Localization of a major susceptibility locus influencing preterm birth.

Preterm birth (PTB) is a complex trait, but little is known regarding its major genetic determinants. The objective of this study is to localize genes that influence susceptibility to PTB in Mexican Americans (MAs), a minority population in the USA, using predominantly microfilmed birth certificate-based data obtained from the San Antonio Family Birth Weight Study. Only 1302 singleton births from 288 families with information on PTB and significant covariates were considered for genetic analysis. PTB is defined as a childbirth that occurs at <37 completed weeks of gestation, and the prevalence of PTB in this sample was 6.4%. An ∼10 cM genetic map was used to conduct a genome-wide linkage analysis using the program SOLAR. The heritability of PTB was high (h(2) ± SE: 0.75 ± 0.20) and significant (P = 4.5 × 10(-5)), after adjusting for the significant effects of birthweight and birth order. We found significant evidence for linkage of PTB (LOD = 3.6; nominal P = 2.3 × 10(-5); empirical P = 1.0 × 10(-5)) on chromosome 18q between markers D18S1364 and D18S541. Several other chromosomal regions (2q, 9p, 16q and 20q) were also potentially linked with PTB. A strong positional candidate gene in the 18q linked region is SERPINB2 or PAI-2, a member of the plasminogen activator system that is associated with various reproductive processes. In conclusion, to our knowledge, perhaps for the first time in MAs or US populations, we have localized a major susceptibility locus for PTB on chromosome 18q21.33-q23.

[1]  Z. Qiu,et al.  CD226 Gly307Ser association with multiple autoimmune diseases: a meta-analysis. , 2013, Human immunology.

[2]  Siobhan M. Dolan,et al.  Genome-wide association studies in preterm birth: implications for the practicing obstetrician-gynaecologist , 2013, BMC Pregnancy and Childbirth.

[3]  S. Bae,et al.  Association between the CD226 rs763361 polymorphism and susceptibility to autoimmune diseases: a meta-analysis , 2012, Lupus.

[4]  Qing Zhou,et al.  A hypermorphic missense mutation in PLCG2, encoding phospholipase Cγ2, causes a dominantly inherited autoinflammatory disease with immunodeficiency. , 2012, American journal of human genetics.

[5]  Erik Engelen,et al.  RTTN mutations link primary cilia function to organization of the human cerebral cortex. , 2012, American journal of human genetics.

[6]  U. Yallampalli,et al.  Gestational Protein Restriction Reduces Expression of Hsd17b2 in Rat Placental Labyrinth1 , 2012, Biology of reproduction.

[7]  V. Eapen,et al.  Pathogenetic model for Tourette syndrome delineates overlap with related neurodevelopmental disorders including Autism , 2012, Translational Psychiatry.

[8]  C. Redies,et al.  Cadherins and neuropsychiatric disorders , 2012, Brain Research.

[9]  K. Doheny,et al.  No Observed Association for Mitochondrial SNPs with Preterm Delivery and Related Outcomes , 2012, Pediatric Research.

[10]  E. Corwin,et al.  Racial Differences in the Health of Childbearing-Aged Women , 2012, MCN. The American journal of maternal child nursing.

[11]  K. Khan,et al.  Economic costs associated with moderate and late preterm birth: primary and secondary evidence. , 2012, Seminars in fetal & neonatal medicine.

[12]  A. Hofman,et al.  Angiogenic and Fibrinolytic Factors in Blood During the First Half of Pregnancy and Adverse Pregnancy Outcomes , 2012, Obstetrics and gynecology.

[13]  Brian Tomlinson,et al.  Identification of IGF1, SLC4A4, WWOX, and SFMBT1 as Hypertension Susceptibility Genes in Han Chinese with a Genome-Wide Gene-Based Association Study , 2012, PloS one.

[14]  R. Pickler,et al.  Second trimester maternal plasma levels of cytokines IL-1Ra, Il-6 and IL-10 and preterm birth , 2012, Journal of Perinatology.

[15]  G. Lietz,et al.  Importance of β,β-carotene 15,15'-monooxygenase 1 (BCMO1) and β,β-carotene 9',10'-dioxygenase 2 (BCDO2) in nutrition and health. , 2012, Molecular nutrition & food research.

[16]  R. Pickler,et al.  Acculturation, depressive symptoms, estriol, progesterone, and preterm birth in Hispanic women , 2012, Archives of Women's Mental Health.

[17]  Scott M. Williams,et al.  Candidate gene analysis of spontaneous preterm delivery: New insights from re-analysis of a case-control study using case-parent triads and control-mother dyads , 2011, BMC Medical Genetics.

[18]  B. Zuckerman,et al.  Associations between gene polymorphisms in fatty acid metabolism pathway and preterm delivery in a US urban black population , 2011, Human Genetics.

[19]  M. Schubert,et al.  Vitamin A: a multifunctional tool for development. , 2011, Seminars in cell & developmental biology.

[20]  A. Paulson,et al.  A combination of enhancer/silencer modules regulates spatially restricted expression of cadherin‐7 in neural epithelium , 2011, Developmental dynamics : an official publication of the American Association of Anatomists.

[21]  S. Fowler,et al.  The late preterm birth rate and its association with comorbidities in a population-based study. , 2011, American journal of perinatology.

[22]  M. Yuzaki,et al.  Cbln family proteins promote synapse formation by regulating distinct neurexin signaling pathways in various brain regions , 2011, The European journal of neuroscience.

[23]  Leena Peltonen,et al.  An Evolutionary Genomic Approach to Identify Genes Involved in Human Birth Timing , 2011, PLoS genetics.

[24]  M. McConaha,et al.  Microarray assessment of the influence of the conceptus on gene expression in the mouse uterus during decidualization. , 2011, Reproduction.

[25]  Sheng-Hsiang Li,et al.  SERPINE2, an inhibitor of plasminogen activators, is highly expressed in the human endometrium during the secretory phase , 2011, Reproductive biology and endocrinology : RB&E.

[26]  L. Peltonen,et al.  Mapping a New Spontaneous Preterm Birth Susceptibility Gene, IGF1R, Using Linkage, Haplotype Sharing, and Association Analysis , 2011, PLoS genetics.

[27]  Scott M. Williams,et al.  A genetic association study of maternal and fetal candidate genes that predispose to preterm prelabor rupture of membranes (PROM). , 2010, American journal of obstetrics and gynecology.

[28]  M. Neale,et al.  Racial Differences in Genetic and Environmental Risk to Preterm Birth , 2010, PloS one.

[29]  Siobhan M. Dolan,et al.  Synopsis of Preterm Birth Genetic Association Studies: The Preterm Birth Genetics Knowledge Base (PTBGene) , 2010, Public Health Genomics.

[30]  Scott M. Williams,et al.  Association of Genetic Variants, Ethnicity and Preterm Birth with Amniotic Fluid Cytokine Concentrations , 2010, Annals of human genetics.

[31]  Siobhan M. Dolan,et al.  Genetic and environmental contributions to racial disparities in preterm birth. , 2010, The Mount Sinai journal of medicine, New York.

[32]  J. Lawn,et al.  Global report on preterm birth and stillbirth (1 of 7): definitions, description of the burden and opportunities to improve data , 2010, BMC pregnancy and childbirth.

[33]  Scott M. Williams,et al.  Identification of fetal and maternal single nucleotide polymorphisms in candidate genes that predispose to spontaneous preterm labor with intact membranes. , 2009, American journal of obstetrics and gynecology.

[34]  B. Feenstra,et al.  Maternal contributions to preterm delivery. , 2009, American journal of epidemiology.

[35]  Yudi Pawitan,et al.  Maternal effects for preterm birth: a genetic epidemiologic study of 630,000 families. , 2009, American journal of epidemiology.

[36]  A. Chan,et al.  Novel association of the CD226 (DNAM-1) Gly307Ser polymorphism in Wegener's granulomatosis and confirmation for multiple sclerosis in German patients , 2009, Genes and Immunity.

[37]  Tomas W. Fitzgerald,et al.  Genomic and Genic Deletions of the FOX Gene Cluster on 16q24.1 and Inactivating Mutations of FOXF1 Cause Alveolar Capillary Dysplasia and Other Malformations , 2009, American journal of human genetics.

[38]  Tatiana I. Axenovich,et al.  Linkage analysis of adult height in a large pedigree from a Dutch genetically isolated population , 2009, Human Genetics.

[39]  Scott M. Williams,et al.  Spontaneous preterm birth in African Americans is associated with infection and inflammatory response gene variants. , 2009, American journal of obstetrics and gynecology.

[40]  J. Martin,et al.  Births : final data for 2006 , 2009 .

[41]  R. Duggirala,et al.  Genome-Wide Linkage Scan for Genes Influencing Plasma Triglyceride Levels in the Veterans Administration Genetic Epidemiology Study , 2009, Diabetes.

[42]  J. Plunkett,et al.  The Genetics of Birth Timing: Insights into a Fundamental Component of Human Development , 2008, Clinical genetics.

[43]  D. Hougaard,et al.  Polymorphisms in the tumor necrosis factor alpha and interleukin 1‐beta promoters with possible gene regulatory functions increase the risk of preterm birth , 2008, Acta obstetricia et gynecologica Scandinavica.

[44]  S. Thornton,et al.  Preterm Birth: Causes, Consequences and Prevention , 2008 .

[45]  Scott M. Williams,et al.  Preterm Birth in Caucasians Is Associated with Coagulation and Inflammation Pathway Gene Variants , 2008, PloS one.

[46]  S. Witkin,et al.  ORIGINAL ARTICLE: Maternal and Neonatal Interleukin‐1 Receptor Antagonist Genotype and Pregnancy Outcome in a Population with a High Rate of Pre‐term Birth , 2008, American journal of reproductive immunology.

[47]  S. Andersson,et al.  Estrogen and progesterone metabolism in the cervix during pregnancy and parturition. , 2008, The Journal of clinical endocrinology and metabolism.

[48]  R. Menon.  Spontaneous preterm birth, a clinical dilemma: Etiologic, pathophysiologic and genetic heterogeneities and racial disparity , 2008, Acta obstetricia et gynecologica Scandinavica.

[49]  D. Schendel,et al.  Birth Weight and Gestational Age Characteristics of Children With Autism, Including a Comparison With Other Developmental Disabilities , 2008, Pediatrics.

[50]  Bjarni V. Halldórsson,et al.  Many sequence variants affecting diversity of adult human height , 2008, Nature Genetics.

[51]  J. Soul,et al.  Positive Screening for Autism in Ex-preterm Infants: Prevalence and Risk Factors , 2008, Pediatrics.

[52]  M. Poutanen,et al.  Placenta defects and embryonic lethality resulting from disruption of mouse hydroxysteroid (17-beta) dehydrogenase 2 gene. , 2008, Molecular endocrinology.

[53]  G. Saade,et al.  The Effect of Acculturation on Progesterone/Estriol Ratios and Preterm Birth in Hispanics , 2008, Obstetrics and gynecology.

[54]  Roberto Romero,et al.  Epidemiology and causes of preterm birth , 2008, The Lancet.

[55]  G. Willemsen,et al.  Heritability of parturition timing: an extended twin design analysis. , 2007, American journal of obstetrics and gynecology.

[56]  K. Johnson,et al.  Evaluation of Fetal and Maternal Genetic Variation in the Progesterone Receptor Gene for Contributions to Preterm Birth , 2007, Pediatric Research.

[57]  M. Marazita,et al.  Maternal and fetal variation in genes of cholesterol metabolism is associated with preterm delivery , 2007, Journal of Perinatology.

[58]  P. Gallagher,et al.  Erythrocyte disorders in the perinatal period. , 2007, Seminars in perinatology.

[59]  Assuring Healthy Outcomes,et al.  Preterm Birth : Causes , Consequences , and Prevention , 2005 .

[60]  O. Mäkitie,et al.  Glucose regulation in young adults with very low birth weight. , 2007, The New England journal of medicine.

[61]  J. Dambrosia,et al.  Genetic Polymorphisms and Spontaneous Preterm Birth , 2007, Obstetrics and gynecology.

[62]  Scott M. Williams,et al.  Genetic Associations in Preterm Birth: A Primer of Marker Selection, Study Design, and Data Analysis , 2006, The Journal of the Society for Gynecologic Investigation: JSGI.

[63]  E. Steegers,et al.  Concentrations of plasminogen activators and their inhibitors in blood preconceptionally, during and after pregnancy. , 2006, European journal of obstetrics, gynecology, and reproductive biology.

[64]  Richard P. Granato,et al.  A quantitative trait locus (QTL) on chromosome 6q influences birth weight in two independent family studies. , 2006, Human molecular genetics.

[65]  Richard P. Granato,et al.  A genomewide search finds major susceptibility loci for gallbladder disease on chromosome 1 in Mexican Americans. , 2006, American journal of human genetics.

[66]  A. Olshan,et al.  Genetic variation in the sodium-dependent vitamin C transporters, SLC23A1, and SLC23A2 and risk for preterm delivery. , 2006, American journal of epidemiology.

[67]  K. Ward,et al.  The Heritability of Preterm Delivery , 2005, Obstetrics and gynecology.

[68]  John Blangero,et al.  Genome-wide linkage analyses of type 2 diabetes in Mexican Americans: the San Antonio Family Diabetes/Gallbladder Study. , 2005, Diabetes.

[69]  Stephen J Chanock,et al.  Risk of Spontaneous Preterm Birth is Associated With Common Proinflammatory Cytokine Polymorphisms , 2005, Epidemiology.

[70]  Yibin Wang,et al.  p38 MAP kinase inhibition enables proliferation of adult mammalian cardiomyocytes. , 2005, Genes & development.

[71]  Gerard Tromp,et al.  Functionally significant SNP MMP8 promoter haplotypes and preterm premature rupture of membranes (PPROM). , 2004, Human molecular genetics.

[72]  William McGuire,et al.  Epidemiology of preterm birth , 2004, BMJ : British Medical Journal.

[73]  Samuel Parry,et al.  A polymorphism in the promoter region of TNF and bacterial vaginosis: preliminary evidence of gene-environment interaction in the etiology of spontaneous preterm birth. , 2004, American journal of obstetrics and gynecology.

[74]  Tianhua Niu,et al.  A candidate gene association study on preterm delivery: application of high-throughput genotyping technology and advanced statistical methods. , 2004, Human molecular genetics.

[75]  David I W Phillips,et al.  Fetal programming of the hypothalamic-pituitary-adrenal (HPA) axis: low birth weight and central HPA regulation. , 2004, The Journal of clinical endocrinology and metabolism.

[76]  A. Basu,et al.  Dehydrated hereditary stomatocytosis with transient perinatal ascites , 2003, Archives of disease in childhood. Fetal and neonatal edition.

[77]  G. Aylward.  Cognitive function in preterm infants: no simple answers. , 2003, JAMA.

[78]  D. Barker.  Fetal programming of coronary heart disease , 2002, Trends in Endocrinology & Metabolism.

[79]  Roberto Romero,et al.  Fetal plasma MMP-9 concentrations are elevated in preterm premature rupture of the membranes. , 2002, American journal of obstetrics and gynecology.

[80]  R. Romero,et al.  A polymorphism in the matrix metalloproteinase-9 promoter is associated with increased risk of preterm premature rupture of membranes in African Americans. , 2002, Molecular human reproduction.

[81]  M. Babron,et al.  Pleiotropic syndrome of dehydrated hereditary stomatocytosis, pseudohyperkalemia, and perinatal edema maps to 16q23-q24. , 2000, Blood.

[82]  N. Martin,et al.  Genetic influences on premature parturition in an Australian twin sample , 2000, Twin Research.

[83]  S Cnattingius,et al.  Genetic influence on birthweight and gestational length determined by studies in offspring of twins , 2000, BJOG : an international journal of obstetrics and gynaecology.

[84]  P. O'Connell,et al.  Linkage of type 2 diabetes mellitus and of age at onset to a genetic location on chromosome 10q in Mexican Americans. , 1999, American journal of human genetics.

[85]  L. Bogic,et al.  Tissue plasminogen activator and its receptor in the human amnion, chorion, and decidua at preterm and term. , 1999, Biology of Reproduction.

[86]  L. Almasy,et al.  Multipoint quantitative-trait linkage analysis in general pedigrees. , 1998, American journal of human genetics.

[87]  T. Porter,et al.  The Risk of Preterm Birth Across Generations , 1997, Obstetrics and gynecology.

[88]  J. Blangero,et al.  Genetic and environmental contributions to cardiovascular risk factors in Mexican Americans. The San Antonio Family Heart Study. , 1996, Circulation.

[89]  E. Lander,et al.  Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results , 1995, Nature Genetics.

[90]  C. Amos.  Robust variance-components approach for assessing genetic linkage in pedigrees. , 1994, American journal of human genetics.

[91]  K. Liang,et al.  Asymptotic Properties of Maximum Likelihood Estimators and Likelihood Ratio Tests under Nonstandard Conditions , 1987 .

[92]  J. Mathews,et al.  Extensions to multivariate normal models for pedigree analysis , 1982, Annals of human genetics.

[93]  R C Elston,et al.  Multifactorial qualitative traits: genetic analysis and prediction of recurrence risks. , 1974, Biometrics.

[94]  Cedric A. B. Smith,et al.  Introduction to Quantitative Genetics , 1960 .

[95]  M. Hallman,et al.  A study of collectin genes in spontaneous preterm birth reveals an association with a common surfactant protein D gene polymorphism , 2012, Pediatric Research.

[96]  Joy E. Lawn,et al.  Born too soon: the global action report on preterm birth , 2012 .

[97]  J. Mulliken,et al.  Nonsyndromic cleft lip and palate: CRISPLD genes and the folate gene pathway connection. , 2011, Birth defects research. Part A, Clinical and molecular teratology.

[98]  Ana Pilar Betran,et al.  The worldwide incidence of preterm birth: a systematic review of maternal mortality and morbidity. , 2010, Bulletin of the World Health Organization.

[99]  Assuring Healthy Outcomes,et al.  Committee on Understanding Premature Birth and Assuring Healthy Outcomes , 2007 .

[100]  G. Rice,et al.  Gene expression of plasminogen activation cascade components in human term gestational tissues with labour onset. , 1998, Molecular human reproduction.

[101]  R. Duggirala,et al.  A variance component approach to dichotomous trait linkage analysis using a threshold model , 1997, Genetic epidemiology.