-like growth factor binding protein 1	9
EGR1	3238	early growth response 1	9
FAS	11920	Fas (TNF receptor superfamily, member 6)	9
ADRB2	286	adrenergic, beta-2-, receptor, surface	9
MMP8	7175	matrix metallopeptidase 8 (neutrophil collagenase)	9
PTGER4	9596	prostaglandin E receptor 4 (subtype EP4)	8
CSF3	2438	colony stimulating factor 3 (granulocyte)	8
TNFRSF1A	11916	tumor necrosis factor receptor superfamily, member 1A	8
NES	7756	nestin	8
FGFR3	3690	fibroblast growth factor receptor 3 (achondroplasia, thanatophoric dwarfism)	8
MAPK3	6877	mitogen-activated protein kinase 3	8
COX8A	2294	cytochrome c oxidase subunit 8A (ubiquitous)	8
ESR2	3468	estrogen receptor 2 (ER beta)	8
PPARA	9232	peroxisome proliferator-activated receptor alpha	8
FSHR	3969	follicle stimulating hormone receptor	8
基因名称	基因ID	基因全称	有基因记录的文献数
MAPK14	6876	mitogen-activated protein kinase 14	8
RPS27A	10417	ribosomal protein S27a	8
H19	4713	H19, imprinted maternally expressed transcript	8
SP1	11205	Sp1 transcription factor	7
SOD2	11180	superoxide dismutase 2, mitochondrial	7
MT-CO2	7421	mitochondrially encoded cytochrome c oxidase II	7
IL17A	5981	interleukin 17A	7
IGFBP3	5472	insulin-like growth factor binding protein 3	7
PTGER3	9595	prostaglandin E receptor 3 (subtype EP3)	7
IRF6	6121	interferon regulatory factor 6	7
MYD88	7562	myeloid differentiation primary response gene (88)	7
PLAT	9051	plasminogen activator, tissue	7
ICAM1	5344	intercellular adhesion molecule 1 (CD54), human rhinovirus receptor	7
MAPK8	6881	mitogen-activated protein kinase 8	7
MMP3	7173	matrix metallopeptidase 3 (stromelysin 1, progelatinase)	7
HSD11B2	5209	hydroxysteroid (11-beta) dehydrogenase 2	7
CD8A	1706	CD8a molecule	7
SLC6A3	11049	solute carrier family 6 (neurotransmitter transporter, dopamine), member 3	7
SLC12A1	10910	solute carrier family 12 (sodium/potassium/chloride transporters), member 1	6
NFE2L2	7782	nuclear factor (erythroid-derived 2)-like 2	6
HPGD	5154	hydroxyprostaglandin dehydrogenase 15-(NAD)	6
PTGER2	9594	prostaglandin E receptor 2 (subtype EP2), 53kDa	6
ABCA3	33	ATP-binding cassette, sub-family A (ABC1), member 3	6
SMN1	11117	survival of motor neuron 1, telomeric	6
CXCL10	10637	chemokine (C-X-C motif) ligand 10	6
DEFB1	2766	defensin, beta 1	6
LPAL2	21210	lipoprotein, Lp(a)-like 2	6
NOS1	7872	nitric oxide synthase 1 (neuronal)	6
FGFR1	3688	fibroblast growth factor receptor 1 (fms-related tyrosine kinase 2, Pfeiffer syndrome)	6
CASP1	1499	caspase 1, apoptosis-related cysteine peptidase (interleukin 1, beta, convertase)	6
AR	644	androgen receptor (dihydrotestosterone receptor; testicular feminization; spinal and bulbar muscular atrophy; Kennedy disease)	6
ATM	795	ataxia telangiectasia mutated	6
ZMPSTE24	12877	zinc metallopeptidase (STE24 homolog, S. cerevisiae)	6
CXCL1	4602	chemokine (C-X-C motif) ligand 1 (melanoma growth stimulating activity, alpha)	6
NDP	7678	Norrie disease (pseudoglioma)	6
TLR3	11849	toll-like receptor 3	6
FLG	3748	filaggrin	5
SLC6A4	11050	solute carrier family 6 (neurotransmitter transporter, serotonin), member 4	5
RUNX2	10472	runt-related transcription factor 2	5
基因名称	基因ID	基因全称	有基因记录的文献数
ABCB1	40	ATP-binding cassette, sub-family B (MDR/TAP), member 1	5
NR3C2	7979	nuclear receptor subfamily 3, group C, member 2	5
EGFR	3236	epidermal growth factor receptor (erythroblastic leukemia viral (v-erb-b) oncogene homolog, avian)	5
LOR	6663	loricrin	5
HDAC9	14065	histone deacetylase 9	5
TNFRSF1B	11917	tumor necrosis factor receptor superfamily, member 1B	5
EPO	3415	erythropoietin	5
NOD2	5331	nucleotide-binding oligomerization domain containing 2	5
LEPR	6554	leptin receptor	5
CTNNB1	2514	catenin (cadherin-associated protein), beta 1, 88kDa	5
THBS1	11785	thrombospondin 1	5
TNFAIP3	11896	tumor necrosis factor, alpha-induced protein 3	5
S100A6	10496	S100 calcium binding protein A6	5
TGFB2	11768	transforming growth factor, beta 2	5
IL5	6016	interleukin 5 (colony-stimulating factor, eosinophil)	5
SLC2A4	11009	solute carrier family 2 (facilitated glucose transporter), member 4	5
ACPP	125	acid phosphatase, prostate	5
TCEAL1	11616	transcription elongation factor A (SII)-like 1	5
COL1A2	2198	collagen, type I, alpha 2	5
CTGF	2500	connective tissue growth factor	5
F2R	3537	coagulation factor II (thrombin) receptor	5
CD163	1631	CD163 molecule	5
JAG1	6188	jagged 1 (Alagille syndrome)	5
IL12A	5969	interleukin 12A (natural killer cell stimulatory factor 1, cytotoxic lymphocyte maturation factor 1, p35)	5
TIRAP	17192	toll-interleukin 1 receptor (TIR) domain containing adaptor protein	5
FOXP3	6106	forkhead box P3	5
MEST	7028	mesoderm specific transcript homolog (mouse)	5
CFH	4883	complement factor H	5
IRAK1	6112	interleukin-1 receptor-associated kinase 1	5
PRKAR2A	9391	protein kinase, cAMP-dependent, regulatory, type II, alpha	5
TIMP2	11821	TIMP metallopeptidase inhibitor 2	5
CDKN1C	1786	cyclin-dependent kinase inhibitor 1C (p57, Kip2)	4
GORASP1	16769	golgi reassembly stacking protein 1, 65kDa	4
HLA-G	4964	major histocompatibility complex, class I, G	4
PON1	9204	paraoxonase 1	4
RAF1	9829	v-raf-1 murine leukemia viral oncogene homolog 1	4
PTPN11	9644	protein tyrosine phosphatase, non-receptor type 11 (Noonan syndrome 1)	4
LCN2	6526	lipocalin 2	4
CALCA	1437	calcitonin-related polypeptide alpha	4
基因名称	基因ID	基因全称	有基因记录的文献数
KCNH2	6251	potassium voltage-gated channel, subfamily H (eag-related), member 2	4
TIMP1	11820	TIMP metallopeptidase inhibitor 1	4
GPX1	4553	glutathione peroxidase 1	4
SERPINB2	8584	serpin peptidase inhibitor, clade B (ovalbumin), member 2	4
NLRP3	16400	NLR family, pyrin domain containing 3	4
MIF	7097	macrophage migration inhibitory factor (glycosylation-inhibiting factor)	4
IL1R2	5994	interleukin 1 receptor, type II	4
ERAL1	3424	Era G-protein-like 1 (E. coli)	4
IFNA1	5417	interferon, alpha 1	4
PLAGL1	9046	pleiomorphic adenoma gene-like 1	4
CYP27B1	2606	cytochrome P450, family 27, subfamily B, polypeptide 1	4
ZEB1	11642	zinc finger E-box binding homeobox 1	4
CXCL12	10672	chemokine (C-X-C motif) ligand 12 (stromal cell-derived factor 1)	4
LBP	6517	lipopolysaccharide binding protein	4
WNT4	12783	wingless-type MMTV integration site family, member 4	4
IL4R	6015	interleukin 4 receptor	4
INSR	6091	insulin receptor	4
MAPK10	6872	mitogen-activated protein kinase 10	4
DES	2770	desmin	4
PHEX	8918	phosphate regulating endopeptidase homolog, X-linked (hypophosphatemia, vitamin D resistant rickets)	4
PTPRC	9666	protein tyrosine phosphatase, receptor type, C	4
SLC26A4	8818	solute carrier family 26, member 4	4
TEK	11724	TEK tyrosine kinase, endothelial (venous malformations, multiple cutaneous and mucosal)	4
TLR6	16711	toll-like receptor 6	4
TSHB	12372	thyroid stimulating hormone, beta	4
CCL3	10627	chemokine (C-C motif) ligand 3	4
CYP17A1	2593	cytochrome P450, family 17, subfamily A, polypeptide 1	4
CYP19A1	2594	cytochrome P450, family 19, subfamily A, polypeptide 1	4
FSHB	3964	follicle stimulating hormone, beta polypeptide	4
IL10RA	5964	interleukin 10 receptor, alpha	4
VIM	12692	vimentin	4
ADAMTS2	218	ADAM metallopeptidase with thrombospondin type 1 motif, 2	4
ADAMTS4	220	ADAM metallopeptidase with thrombospondin type 1 motif, 4	4
ATP2A3	813	ATPase, Ca++ transporting, ubiquitous	4
CHRNA9	14079	cholinergic receptor, nicotinic, alpha 9	4
COL2A1	2200	collagen, type II, alpha 1	4
COL5A1	2209	collagen, type V, alpha 1	4
HBG2	4832	hemoglobin, gamma G	4
NOX5	14874	NADPH oxidase, EF-hand calcium binding domain 5	4
基因名称	基因ID	基因全称	有基因记录的文献数
RELA	9955	v-rel reticuloendotheliosis viral oncogene homolog A, nuclear factor of kappa light polypeptide gene enhancer in B-cells 3, p65 (avian)	4
TF	11740	transferrin	4
TLR10	15634	toll-like receptor 10	4
PLCB1	15917	phospholipase C, beta 1 (phosphoinositide-specific)	4
MASP2	6902	mannan-binding lectin serine peptidase 2	3
CYP3A4	2637	cytochrome P450, family 3, subfamily A, polypeptide 4	3
GHRL	18129	ghrelin/obestatin preprohormone	3
GJB2	4284	gap junction protein, beta 2, 26kDa	3
BGN	1044	biglycan	3
GHR	4263	growth hormone receptor	3
NEU1	7758	sialidase 1 (lysosomal sialidase)	3
PSEN1	9508	presenilin 1 (Alzheimer disease 3)	3
SMAD7	6773	SMAD family member 7	3
CAMP	1472	cathelicidin antimicrobial peptide	3
DEFB4	2767	defensin, beta 4	3
IGF1R	5465	insulin-like growth factor 1 receptor	3
CAP1	20040	CAP, adenylate cyclase-associated protein 1 (yeast)	3
GDF9	4224	growth differentiation factor 9	3
PHOX2B	9143	paired-like homeobox 2b	3
CCL8	10635	chemokine (C-C motif) ligand 8	3
KCNB1	6231	potassium voltage-gated channel, Shab-related subfamily, member 1	3
SLC27A4	10998	solute carrier family 27 (fatty acid transporter), member 4	3
HMGB1	4983	high-mobility group box 1	3
FASLG	11936	Fas ligand (TNF superfamily, member 6)	3
FZD4	4042	frizzled homolog 4 (Drosophila)	3
TXN	12435	thioredoxin	3
MAP2	6839	microtubule-associated protein 2	3
NGF	7808	nerve growth factor (beta polypeptide)	3
PROK1	18454	prokineticin 1	3
COMT	2228	catechol-O-methyltransferase	3
FOXO1	3819	forkhead box O1	3
FOXO3	3821	forkhead box O3	3
HGF	4893	hepatocyte growth factor (hepapoietin A; scatter factor)	3
KISS1	6341	KiSS-1 metastasis-suppressor	3
TYMS	12441	thymidylate synthetase	3
RELB	9956	v-rel reticuloendotheliosis viral oncogene homolog B, nuclear factor of kappa light polypeptide gene enhancer in B-cells 3 (avian)	3
UGT1A1	12530	UDP glucuronosyltransferase 1 family, polypeptide A1	3
CDKN2A	1787	cyclin-dependent kinase inhibitor 2A (melanoma, p16, inhibits CDK4)	3
CYP21A2	2600	cytochrome P450, family 21, subfamily A, polypeptide 2	3
基因名称	基因ID	基因全称	有基因记录的文献数
GATA6	4174	GATA binding protein 6	3
ITGB4	6158	integrin, beta 4	3
S100A8	10498	S100 calcium binding protein A8	3
SOD3	11181	superoxide dismutase 3, extracellular	3
CD68	1693	CD68 molecule	3
MIRN210	31587	microRNA 210	3
PPT1	9325	palmitoyl-protein thioesterase 1 (ceroid-lipofuscinosis, neuronal 1, infantile)	3
ZEB2	14881	zinc finger E-box binding homeobox 2	3
ABCA1	29	ATP-binding cassette, sub-family A (ABC1), member 1	3
CREBBP	2348	CREB binding protein (Rubinstein-Taybi syndrome)	3
P2RX7	8537	purinergic receptor P2X, ligand-gated ion channel, 7	3
UCP2	12518	uncoupling protein 2 (mitochondrial, proton carrier)	3
CACNA1G	1394	calcium channel, voltage-dependent, T type, alpha 1G subunit	3
MARK2	3332	MAP/microtubule affinity-regulating kinase 2	3
SLC27A1	10995	solute carrier family 27 (fatty acid transporter), member 1	3
TFRC	11763	transferrin receptor (p90, CD71)	3
TICAM1	18348	toll-like receptor adaptor molecule 1	3
FADS2	3575	fatty acid desaturase 2	3
FGF7	3685	fibroblast growth factor 7 (keratinocyte growth factor)	3
OPRM1	8156	opioid receptor, mu 1	3
SPAG8	14105	sperm associated antigen 8	3
CRHR1	2357	corticotropin releasing hormone receptor 1	3
DICER1	17098	dicer 1, ribonuclease type III	3
FTO	24678	fat mass and obesity associated	3
MMP12	7158	matrix metallopeptidase 12 (macrophage elastase)	3
CAV1	1527	caveolin 1, caveolae protein, 22kDa	3
ECE1	3146	endothelin converting enzyme 1	3
FBN1	3603	fibrillin 1	3
FST	3971	follistatin	3
IL9	6029	interleukin 9	3
MT-RNR1	7470	mitochondrially encoded 12S RNA	3
SCNN1A	10599	sodium channel, nonvoltage-gated 1 alpha	3
SDHC	10682	succinate dehydrogenase complex, subunit C, integral membrane protein, 15kDa	3
WT1	12796	Wilms tumor 1	3
ATG16L1	21498	ATG16 autophagy related 16-like 1 (S. cerevisiae)	3
CASP8	1509	caspase 8, apoptosis-related cysteine peptidase	3
FURIN	8568	furin (paired basic amino acid cleaving enzyme)	3
FUT1	4012	fucosyltransferase 1 (galactoside 2-alpha-L-fucosyltransferase, H blood group)	3
HBA2	4824	hemoglobin, alpha 2	3
IFNB1	5434	interferon, beta 1, fibroblast	3
基因名称	基因ID	基因全称	有基因记录的文献数
KRT5	6442	keratin 5 (epidermolysis bullosa simplex, Dowling-Meara/Kobner/Weber-Cockayne types)	3
OPRD1	8153	opioid receptor, delta 1	3
OXT	8528	oxytocin, prepro- (neurophysin I)	3
PDGFRA	8803	platelet-derived growth factor receptor, alpha polypeptide	3
SERPINC1	775	serpin peptidase inhibitor, clade C (antithrombin), member 1	3
SLC2A1	11005	solute carrier family 2 (facilitated glucose transporter), member 1	3
CSH1	2440	chorionic somatomammotropin hormone 1 (placental lactogen)	3
ETS1	3488	v-ets erythroblastosis virus E26 oncogene homolog 1 (avian)	3
HDAC1	4852	histone deacetylase 1	3
ITGA6	6142	integrin, alpha 6	3
MET	7029	met proto-oncogene (hepatocyte growth factor receptor)	3
TRAF1	12031	TNF receptor-associated factor 1	3
CD1D	1637	CD1d molecule	3
CYP2E1	2631	cytochrome P450, family 2, subfamily E, polypeptide 1	3
DLL4	2910	delta-like 4 (Drosophila)	3
FAM129B	25282	family with sequence similarity 129, member B	3
IRS1	6125	insulin receptor substrate 1	3
LTF	6720	lactotransferrin	3
MTRR	7473	5-methyltetrahydrofolate-homocysteine methyltransferase reductase	3
PLOD1	9081	procollagen-lysine 1, 2-oxoglutarate 5-dioxygenase 1	3
VIP	12693	vasoactive intestinal peptide	3
ABCA12	14637	ATP-binding cassette, sub-family A (ABC1), member 12	3
ABCC2	53	ATP-binding cassette, sub-family C (CFTR/MRP), member 2	3
ABO	79	ABO blood group (transferase A, alpha 1-3-N-acetylgalactosaminyltransferase; transferase B, alpha 1-3-galactosyltransferase)	3
ADCY10	21285	adenylate cyclase 10 (soluble)	3
APLP2	598	amyloid beta (A4) precursor-like protein 2	3
CCND1	1582	cyclin D1	3
CD69	1694	CD69 molecule	3
COL5A2	2210	collagen, type V, alpha 2	3
DLL1	2908	delta-like 1 (Drosophila)	3
EPAS1	3374	endothelial PAS domain protein 1	3
HAS2	4819	hyaluronan synthase 2	3
IL12RB1	5971	interleukin 12 receptor, beta 1	3
MDK	6972	midkine (neurite growth-promoting factor 2)	3
PLG	9071	plasminogen	3
PRKAA2	9377	protein kinase, AMP-activated, alpha 2 catalytic subunit	3
S100A10	10487	S100 calcium binding protein A10	3
SIRT1	14929	sirtuin (silent mating type information regulation 2 homolog) 1 (S. cerevisiae)	3
TPO	12015	thyroid peroxidase	3
基因名称	基因ID	基因全称	有基因记录的文献数
VCAM1	12663	vascular cell adhesion molecule 1	3
AIF1	352	allograft inflammatory factor 1	3
BAX	959	BCL2-associated X protein	3
CCND2	1583	cyclin D2	3
CD27	11922	CD27 molecule	3
CDH17	1756	cadherin 17, LI cadherin (liver-intestine)	3
COL4A3	2204	collagen, type IV, alpha 3 (Goodpasture antigen)	3
CREB1	2345	cAMP responsive element binding protein 1	3
CXCL9	7098	chemokine (C-X-C motif) ligand 9	3
CYCS	19986	cytochrome c, somatic	3
HSD11B1	5208	hydroxysteroid (11-beta) dehydrogenase 1	3
MMP13	7159	matrix metallopeptidase 13 (collagenase 3)	3
MSMB	7372	microseminoprotein, beta-	3
NCAM1	7656	neural cell adhesion molecule 1	3
NCOA1	7668	nuclear receptor coactivator 1	3
NEFL	7739	neurofilament, light polypeptide 68kDa	3
NTRK2	8032	neurotrophic tyrosine kinase, receptor, type 2	3
PARP1	270	poly (ADP-ribose) polymerase family, member 1	3
PYCARD	16608	PYD and CARD domain containing	3
RARA	9864	retinoic acid receptor, alpha	3
RXRA	10477	retinoid X receptor, alpha	3

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Table 1
表1
表1 筛选出的基因列表中排前5%的早产相关基因
Table 1 Top 5% preterm birth related genes after filtering

基因名称	基因ID	基因名全称	有基因记录的文献数量
TNF	11892	Tumor necrosis factor (TNF superfamily, member 2)	156
IL6	6018	Interleukin 6 (Interferon, beta 2)	155
IL1B	5992	Interleukin 1 beta	140
IL8	6025	Interleukin 8	85
NFKB1	7794	Nuclear factor of kappa light polypeptide gene Enhancer in B-cells 1 (p105)	68
COL1A1	2197	Collagen type I alpha 1 chain	68
PTGS2	9605	Prostaglandin-endoperoxide synthase 2 (Prostaglandin G/H synthase and cyclooxygenase)	63
TLR4	11850	Toll-like receptor 4	57
VEGFA	12680	Vascular endothelial growth factor A	57
IL10	5962	Interleukin 10	53
MT-RNR2	7471	Mitochondrially encoded 16S RNA	51
INS	6081	Insulin	46
PGR	8910	Progesterone receptor	42
IGF1	5464	Insulin-like growth factor 1 (Somatomedin C)	39
TGFB1	11766	Transforming growth factor beta 1	39
SFTPD	10803	Surfactant, pulmonary-associated protein D	38
MMP9	7176	Matrix metallopeptidase 9 (Gelatinase B, 92kDa gelatinase, 92 kDa type IV collagenase)	36
NR3C1	7978	Nuclear receptor subfamily 3, group C, member 1 (Glucocorticoid receptor)	35
SFTPA2B	23441	Surfactant, pulmonary-associated protein A2B	34
IL1A	5991	Interleukin 1 alpha	33

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通过对疾病数据库OMIM、ClinVar和CTD的挖掘,找到1个早产相关基因(SERPINH1)。由于该基因已存在于上述355个基因中,因此最终用于分析的基因数目不变。

GO富集分析发现174种显著的生物学功能(FDR<0.05)。根据显著性由高到低排列,前10种生物学功能包括：受体配体活性(receptor ligand activity)、细胞因子受体结合(cytokine receptor binding)、细胞因子活性(cytokine activity)、生长因子活性(growth factor activity)、生长因子结合(growth factor binding)、蛋白酶结合(protease binding)、血红素结合(heme binding)、生长因子受体结合(growth factor receptor binding)、四吡咯结合(tetrapyrrole binding)和脂多糖结合(lipopolysaccharide binding) (图1,附表3)。其中具有受体配体活性功能的基因数量最多,共有61个。

图1

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图1基因分子功能的GO富集

颜色代表FDR值的大小,由蓝色到红色FDR值逐渐变小,圆点的面积代表基因的数量。
Fig. 1GO enrichment analysis of molecular function in genes



Supplementary Table 3
附表3
附表3 早产相关基因分子功能的GO富集
Supplementary Table 3 GO enrichment result of preterm related genes in molecular functions

分子功能	基因数量	P值	FDR
receptor ligand activity	61	2.34*10-32	1.03*10-29
cytokine receptor binding	45	3.51*10-28	7.77*10-26
cytokine activity	36	4.29*10-23	6.32*10-21
growth factor activity	30	1.23*10-20	1.36*10-18
growth factor binding	27	1.03*10-19	9.14*10-18
protease binding	20	4.11*10-13	3.03*10-11
heme binding	20	1.02*10-12	6.44*10-11
growth factor receptor binding	20	1.18*10-12	6.52*10-11
tetrapyrrole binding	20	4.17*10-12	2.05*10-10
lipopolysaccharide binding	11	1.75*10-11	7.75*10-10

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KEGG富集分析发现的显著信号通路达到158个(FDR<0.05)。前10条通路根据显著性由高到低排列分别是：糖尿病并发症中的AGE-RAGE信号通路(AGE-RAGE signaling pathway in diabetic complications),Chagas病(美洲锥虫病),IL-17信号通路(IL-17 signaling pathway),TNF信号通路(TNF signaling pathway),PI3K-Akt信号通路(PI3K-Akt signaling pathway),Toll样受体信号通路(Toll-like receptor signaling pathway),结核(tuberculosis),炎症性肠病(inflammatory bowel disease (IBD)),乙型肝炎(hepatitis B)和流体剪切力和动脉粥样硬化(fluid shear stress and atherosclerosis) (图2,附表4)。

图2

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图2基因KEGG通路的富集结果

颜色代表FDR值的大小,由蓝色到红色FDR值逐渐变小,圆点的面积代表基因的数量。
Fig. 2KEGG enrichment analysis of genes



Supplementary Table 4
附表4
附表4 早产相关基因KEGG通路富集
Supplementary Table 4 KEGG enrichment result of preterm related genes

通路	基因数量	P值	FDR
AGE-RAGE signaling pathway in diabetic complications	35	1.02*10-25	9.75*10-24
Chagas disease (American trypanosomiasis)	35	3.26*10-25	1.56*10-23
IL-17 signaling pathway	33	1.63*10-24	5.19*10-23
TNF signaling pathway	34	5.68*10-23	1.36*10-21
PI3K-Akt signaling pathway	57	2.78*10-22	5.33*10-21
Toll-like receptor signaling pathway	32	1.33*10-21	2.13*10-20
Tuberculosis	40	4.46*10-21	6.10*10-20
Inflammatory bowel disease (IBD)	25	8.31*10-20	9.07*10-19
Hepatitis B	37	8.53*10-20	9.07*10-19
Fluid shear stress and atherosclerosis	34	2.34*10-19	2.24*10-18

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Reactome通路富集分析中前10个显著通路分别是：白细胞介素信号(Signaling by Interleukins),白细胞介素4和白细胞介素-13信号传导(Interleukin-4 and Interleukin-13 signaling),白细胞介素10信号传导(Interleukin-10 signaling),Toll样受体级联(Toll-like Receptor Cascades),Toll样受体4 (TLR4)级联(Toll Like Receptor 4 (TLR4) Cascade),Toll样受体TLR1：TLR2级联(Toll Like Receptor TLR1: TLR2 Cascade),Toll样受体2 (TLR2)级联(Toll Like Receptor 2 (TLR2) Cascade),免疫系统疾病(Diseases of Immune System),与TLR信号级联相关疾病(Diseases associated with the TLR signaling cascade),质膜上启动的MyD88:MAL (TIRAP)级联(MyD88:MAL (TIRAP) cascade initiated on plasma membrane) (图3,附表5)。

图3

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图3基因Reactome通路的富集

颜色代表FDR值的大小,由蓝色到红色FDR值逐渐变小,圆点的面积代表基因的数量。
Fig. 3Reactome enrichment analysis of genes



Supplementary Table 5
附表5
附表5 早产相关基因Reactome通路富集
Supplementary Table 5 Reactome enrichment result of preterm related genes

通路	基因数量	P值	FDR
Signaling by Interleukins	78	2.15*10-37	1.47*10-34
Interleukin-4 and Interleukin-13 signaling	40	2.20*10-33	7.54*10-31
Interleukin-10 signaling	20	1.26*10-18	2.87*10-16
Toll-like Receptor Cascades	32	3.57*10-18	6.12*10-16
Toll Like Receptor 4 (TLR4) Cascade	28	1.53*10-16	2.09*10-14
Toll Like Receptor TLR1:TLR2 Cascade	23	1.18*10-14	1.15*10-12
Toll Like Receptor 2 (TLR2) Cascade	23	1.18*10-14	1.15*10-12
Diseases of Immune System	13	2.88*10-14	2.19*10-12
Diseases associated with the TLR signaling cascade	13	2.88*10-14	2.19*10-12
MyD88:MAL(TIRAP) cascade initiated on plasma membrane	34	6.15*10-13	3.83*10-11

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2.2 基因特征的收集与分析结果

对比早产基因的每个基因转录本数量和全基因组每个基因的转录本数量,早产基因的转录本数量平均值(8.2)要高于全基因组基因的转录本数量平均值(7.5) (图4A)。在显著性水平α=0.1的情况下,差异显著(t检验：P=0.06)。针对GC含量的比较,早产基因和全基因组基因之间没有明显差异(t检验：P=0.70,α=0.1) (图4B)。

图4

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图4对比早产基因和全基因组基因的转录本数量以及GC含量

A：转录本数量分布(个);B：GC含量分布(%)。红色的曲线代表全基因组,黑色的曲线代表早产基因。
Fig. 4Comparisons between preterm birth related genes and genes in whole genome in terms of transcript numbers and GC contents



在早产基因长度和全基因组编码蛋白的基因长度的比较中发现,早产基因的平均长度为63 100 bp,而全基因组基因的长度平均为61 191 bp (图5)。在显著性水平α=0.1的情况下,差异不显著(t检验：P=0.73)。

图5

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图5对比早产基因和全基因组编码蛋白基因的长度

红色的曲线代表全基因组,黑色的曲线代表早产基因。
Fig. 5Comparisons between preterm birth related genes and protein coding genes in whole genome in terms of gene lengths

3 讨论

早产是新生儿健康研究领域的一个极其重要的研究方向。虽然关于早产发生发展的分子作用机制尚不明确,但是已有大量研究表明早产的发生与遗传有关,并已产生了大量的数据。本研究通过文本挖掘工具挖掘PubMed中所检索的2264篇早产相关文献中的基因,结合阈值和人工审核的两层过滤以及疾病数据库记录,最终锁定355个早产相关基因。这是目前为止从文献中挖掘的最新的早产相关基因数据集。富集分析表明早产相关基因大多集中在免疫相关通路,基因特征分析发现早产相关基因和全基因组基因对比,GC含量和基因长度没有差异,而转录本数量有差异。

以往的研究发现,免疫和炎症反应对维持妊娠和决定分娩时间起重要作用^[8,20,21]。其中,由于父源和母源抗原的同时存在,母胎免疫耐受的维持在妊娠期间起重要作用,而这种稳态的破坏,可能会导致早产的发生^[20]。先天免疫细胞通过释放炎性因子来影响妊娠过程和分娩时间,例如巨噬细胞释放的炎性因子可能促进催产素的产生,从而使子宫发生收缩,为分娩做准备^[22]。同时,先天免疫和获得性免疫之间的失衡,也可能导致早产发生^[23]。本研究采用挖掘得到的早产相关基因进行KEGG和Reactome富集分析,结果发现早产基因大多集中在免疫和炎症反应相关通路,这一点与以往的研究发现相吻合。先天免疫系统反映了对感染的应答作用,包括但不限于巨噬细胞、toll-like受体、噬中性粒细胞和细胞因子等;获得性免疫系统主要是T淋巴细胞和B淋巴细胞^[24]。GO富集分析的结果也体现了早产相关基因具备与免疫过程密切相关的分子功能,包括受体配体活性、细胞因子受体活性等。本研究找到的前20个早产相关基因中,大多与免疫直接或间接相关。其中研究TNF基因的文献数目最多,研究包括胎儿肠膜发育和早产介导炎症^[25]、环境内分泌物与孕期炎症生物标志物^[26]。

据文献报道,人类基因组可能在疾病中具备一定特征^[27,28],如慢性阻塞性肺疾病相关的基因转录本复杂度与对照组显著不同^[29],内源性疾病的基因编码区具有高GC含量^[30],在神经发育和神经退行性疾病中发现基因的长度扮演重要角色^[31],其中在自闭症可能的候选基因中有许多长基因^[32]。为进一步探索早产相关基因的基因组特征,本研究对比了早产相关基因与全基因组基因在转录本数量、GC含量和基因长度上的差异。其中,转录本数量存在差异。有研究发现,具有较多转录本数量的基因多为管家基因或必需基因,在生物学上起重要作用^[33],然而针对转录本数量较多的早产相关基因,目前尚无文献报道。这些基因在早产所起的作用,仍需要进一步研究。GC含量在本研究中反映的是鸟嘌呤和胞嘧啶在每个基因中所占的比例。本研究并未发现早产相关基因与全基因组基因GC含量上存在显著差异。同时,早产基因在基因长度上与全基因组的所有基因相比,也无明显差异。

然而,本研究也有一定的局限性。首先,在数据库的甄选上,挖掘文献中早产相关基因时,也可以考虑包括中文数据库,例如CNKI,可以挖掘更多与中国人早产相关的研究和相关基因。其次,对基因的特征分析可以引入更多的变量,如种族信息等。对不同种族的研究,或许可以找到疾病相关且种族特异的遗传背景^[34]。

综上所述,本研究结合文本挖掘和两层过滤方法以及疾病数据库记录,最终锁定355个早产相关基因,是截止到投稿时,最新的早产相关基因的整合记录。富集分析表明早产相关基因大多集中在免疫相关信号通路,基因特征分析提示了早产相关基因的转录本数量对比全基因组基因有一定差异。本研究对早产基因的挖掘和整合,可以为早产的遗传研究提供重要资源和提示相关研究方向。

(责任编委: 方向东)

附录

附表1~5见文章电子版www.chinagene.cn。

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[1] Liu L, Oza S, Hogan D, Chu Y, Perin J, Zhu J, Lawn JE, Cousens S, Mathers C, Black RE . Global, regional, and national causes of under-5 mortality in 2000-15: an updated systematic analysis with implications for the sustainable development goals
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[2] Blencowe H, Cousens S, Oestergaard MZ, Chou D, Moller AB, Narwal R, Adler A, Vera Garcia C, Rohde S, Say L, Lawn JE . National, regional, and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: a systematic analysis and implications
. Lancet, 2012,379(9832):2162-2172.
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[3] Sipola-Lepp?nen M, V??r?sm?ki M, Tikanm?ki M, Matinolli HM, Miettola S, Hovi P, Wehkalampi K, Ruokonen A, Sundvall J, Pouta A, Eriksson JG, J?rvelin MR, Kajantie E , Cardiometabolic risk factors in young adults who were born preterm
. Am J Epidemiol, 2015,181(11):861-873.
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[4] Wu W, Witherspoon DJ, Fraser A, Clark EA, Rogers A, Stoddard GJ, Manuck TA, Chen K, Esplin MS, Smith KR, Varner MW, Jorde LB . The heritability of gestational age in a two-million member cohort: implications for spontaneous preterm birth
. Hum Genet, 2015,134(7):803-808.
URLPMID:4678031 [本文引用: 1]
Preterm birth (PTB), defined as birth prior to a gestational age (GA) of 37 completed weeks, affects more than 10% of births worldwide. PTB is the leading cause of neonatal mortality and is associated with a broad spectrum of lifelong morbidity in survivors. The etiology of spontaneous PTB (SPTB) is complex and has an important genetic component. Previous studies have compared monozygotic and dizygotic twin mothers and their families to estimate the heritability of SPTB, but these approaches cannot separate the relative contributions of the maternal and the fetal genomes to GA or SPTB. Using the Utah Population Database, we assessed the heritability of GA in more than 2 million post-1945 Utah births, the largest familial GA dataset ever assembled. We estimated a narrow-sense heritability of 13.3% for GA and a broad-sense heritability of 24.5%. A maternal effect (which includes the effect of the maternal genome) accounts for 15.2% of the variance of GA, and the remaining 60.3% is contributed by individual environmental effects. Given the relatively low heritability of GA and SPTB in the general population, multiplex SPTB pedigrees are likely to provide more power for gene detection than will samples of unrelated individuals. Furthermore, nongenetic factors provide important targets for therapeutic intervention.

[5] Kistka ZA, DeFranco EA, Ligthart L, Willemsen G, Plunkett J, Muglia LJ, Boomsma DI . Heritability of parturition timing: an extended twin design analysis
Am J Obstet Gynecol, 2008, 199(1): 43.e1-5.
URLPMID:18295169 [本文引用: 1]
The objective of the study was to assess relative maternal and paternal genetic influences on birth timing. Utilizing The Netherlands Twin Registry, we examined the correlation in birth timing of infants born to monozygotic (MZ) twins and their first-degree relatives (dizygotic twins and siblings of twins). Genetic models estimated the relative influence of genetic and common environmental factors through model fitting of additive genetic (A), common environmental (C), individual-specific environmental factors, and combinations thereof. We evaluated birth timing correlation among the infants of 1390 twins and their 644 siblings. The correlation in MZ female twins ( r = 0.330) was greater than MZ male twins ( r = 610.096). Positive correlation were also found in sister-sister pairs ( r = 0.223) but not in brother-brother ( r = 610.045) or brother-sister pairs ( r = 610.038). The most parsimonious AE model indicated a significant maternal contribution of genetic and individual-specific environmental factors to birth timing, but no paternal heritability was demonstrated. Heritability of birth timing in women was 34%; and the remaining variance (66%) was caused by individual-specific environmental factors. Our data implicate a significant contribution of maternal but not paternal genetic influences on birth timing.

[6] York TP, Eaves LJ, Lichtenstein P, Neale MC, Svensson A, Latendresse S, L?ngstr?m N , Strauss JF 3rd. Fetal and maternal genes' influence on gestational age in a quantitative genetic analysis of 244,000 Swedish births
. Am J Epidemiol, 2013,178(4):543-550.
URLPMID:23568591 [本文引用: 1]
Although there is increasing evidence that genetic factors influence gestational age, it is unclear to what extent this is due to fetal and/or maternal genes. In this study, we apply a novel analytical model to estimate genetic and environmental contributions to pregnancy history records obtained from 165,952 Swedish families consisting of offspring of twins, full siblings, and half-siblings (1987-2008). Results indicated that fetal genetic factors explained 13.1% (95% confidence interval (CI): 6.8, 19.4) of the variation in gestational age at delivery, while maternal genetic factors accounted for 20.6% (95% CI: 18.1, 23.2). The largest contribution to differences in the timing of birth were environmental factors, of which 10.1% (95% CI: 7.0, 13.2) was due to factors shared by births of the same mother, and 56.2% (95% CI: 53.0, 59.4) was pregnancy specific. Similar models fit to the same data dichotomized at clinically meaningful thresholds (e. g., preterm birth) resulted in less stable parameter estimates, but the collective results supported a model of homogeneous genetic and environmental effects across the range of gestational age. Since environmental factors explained most differences in the timing of birth, genetic studies may benefit from understanding the specific effect of fetal and maternal genes in the context of these yet-unidentified factors.

[7] Liang HY, Wu BY, Chen DF, Yang F, Hu HY, Chen L, Xu XP . Association of PON2 Gene Polymorphisms in Neonates with Preterm
Hereditas(Beijing), 2002,24(5):515-518.
URLMagsci [本文引用: 1]
探讨新生儿对氧磷酶2基因多态性（PON2148，PON2311）对早产的影响。采用横断面调查方法，使用统一的调查表，由安庆市各县医院对入院分娩孕妇及其单胎、活产、早产和对照新生儿进行调查，共得到有效样本194个母亲-新生儿对。单因素分析结果显示：PON2 Ala148Ala纯合子基因型与Gly148Gly纯合子基因型 / Ala148Gly杂合子基因型比较致早产的危险性升高且有显著意义；同样，PON2 Ser311Ser纯合子基因型致早产的危险性升高且有显著意义。进一步分析PON2148位点多态性和PON2311位点多态性是否存在交互作用，结果显示：这两个位点多态性之间无明显交互作用。对氧磷酶2基因PON2148位点多态性和PON2311位点多态性与新生儿早产相关，但PON2148位点多态性和PON2311位点多态性之间对早产的影响无明显交互作用。<br><br>Association of PON2 Gene Polymorphisms in Neonates with Preterm<br>LIANG Hong-ye1,WU Bai-yang1,CHEN Da-fang1,YANG Fan2,HU Hai-yan2,CHEN Li1,XU Xi-ping1.<br>1.Department of Biology & Genetics,Peking University Health Science Center,Beijing 100083,China;<br>2.Anqing Branch of Institute for Biomedicine,Anhui Medical University,Anqing 246000,China<br>Abstract:The objective is to investigate whether gene polymorphisms in the PON2 gene (PON2148 and PON2311) of neonates are associated with preterm. Using standard questionnaires,194 singleton live born mother-neonate pairs (include preterm cases and term controls) were investigated by the trained field workers with cross-sectional survey at the hospitals in Anqing,Anhui Province,China. Epidemiological and clinical data and blood samples were obtained from 194 mother-neonate pairs. Among neonates,PON2 Ala148Ala homozygote is significantly associated with preterm,compared with Gly148Gly homozygote / Ala148Gly heterozygote before and after adjustment confounders and the same was true for PON2 Ser311Ser homozygote. However,when PON2148 polymorphism and PON2311 polymorphism were considered jointly,no significant gene interaction between PON2148 polymorphism and PON2311 polymorphism in relation to preterm was observed. We draw a conclusion from this research that both PON2148 polymorphism and PON2311 polymorphism in neonates are significantly associated with preterm respectively. But the gene interactions between PON2148 polymorphism and PON2311 polymorphism in neonates are not significantly associated with preterm.<br>Key words：paraoxonase 2 gene (PON2 gene);gene polymorphism;preterm;genotype<br>
梁红业, 吴白燕, 陈大方, 杨帆, 胡海燕, 陈栎, 徐希平 , 新生儿PON2基因多态性与早产的关系
遗传, 2002,24(5):515-518.
URLMagsci [本文引用: 1]
探讨新生儿对氧磷酶2基因多态性（PON2148，PON2311）对早产的影响。采用横断面调查方法，使用统一的调查表，由安庆市各县医院对入院分娩孕妇及其单胎、活产、早产和对照新生儿进行调查，共得到有效样本194个母亲-新生儿对。单因素分析结果显示：PON2 Ala148Ala纯合子基因型与Gly148Gly纯合子基因型 / Ala148Gly杂合子基因型比较致早产的危险性升高且有显著意义；同样，PON2 Ser311Ser纯合子基因型致早产的危险性升高且有显著意义。进一步分析PON2148位点多态性和PON2311位点多态性是否存在交互作用，结果显示：这两个位点多态性之间无明显交互作用。对氧磷酶2基因PON2148位点多态性和PON2311位点多态性与新生儿早产相关，但PON2148位点多态性和PON2311位点多态性之间对早产的影响无明显交互作用。<br><br>Association of PON2 Gene Polymorphisms in Neonates with Preterm<br>LIANG Hong-ye1,WU Bai-yang1,CHEN Da-fang1,YANG Fan2,HU Hai-yan2,CHEN Li1,XU Xi-ping1.<br>1.Department of Biology & Genetics,Peking University Health Science Center,Beijing 100083,China;<br>2.Anqing Branch of Institute for Biomedicine,Anhui Medical University,Anqing 246000,China<br>Abstract:The objective is to investigate whether gene polymorphisms in the PON2 gene (PON2148 and PON2311) of neonates are associated with preterm. Using standard questionnaires,194 singleton live born mother-neonate pairs (include preterm cases and term controls) were investigated by the trained field workers with cross-sectional survey at the hospitals in Anqing,Anhui Province,China. Epidemiological and clinical data and blood samples were obtained from 194 mother-neonate pairs. Among neonates,PON2 Ala148Ala homozygote is significantly associated with preterm,compared with Gly148Gly homozygote / Ala148Gly heterozygote before and after adjustment confounders and the same was true for PON2 Ser311Ser homozygote. However,when PON2148 polymorphism and PON2311 polymorphism were considered jointly,no significant gene interaction between PON2148 polymorphism and PON2311 polymorphism in relation to preterm was observed. We draw a conclusion from this research that both PON2148 polymorphism and PON2311 polymorphism in neonates are significantly associated with preterm respectively. But the gene interactions between PON2148 polymorphism and PON2311 polymorphism in neonates are not significantly associated with preterm.<br>Key words：paraoxonase 2 gene (PON2 gene);gene polymorphism;preterm;genotype<br>

[8] Annells MF, Hart PH, Mullighan CG, Heatley SL, Robinson JS, Bardy P, McDonald HM . Interleukins-1, -4, -6, -10, tumor necrosis factor, transforming growth factor-beta, FAS, and mannose-binding protein C gene polymorphisms in australian women: risk of preterm birth
. Am J Obstet Gynecol, 2004,191(6):2056-2067.
URL [本文引用: 2]

[9] Krediet TG, Wiertsema SP, Vossers MJ, Hoeks SB, Fleer A, Ruven HJ, Rijkers GT . Toll-like receptor 2 polymorphism is associated with preterm birth
. Pediatr Res, 2007,62(4):474-476.
URLPMID:17667860 [本文引用: 1]
Abstract Evidence is increasing for a role of polymorphisms in maternal or fetal innate immune response genes in preterm birth. Toll-like receptors (TLRs) are important receptors in the innate immunity. The genotype distribution of two TLR2 single nucleotide polymorphisms (SNPs) and one TLR4 SNP were determined among 524 neonates and associated with gestational age (GA). Genomic DNA was isolated from prospectively collected blood samples and polymorphisms in TLR2 (T-16934A, RS4696480 and Arg753Gln, RS5743708) and TLR4 (Thr399Ile, RS4986791) were determined using sequence specific primers by PCR. Allele frequencies of two TLR2 SNPs and one TLR4 SNP were analyzed according to prematurity. Analysis among 305 infants, after exclusion of infants born after multiple pregnancy or because of preeclampsia, revealed significantly shorter GAs for infants carrying two polymorphic TLR2 alleles (-16934TA/AA and 753ArgGln/GlnGln) compared with infants carrying one polymorphic and one wild-type allele or two wild-type alleles (median GA 30.6 wk versus 34.1-36.8 wk, respectively, p < 0.02). Carriage of two variant TLR2 alleles potentially leads to aberrant innate immune responses, which may have contributed to very preterm birth.

[10] Papazoglou D, Galazios G, Koukourakis MI, Kontomanolis EN, Maltezos E . Association of -634G/C and 936C/T polymorphisms of the vascular endothelial growth factor with spontaneous preterm delivery
. Acta Obstet Gyn Scan, 2004,83(5):461-465.
URLPMID:15059159 [本文引用: 1]
Background.68 There is convincing evidence for a central role of vascular endothelial growth factor (VEGF) in fetal and placental angiogenesis. Our present study was undertaken to examine the possible relationship between two common functional VEGF gene polymorphisms (6102634G/C and 936C/T), linked with altered VEGF gene responsiveness, and spontaneous preterm delivery. Methods.68 Genomic DNA was extracted from whole blood from 54 women with preterm labor and 79 menopausal women with at least two term spontaneous labors. DNA samples were analyzed by polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP). Results.68 Individuals with 936T/T or 936C/T genotype demonstrated a statistically significant association with preterm delivery compared with those sharing 936C/C genotype [ P 02=020.0009, risk factor 2.05, 95% confidence interval (CI) 1.37–3.06]. There were no significant associations between spontaneous preterm delivery and 6166634 genotypes. Conclusion.02 An association was demonstrated between the VEGF 936C/T polymorphism and deliveries before 3702weeks of gestation.

[11] Chen BH, Carmichael SL, Shaw GM, Iovannisci DM, Lammer EJ . Association between 49 infant gene polymorphisms and preterm delivery
. Am J Med Genet A, 2007,143A(17):1990-1906.
URLPMID:17676631 [本文引用: 1]
The occurrence of preterm delivery has been increasing in the U.S. Previous studies have identified risk factors for preterm delivery that may have genetic influences. We conducted a case-control study comparing the frequencies of 49 genetic polymorphisms among 62 preterm infants and 553 term infants. The polymorphisms that we examined were involved in xenobiotic-metabolism, blood pressure, coagulation, the inflammatory response, cell-cell interaction, or folate-homocysteine metabolism. Univariate ana- lyses on the individual polymorphisms revealed a statistically significant effect for the variant genotypes compared to the wildtype genotypes in SERPINE1 11053G > T (OR = 0.4, 95% CI=0.2-0.8). This finding suggests the coagulation/ thrombophilic pathway may influence the development of preterm delivery. (c) 2007 Wiley-Liss, Inc.

[12] Zhang H, Baldwin DA, Bukowski RK, Parry S, Xu Y, Song C, Andrews WW, Saade GR, Esplin MS, Sadovsky Y, Reddy UM, Ilekis J, Varner M, Biggio JR Jr . A genome-wide association study of early spontaneous preterm delivery
. Genet Epidemiol, 2015,39(3):217-226.
URLPMID:25599974 [本文引用: 1]
ABSTRACT Preterm birth is the leading cause of infant morbidity and mortality. Despite extensive research, the genetic contributions to spontaneous preterm birth (SPTB) are not well understood. Term controls were matched with cases by race/ethnicity, maternal age, and parity prior to recruitment. Genotyping was performed using Affymetrix SNP Array 6.0 assays. Statistical analyses utilized PLINK to compare allele occurrence rates between case and control groups, and incorporated quality control and multiple-testing adjustments. We analyzed DNA samples from mother–infant pairs from early SPTB cases (200/7–336/7 weeks, 959 women and 979 neonates) and term delivery controls (390/7–416/7 weeks, 960 women and 985 neonates). For validation purposes, we included an independent validation cohort consisting of early SPTB cases (293 mothers and 243 infants) and term controls (200 mothers and 149 infants). Clustering analysis revealed no population stratification. Multiple maternal SNPs were identified with association P -values between 10 × 10–5 and 10 × 10–6. The most significant maternal SNP was rs17053026 on chromosome 3 with an odds ratio (OR) 0.44 with a P -value of 1.0 × 10–6. Two neonatal SNPs reached the genome-wide significance threshold, including rs17527054 on chromosome 6p22 with a P -value of 2.7 × 10–12 and rs3777722 on chromosome 6q27 with a P -value of 1.4 × 10–10. However, we could not replicate these findings after adjusting for multiple comparisons in a validation cohort. This is the first report of a genome-wide case-control study to identify single nucleotide polymorphisms (SNPs) that correlate with SPTB.

[13] Zhang GB, Feenstra B, Bacelis J, Liu X, Muglia LM, Juodakis J, Miller DE, Litterman N, Jiang PP, Russell L, Hinds DA, Hu Y, Weirauch MT, Chen X, Chavan AR, Wagner GP, Pavli?ev M, Nnamani MC, Maziarz J, Karjalainen MK, R?met M, Sengpiel V, Geller F, Boyd HA, Palotie A, Momany A, Bedell B, Ryckman KK, Huusko JM, Forney CR, Kottyan LC, Hallman M, Teramo K, Nohr EA, Davey Smith G, Melbye M, Jacobsson B, Muglia LJ . Genetic associations with gestational duration and spontaneous preterm birth
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[14] McElroy JJ, Gutman CE, Shaffer CM, Busch TD, Puttonen H, Teramo K, Murray JC, Hallman M, Muglia LJ . Maternal coding variants in complement receptor 1 and spontaneous idiopathic preterm birth
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[15] Knijnenburg TA, Vockley JG, Chambwe N, Gibbs DL, Humphries C, Huddleston KC, Klein E, Kothiyal P, Tasseff R, Dhankani V, Bodian DL, Wong WSW, Glusman G, Mauldin DE, Miller M, Slagel J, Elasady S, Roach JC, Kramer R, Leinonen K, Linthorst J, Baveja R, Baker R, Solomon BD, Eley G, Iyer RK, Maxwell GL, Bernard B, Shmulevich I, Hood L, Niederhuber JE . Genomic and molecular characterization of preterm birth
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[16] Uzun A, Laliberte A, Parker J, Andrew C, Winterrowd E, Sharma S, Istrail S, Padbury JF . DbPTB: a database for preterm birth
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<p id="p-2">Genome-wide association studies (GWAS) query the entire genome in a hypothesis-free, unbiased manner. Since they have the potential for identifying novel genetic variants, they have become a very popular approach to the investigation of complex diseases. Nonetheless, since the success of the GWAS approach varies widely, the identification of genetic variants for complex diseases remains a difficult problem. We developed a novel bioinformatics approach to identify the nominal genetic variants associated with complex diseases. To test the feasibility of our approach, we developed a web-based aggregation tool to organize the genes, genetic variations and pathways involved in preterm birth. We used semantic data mining to extract all published articles related to preterm birth. All articles were reviewed by a team of curators. Genes identified from public databases and archives of expression arrays were aggregated with genes curated from the literature. Pathway analysis was used to impute genes from pathways identified in the curations. The curated articles and collected genetic information form a unique resource for investigators interested in preterm birth. The Database for Preterm Birth exemplifies an approach that is generalizable to other disorders for which there is evidence of significant genetic contributions.

[17] Yu G, Wang LG, Han Y, He QY . ClusterProfiler: an R package for comparing biological themes among gene clusters
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Abstract Increasing quantitative data generated from transcriptomics and proteomics require integrative strategies for analysis. Here, we present an R package, clusterProfiler that automates the process of biological-term classification and the enrichment analysis of gene clusters. The analysis module and visualization module were combined into a reusable workflow. Currently, clusterProfiler supports three species, including humans, mice, and yeast. Methods provided in this package can be easily extended to other species and ontologies. The clusterProfiler package is released under Artistic-2.0 License within Bioconductor project. The source code and vignette are freely available at http://bioconductor.org/packages/release/bioc/html/clusterProfiler.html.

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. Bioinformatics, 2009,25(6):838-840.
URLPMID:19188191 [本文引用: 1]
Summary:SciMiner is a web-based literature mining and functional analysis tool that identifies genes and proteins using a context specific analysis of MEDLINE abstracts and full texts. SciMiner accepts a free text query (PubMed Entrez search) or a list of PubMed identifiers as input. SciMiner uses both regular expression patterns and dictionaries of gene symbols and names compiled from multiple sources. Ambiguous acronyms are resolved by a scoring scheme based on the co-occurrence of acronyms and corresponding description terms, which incorporates optional user-defined filters. Functional enrichment analyses are used to identify highly relevant targets (genes and proteins), GO (Gene Ontology) terms, MeSH (Medical Subject Headings) terms, pathways and protein rotein interaction networks by comparing identified targets from one search result with those from other searches or to the full HGNC [HUGO (Human Genome Organization) Gene Nomenclature Committee] gene set. The performance of gene/protein name identification was evaluated using the BioCreAtIvE (Critical Assessment of Information Extraction systems in Biology) version 2 (Year 2006) Gene Normalization Task as a gold standard. SciMiner achieved 87.1% recall, 71.3% precision and 75.8%F-measure. SciMiner's literature mining performance coupled with functional enrichment analyses provides an efficient platform for retrieval and summary of rich biological information from corpora of users' interests. Availability:http://jdrf.neurology.med.umich.edu/SciMiner/. A server version of the SciMiner is also available for download and enables users to utilize their institution's journal subscriptions. Contact:juhur@umich.edu Supplementary information:Supplementary dataare available atBioinformaticsonline.

[19] Fabregat A, Jupe S, Matthews L, Sidiropoulos K, Gillespie M, Garapati P, Haw R, Jassal B, Korninger F, May B, Milacic M, Roca CD, Rothfels K, Sevilla C, Shamovsky V, Shorser S, Varusai T, Viteri G, Weiser J, Wu G, Stein L, Hermjakob H, D'Eustachio P . The reactome pathway knowledgebase
. Nucleic Acids Res, 2018,46(D1):D649-D655.
URLPMID:24243840 [本文引用: 1]
Reactome (http://www.reactome.org) is a manually curated open-source open-data resource of human pathways and reactions. The current version 46 describes 7088 human proteins (34% of the predicted human proteome), participating in 6744 reactions based on data extracted from 15 107 research publications with PubMed links. The Reactome Web site and analysis tool set have been completely redesigned to increase speed, flexibility and user friendliness. The data model has been extended to support annotation of disease processes due to infectious agents and to mutation.

[20] Romero R, Dey SK, Fisher SJ . Preterm labor: one syndrome, many causes
Science(New York, N.Y.), 2014,345(6198):760-765.
URLPMID:25124429 [本文引用: 2]
Preterm birth is associated with 5 to 18% of pregnancies and is a leading cause of infant morbidity and mortality. Spontaneous preterm labor, a syndrome caused by multiple pathologic processes, leads to 70% of preterm births. The prevention and the treatment of preterm labor have been long-standing challenges. We summarize the current understanding of the mechanisms of disease implicated in this condition and review advances relevant to intra-amniotic infection, decidual senescence, and breakdown of maternal-fetal tolerance. The success of progestogen treatment to prevent preterm birth in a subset of patients at risk is a cause for optimism. Solving the mystery of preterm labor, which compromises the health of future generations, is a formidable scientific challenge worthy of investment.

[21] Macones GA, Parry S, Elkousy M, Clothier B, Ural SH, Strauss JF 3rd . A polymorphism in the promoter region of TNF and bacterial vaginosis: preliminary evidence of gene-environment interaction in the etiology of spontaneous preterm birth
. Am J Obstet Gynecol, 2004,190(6):1509-1519.
URLPMID:15284723 [本文引用: 1]
Author information: (1)Perinatology Research Branch, National Institute of Child Health & Human Development/National Institutes of Health/Department of Health and Human Services, Bethesda, MD, USA.

[22] Fang X, Wong S, Mitchell BF . Effects of LPS and IL-6 on oxytocin receptor in non-pregnant and pregnant rat uterus
. Am J Reprod Immunol, 2000,44(2):65-72.
URLPMID:10994633 [本文引用: 1]
PROBLEM: Little is known regarding the regulation of the timing of parturition. Recent evidence suggests an interaction between the immune system and uterine contractility in late gestation. METHOD: Pregnant rats were treated with LPS in vivo in attempts to establish a model of premature parturition induced by the pro-inflammatory response. Uterine explants were incubated in vitro to determine the effects of IL-6 on uterine synthesis of oxytocin (OT) and its receptor (OTR). RESULTS: LPS injection was quite toxic to pregnant rats and gave extremely variable results. In animals that delivered, there was a marked increase in the uterine concentrations of OTR and OTR mRNA. There was no consistent effect regarding the timing of parturition. IL-6 caused a significant increase in the concentration of OTR mRNA in uterine explants from pregnant rats but not in tissues from non-pregnant animals. CONCLUSION: Rat uterine concentrations of OTR are regulated by IL-6. Pro-inflammatory cytokines may stimulate uterine contractility in late gestation rat uterine tissues through a mechanism involving stimulation of OTR.

[23] Gomez-Lopez N, StLouis D, Lehr MA, Sanchez- Rodriguez EN, Arenas-Hernandez M . Immune cells in term and preterm labor
. Cell Mol Immunol, 2014,11(6):571-581.
URLPMID:24954221 [本文引用: 1]
Abstract Labor resembles an inflammatory response that includes secretion of cytokines/chemokines by resident and infiltrating immune cells into reproductive tissues and the maternal/fetal interface. Untimely activation of these inflammatory pathways leads to preterm labor, which can result in preterm birth. Preterm birth is a major determinant of neonatal mortality and morbidity; therefore, the elucidation of the process of labor at a cellular and molecular level is essential for understanding the pathophysiology of preterm labor. Here, we summarize the role of innate and adaptive immune cells in the physiological or pathological activation of labor. We review published literature regarding the role of innate and adaptive immune cells in the cervix, myometrium, fetal membranes, decidua and the fetus in late pregnancy and labor at term and preterm. Accumulating evidence suggests that innate immune cells (neutrophils, macrophages and mast cells) mediate the process of labor by releasing pro-inflammatory factors such as cytokines, chemokines and matrix metalloproteinases. Adaptive immune cells (T-cell subsets and B cells) participate in the maintenance of fetomaternal tolerance during pregnancy, and an alteration in their function or abundance may lead to labor at term or preterm. Also, immune cells that bridge the innate and adaptive immune systems (natural killer T (NKT) cells and dendritic cells (DCs)) seem to participate in the pathophysiology of preterm labor. In conclusion, a balance between innate and adaptive immune cells is required in order to sustain pregnancy; an alteration of this balance will lead to labor at term or preterm.

[24] Melville JM, Moss TJ . The immune consequences of preterm birth
. Front Neurosci-Switz, 2013,7:79.
URLPMID:3659282 [本文引用: 1]
Abstract Preterm birth occurs in 11% of live births globally and accounts for 35% of all newborn deaths. Preterm newborns have immature immune systems, with reduced innate and adaptive immunity; their immune systems may be further compromised by various factors associated with preterm birth. The immune systems of preterm infants have a smaller pool of monocytes and neutrophils, impaired ability of these cells to kill pathogens, and lower production of cytokines which limits T cell activation and reduces the ability to fight bacteria and detect viruses in cells, compared to term infants. Intrauterine inflammation is a major contributor to preterm birth, and causes premature immune activation and cytokine production. This can induce immune tolerance leading to reduced newborn immune function. Intrauterine inflammation is associated with an increased risk of early-onset sepsis and likely has long-term adverse immune consequences. Requisite medical interventions further impact on immune development and function. Antenatal corticosteroid treatment to prevent newborn respiratory disease is routine but may be immunosuppressive, and has been associated with febrile responses, reductions in lymphocyte proliferation and cytokine production, and increased risk of infection. Invasive medical procedures result in an increased risk of late-onset sepsis. Respiratory support can cause chronic inflammatory lung disease associated with increased risk of long-term morbidity. Colonization of the infant by microorganisms at birth is a significant contributor to the establishment of the microbiome. Caesarean section affects infant colonization, potentially contributing to lifelong immune function and well-being. Several factors associated with preterm birth alter immune function. A better understanding of perinatal modification of the preterm immune system will allow for the refinement of care to minimize lifelong adverse immune consequences.

[25] Schreurs R, Baumdick ME, Sagebiel AF, Kaufmann M, Mokry M, Klarenbeek PL, Schaltenberg N, Steinert FL, van Rijn JM, Drewniak A, The SML, Bakx R, Derikx JPM, de Vries N, Corpeleijn WE, Pals ST, Gagliani N, Friese MA, Middendorp S, Nieuwenhuis EES, Reinshagen K, Geijtenbeek TBH, van Goudoever JB, Bunders MJ . Human fetal TNF-α-Cytokine-Producing CD4 + effector memory T cells promote intestinal development and mediate inflammation early in life
Immunity, 2019, 50(2): 462-476.e8.
[本文引用: 1]

[26] Ferguson KK, Cantonwine DE, Rivera-González LO, Loch-Caruso R, Mukherjee B, Anzalota Del Toro LV, Jiménez-Vélez B, Calafat AM, Ye X, Alshawabkeh AN, Cordero JF, Meeker JD . Urinary phthalate metabolite associations with biomarkers of inflammation and oxidative stress across pregnancy in Puerto Rico
. Environ Sci Technol, 2014,48(12):7018-7025.
URLPMID:24845688 [本文引用: 1]
Phthalate exposure during pregnancy has been linked to adverse birth outcomes such as preterm birth, and inflammation and oxidative stress may mediate these relationships. In a prospective cohort study of pregnant women recruited early in gestation in Northern Puerto Rico, we investigated the associations between urinary phthalate metabolites and biomarkers of inflammation, including C-reactive protein, IL-1尾, IL-6, IL-10, and TNF-伪, and oxidative stress, including 8-hydroxydeoxyguanosine (OHdG) and 8-isoprostane. Inflammation biomarkers were measured in plasma twice during pregnancy (N = 215 measurements, N = 120 subjects), and oxidative stress biomarkers in urine were measured three times (N = 148 measurements, N = 54 subjects) per woman. In adjusted linear mixed models, metabolites of di-2-ethylhexyl phthalate (DEHP) were associated with increased IL-6 and IL-10 but relationships were generally not statistically significant. All phthalates were associated with increases in oxidative stress markers. Relationships with OHdG were significant for DEHP metabolites as well as mono-n-butyl phthalate (MBP) and monoiso-butyl phthalate (MiBP). For 8-isoprostane, associations with nearly all phthalates were statistically significant and the largest effect estimates were observed for MBP and MiBP (49-50% increase in 8-isoprostane with an interquartile range increase in metabolite concentration). These relationships suggest a possible mechanism for phthalate action that may be relevant to a number of adverse health outcomes.

[27] Collins A . The genomic and functional characteristics of disease genes
. Brief Bioinform, 2014 16(1):16-23.
URLPMID:24425794 [本文引用: 1]
Increasing evidence indicates that genes containing disease causal variation have distinct functional and genomic properties. The importance of understanding these properties is highlighted by efforts to filter lists of variants from next-generation sequencing studies, where the number of potentially deleterious variants, which are in fact unrelated to disease, may be large. Available evidence indicates that the majority of disease genes are 鈥榥on-essential鈥 and their products occupy functionally peripheral positions in protein networks. They tend to be intermediate between genes that have core biological functions, particularly low mutation rates and low haplotype diversity, and genes for which high haplotype diversity and high mutation rates are advantageous (such as those involved in sensory perception and some immune system functions). Evidence presented here supports these conclusions through analysis of integrated data sets incorporating the latest mutational profiles, linkage disequilibrium structure and other genomic properties of individual genes. The analysis highlights the contrasting functions of genes predicted as least and most likely to contain disease variation and provides a basis for filtering gene variant lists to exclude the least plausible disease candidates.

[28] Pengelly RJ, Vergara-Lope A, Alyousfi D, Jabalameli MR, Collins A . Understanding the disease genome: gene essentiality and the interplay of selection, recombination and mutation
. Brief Bioinform, 2019,20(1):267-273.
URLPMID:28968721 [本文引用: 1]
Abstract Despite the identification of many genetic variants contributing to human disease (the 'disease genome'), establishing reliable molecular diagnoses remain challenging in many cases. The ability to sequence the genomes of patients has been transformative, but difficulty in interpretation of voluminous genetic variation often confounds recognition of underlying causal variants. There are numerous predictors of pathogenicity for individual DNA variants, but their utility is reduced because many plausibly pathogenic variants are probably neutral. The rapidly increasing quantity and quality of information on the properties of genes suggests that gene-specific information might be useful for prediction of causal variation when used alongside variant-specific predictors of pathogenicity. The key to understanding the role of genes in disease relates in part to gene essentiality, which has recently been approximated, for example, by quantifying the degree of intolerance of individual genes to loss-of-function variation. Increasing understanding of the interplay between genetic recombination, selection and mutation and their relationship to gene essentiality suggests that gene-specific information may be useful for the interpretation of sequenced genomes. Considered alongside additional distinctive properties of the disease genome, such as the timing of the evolutionary emergence of genes and the roles of their products in protein networks, the case for using gene-specific measures to guide filtering of sequenced genomes seems strong. The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

[29] Lackey L, McArthur E, Laederach A . Increased transcript complexity in genes associated with chronic obstructive pulmonary disease
. PLoS One, 2015,10(10):e0140885.
URLPMID:4610675 [本文引用: 1]
Genome-wide association studies aim to correlate genotype with phenotype. Many common diseases including Type II , Alzheimer's, Parkinson's and (COPD) are complex genetic traits with hundreds of different loci that are associated with varied disease risk. Identifying common features in the genes associated with each disease remains a challenge. Furthermore, the role of post-transcriptional regulation, and in particular alternative splicing, is still poorly understood in most multigenic diseases. We therefore compiled comprehensive lists of genes associated with Type II , Alzheimer's, Parkinson's and COPD in an attempt to identify common features of their corresponding mRNA transcripts within each gene set. The gene is a well-recognized genetic risk factor of COPD and it produces 11 transcript variants, which is exceptional for a gene. This led us to hypothesize that other genes associated with COPD, and complex disorders in general, are highly transcriptionally diverse. We found that COPD-associated genes have a statistically significant enrichment in transcript complexity stemming from a disproportionately high level of alternative splicing, however, Type II , Alzheimer's and genes were not significantly enriched. We also identified a subset of transcriptionally complex COPD-associated genes (~40%) that are differentially expressed between mild, moderate and severe COPD. Although the genes associated with other are not extensively documented, we found preliminary data that idiopathic genes, but not modulators, are also more transcriptionally complex. Interestingly, complex COPD transcripts are more often the product of alternative acceptor site usage. To verify the biological importance of these alternative transcripts, we used RNA-sequencing analyses to determine that COPD-associated genes are frequently expressed in lung and liver tissues and are regulated in a tissue-specific manner. Additionally, many complex COPD-associated genes are spliced differently between COPD and non-COPD patients. Our analysis therefore suggests that post-transcriptional regulation, particularly alternative splicing, is an important feature specific to COPD disease etiology that warrants further investigation.

[30] Peng Z, Uversky VN, Kurgan L . Genes encoding intrinsic disorder in Eukaryota have high GC content
. Intrinsically Disord Proteins, 2016,4(1):e1262225.
URLPMID:28232902 [本文引用: 1]
We analyze a correlation between the GC content in genes of 12 eukaryotic species and the level of intrinsic disorder in their corresponding proteins. Comprehensive computational analysis has revealed that the disordered regions in eukaryotes are encoded by the GC-enriched gene regions and that this enrichment is correlated with the amount of disorder and is present across proteins and species characterized by varying amounts of disorder. The GC enrichment is a result of higher rate of amino acid coded by GC-rich codons in the disordered regions. Individual amino acids have the same GC-content profile between different species. Eukaryotic proteins with the disordered regions encoded by the GC-enriched gene segments carry out important biological functions including interactions with RNAs, DNAs, nucleotides, binding of calcium and metal ions, are involved in transcription, transport, cell division and certain signaling pathways, and are localized primarily in nucleus, cytosol and cytoplasm. We also investigate a possible relationship between GC content, intrinsic disorder and protein evolution. Analysis of a devised 090008age090009 of amino acids, their disorder-promoting capacity and the GC-enrichment of their codons suggests that the early amino acids are mostly disorder-promoting and their codons are GC-rich while most of late amino acids are mostly order-promoting.

[31] Zylka MJ, Simon JM, Philpot BD . Gene length matters in neurons
. Neuron, 2015,86(2):353-355.
URLPMID:25905808 [本文引用: 1]
A recent study by Gabel et al. (2015) found that Mecp2, the gene mutated in Rett syndrome, represses long (> 100 kb) genes associated with neuronal physiology and connectivity by binding to methylated CA sites in DNA. This study adds to a growing body of literature implicating gene length and transcriptional mechanisms in neurodevelopmental and neurodegenerative disorders.

[32] King IF, Yandava CN, Mabb AM, Hsiao JS, Huang HS, Pearson BL, Calabrese JM, Starmer J, Parker JS, Magnuson T, Chamberlain SJ, Philpot BD, Zylka MJ . Topoisomerases facilitate transcription of long genes linked to autism
. Nature, 2013,501(7465):58-62.
URLPMID:23995680 [本文引用: 1]
Abstract Topoisomerases are expressed throughout the developing and adult brain and are mutated in some individuals with autism spectrum disorder (ASD). However, how topoisomerases are mechanistically connected to ASD is unknown. Here we find that topotecan, a topoisomerase 1 (TOP1) inhibitor, dose-dependently reduces the expression of extremely long genes in mouse and human neurons, including nearly all genes that are longer than 200 ilobases. Expression of long genes is also reduced after knockdown of Top1 or Top2b in neurons, highlighting that both enzymes are required for full expression of long genes. By mapping RNA polymerase II density genome-wide in neurons, we found that this length-dependent effect on gene expression was due to impaired transcription elongation. Interestingly, many high-confidence ASD candidate genes are exceptionally long and were reduced in expression after TOP1 inhibition. Our findings suggest that chemicals and genetic mutations that impair topoisomerases could commonly contribute to ASD and other neurodevelopmental disorders.

[33] Ryu JY, Kim HU, Lee SY . Human genes with a greater number of transcript variants tend to show biological features of housekeeping and essential genes
. Mol Biosyst, 2015,11(10):2798-2807.
URLPMID:26279404 [本文引用: 1]
Alternative splicing is a process observed in gene expression that results in a multi-exon gene to produce multiple mRNA variants which might have different functions and activities. Although physiologically important, many aspects of genes with different number of transcript variants (or splice variants) still remain to be characterized. In this study, we provide bioinformatic evidence that genes with a greater number of transcript variants are more likely to play functionally important roles in cells, compared with those having fewer transcript variants. Among 21鈥983 human genes, 3728 genes were found to have a single transcript, and the remaining genes had 2 to 77 transcript variants. The genes with more transcript variants exhibited greater frequencies of acting as housekeeping and essential genes rather than tissue-selective and non-essential genes. They were found to be more conserved among 64 vertebrate species as orthologs, subjected to regulations by transcription factors and microRNAs, and showed hub node-like properties in the human protein rotein interaction network. These findings were also confirmed by metabolic simulations of 60 cancer metabolic models. All these results indicate that genes with a greater number of transcript variants play biologically more fundamental roles.

[34] Rappoport N, Toung J, Hadley D, Wong RJ, Fujioka K, Reuter J, Abbott CW, Oh S, Hu D, Eng C, Huntsman S, Bodian DL, Niederhuber JE, Hong X, Zhang G, Sikora-Wohfeld W, Gignoux CR, Wang H, Oehlert J, Jelliffe-Pawlowski LL, Gould JB, Darmstadt GL, Wang X, Bustamante CD, Snyder MP, Ziv E, Patsopoulos NA, Muglia LJ, Burchard E, Shaw GM, O'Brodovich HM, Stevenson DK, Butte AJ, Sirota M . A genome-wide association study identifies only two ancestry specific variants associated with spontaneous preterm birth
. Sci Rep, 2018,8(1):226.
URLPMID:5760643 [本文引用: 1]
Abstract Preterm birth (PTB), or the delivery prior to 37 weeks of gestation, is a significant cause of infant morbidity and mortality. Although twin studies estimate that maternal genetic contributions account for approximately 30% of the incidence of PTB, and other studies reported fetal gene polymorphism association, to date no consistent associations have been identified. In this study, we performed the largest reported genome-wide association study analysis on 1,349 cases of PTB and 12,595 ancestry-matched controls from the focusing on genomic fetal signals. We tested over 2 million single nucleotide polymorphisms (SNPs) for associations with PTB across five subpopulations: African (AFR), the Americas (AMR), European, South Asian, and East Asian. We identified only two intergenic loci associated with PTB at a genome-wide level of significance: rs17591250 (P090009=0900094.55E-09) on chromosome 1 in the AFR population and rs1979081 (P090009=0900093.72E-08) on chromosome 8 in the AMR group. We have queried several existing replication cohorts and found no support of these associations. We conclude that the fetal genetic contribution to PTB is unlikely due to single common genetic variant, but could be explained by interactions of multiple common variants, or of rare variants affected by environmental influences, all not detectable using a GWAS alone.