Aim: Our goal wasto produce a field synopsis of genetic associations with preterm birth and to set up a publicly available online database summarizing the data. Methods: We performed a systematic review and meta-analyses to identify genetic associations with preterm birth. We have set up a publicly available online database of genetic association data on preterm birth called PTBGene (http://ric.einstein.yu.edu/ptbgene/index.html) and report on a structured synopsis thereof as of December 1, 2008. Results: Data on 189 polymorphisms in 84 genes have been included and 36 meta-analyses have been performed. Five gene variants (4 in maternal DNA, one in newborn DNA) have shown nominally significant associations, but all have weak epidemiological credibility. Conclusion: After publishing this field synopsis, the PTBGene database will be regularly updated to keep track of the evolving evidence base of genetic factors in preterm birth with the goal of promoting knowledge sharing and multicenter collaboration among preterm birth research groups.

1.
Martin JA, Hamilton BE, Sutton PD, Ventura SJ: Births: final data for 2006. Natl Vital Stat Rep 2009;57:1–101.
2.
Merialdi M, Murray JC: The changing face of preterm birth. Pediatrics 2007;120:1133–1134.
3.
Fawke J: Neurological outcomes following preterm birth. Semin Fetal Neonatal Med 2007;12:374–382.
4.
Eriksson JG: The fetal origins hypothesis – 10 years on. BMJ 2005;330:1096–1097.
5.
Lockwood CJ, Kuczynski E: Risk stratification and pathological mechanisms in preterm delivery. Paediatr Perinat Epidemiol 2001;15(suppl 2):78–89.
6.
Hao K, Wang X, Niu T, Xu X, Li A, Chang W, Wang L, Li G, Laird N, Xu X: A candidate gene association study on preterm delivery: application of high-throughput genotyping technology and advanced statistical methods. Hum Mol Genet 2004;13:683–691.
7.
Porter TF, Fraser AM, Hunter CY, Ward RH, Varner MW: The risk of preterm birth across generations. Obstet Gynecol 1997;90:63–67.
8.
Plunkett J, Muglia LJ: Genetic contributions to preterm birth: implications from epidemiological and genetic association studies. Ann Med 2008;40:167–195.
9.
Anum EA, Springel EH, Shriver MD, Strauss JF 3rd: Genetic contributions to disparities in preterm birth. Pediatr Res 2009;65:1–9.
10.
Clausson B, Lichtenstein P, Cnattingius S: Genetic influence on birthweight and gestational length determined by studies in offspring of twins. BJOG 2000;107:375–381.
11.
Treloar SA, Macones GA, Mitchell LE, Martin NG: Genetic influences on premature parturition in an Australian twin sample. Twin Res 2000;3:80–82.
12.
Amory JH, Adams KM, Lin MT, Hansen JA, Eschenbach DA, Hitti J: Adverse outcomes after preterm labor are associated with tumor necrosis factor-(alpha) polymorphism –863, but not –308, in mother-infant pairs. Am J Obstet Gynecol 2004;191:1362–1367.
13.
Erhardt E, Stankovics J, Molnar D, Adamovich K, Melegh B: High prevalence of factor V Leiden mutation in mothers of premature neonates. Biol Neonate 2000;78:145–146.
14.
Genc MR, Gerber S, Nesin M, Witkin SS: Polymorphism in the interleukin-1 gene complex and spontaneous preterm delivery. Am J Obstet Gynecol 2002;187:157–163.
15.
Grisaru-Granovsky S, Tevet A, Bar-Shavit R, Salah Z, Elstein D, Samueloff A, Altarescu G: Association study of protease activated receptor 1 gene polymorphisms and adverse pregnancy outcomes: results of a pilot study in Israel. Am J Med Genet A 2007;143A:2557–2563.
16.
Moore S, Ide M, Randhawa M, Walker JJ, Reid JG, Simpson NA: An investigation into the association among preterm birth, cytokine gene polymorphisms and periodontal disease. BJOG 2004;111:125–132.
17.
Murtha AP, Nieves A, Hauser ER, Swamy GK, Yonish BA, Sinclair TR, Heine RP: Association of maternal IL-1 receptor antagonist intron 2 gene polymorphism and preterm birth. Am J Obstet Gynecol 2006;195:1249–1253.
18.
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 Gynecol Scand 2004;83:461–465.
19.
Simhan HN, Krohn MA, Roberts JM, Zeevi A, Caritis SN: Interleukin-6 promoter174 polymorphism and spontaneous preterm birth. Am J Obstet Gynecol 2003;189:915–918.
20.
Speer EM, Gentile DA, Zeevi A, Pillage G, Huo D, Skoner DP: Role of single nucleotide polymorphisms of cytokine genes in spontaneous preterm delivery. Hum Immunol 2006;67:915–923.
21.
Uma R, Forsyth JS, Struthers AD, Fraser CG, Godfrey V, Murphy DJ: Correlation of angiotensin converting enzyme activity and the genotypes of the I/D polymorphism in the ACE gene with preterm birth and birth weight. Eur J Obstet Gynecol Reprod Biol 2008;141:27–30.
22.
Bertram L, McQueen MB, Mullin K, Blacker D, Tanzi RE: Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database. Nat Genet 2007;39:17–23.
23.
Allen NC, Bagade S, McQueen MB, Ioannidis JP, Kawoura FK, Khoury MJ, Tanzi RE, Bertram L: Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database. Nat Genet 2008;40:827–834.
24.
Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, Moher D, Becker BJ, Sipe TA, Thacker SB: Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA 2000;283:2008–2012.
25.
HuGE Literature Finder. Available at http://www.hugenavigator.net/HuGENavigator/startPagePubLit.do (accessed March 12, 2010).
26.
Yu W, Gwinn M, Clyne M, Yesupriya A, Khoury MJ: A navigator for human genome epidemiology. Nat Genet 2008;40:124–125.
27.
Genetic Association Database (GAD). Available at http://geneticassociationdb.nih.gov/ (accessed March 12, 2010).
28.
Entrez Gene. Available at http://www.ncbi.nlm.nih.gov/sites/entrez (accessed March 12, 2010).
29.
Single Nucleotide Polymorphism Database (dbSNP). Available at http://www.ncbi.nlm.nih.gov/projects/SNP/ (accessed March 12, 2010).
30.
Ioannidis JP, Ntzani EE, Trikalinos TA: ‘Racial’ differences in genetic effects for complex diseases. Nat Genet 2004;36:1312–1318.
31.
Lau J, Ioannidis JP, Schmid CH: Quantitative synthesis in systematic reviews. Ann Intern Med 1997;127:820–826.
32.
Ioannidis JP, Patsopoulos NA, Evangelou E: Uncertainty in heterogeneity estimates in meta-analyses. BMJ 2007;335:914–916.
33.
Trikalinos TA, Salanti G, Khoury MJ, Ioannidis JP: Impact of violations and deviations in Hardy-Weinberg equilibrium on postulated gene-disease associations. Am J Epidemiol 2006;163:300–309.
34.
Harbord RM, Egger M, Sterne JA: A modified test for small-study effects in meta-analyses of controlled trials with binary endpoints. Stat Med 2006;25:3443–3457.
35.
Lau J, Ioannidis JP, Terrin N, Schmid CH, Olkin I: The case of the misleading funnel plot. BMJ 2006;333:597–600.
36.
Ioannidis JP, Trikalinos TA: An exploratory test for an excess of significant findings. Clin Trials 2007;4:245–253.
37.
Ioannidis JP, Boffetta P, Little J, O’Brien TR, Uitterlinden AG, Vineis P, Balding DJ, Chokkalingam A, Dolan SM, Flanders WD, Higgins JP, McCarthy MI, McDermott DH, Page GP, Rebbeck TR, Seminara D, Khoury MJ: Assessment of cumulative evidence on genetic associations: interim guidelines. Int J Epidemiol 2008;37:120–132.
38.
Lie RT, Wilcox AJ, Skjaerven R: Maternal and paternal influences on length of pregnancy. Obstet Gynecol 2006;107:880–885.
39.
Doh K, Sziller I, Vardhana S, Kovacs E, Papp Z, Witkin SS: Beta2-adrenergic receptor gene polymorphisms and pregnancy outcome. J Perinat Med 2004;32:413–417.
40.
Ozkur M, Dogulu F, Ozkur A, Gokmen B, Inaloz SS, Aynacioglu AS: Association of the Gln27Glu polymorphism of the beta-2-adrenergic receptor with preterm labor. Int J Gynaecol Obstet 2002;77:209–215.
41.
Schroder K, Hertzog PJ, Ravasi T, Huma DA: Interferon-gamma: an overview of signals, mechanisms and functions. J Leukoc Biol 2004;75:163–189.
42.
Mattar R, De Souza E, Daher S: Preterm delivery and cytokine gene polymorphisms. J Reprod Med 2006;51:317–320.
43.
Ioannidis JP,Bernstein J, Boffetta P, Danesh J, Dolan S, Hartge P, Hunter D, Inskip P, Jarvelin MR, Little J, Maraganore DM, Bishop JA, O’Brien TR, Petersen G, Riboli E, Seminara D, Taioli E, Uitterlinden AG, Vineis P, Winn DM, Salanti G, Higgins JP, Khoury MJ: A network of investigator networks in human genome epidemiology. Am J Epidemiol 2005;162:302–304.
44.
Pennell CE, Jacobsson B, Williams SM, Buus RM, Muglia LJ, Dolan SM, Morken NH, Ozcelik H, Lye SJ, Relton C: Genetic epidemiologic studies of preterm birth: guidelines for research. Am J Obstet Gynecol 2007;196:107–118.
45.
Contopoulos-Ioannidis DG, Alexiou GA, Gouvias TC, Ioannidis JP: An empirical evaluation of multifarious outcomes in pharmacogenetics: beta-2 adrenoceptor gene polymorphisms in asthmatreatment. Pharmacogenet Genomics 2006;16:705–711.
46.
Seminara D, Khoury MJ, O’Brien TR, Manolio T, Gwinn ML, Little J, Higgins JP, Bernstein JL, Boffetta P, Bondy M, Bray MS, Brenchley PE, Buffler PA, Casas JP, Chokkalingam AP, Danesh J, Davey-Smith G, Dolan S, Duncan R, Gruis NA, Hashibe M, Hunter D, Jarvelin MR, Malmer B, Maraganore DM, Newton-Bishop JA, Riboli E, Salanti G, Taioli E, Timpson N, Uitterlinden AG, Vineis P, Wareham N, Winn DM, Zimmern R, Ioannidis JP; Human Genome Epidemiology Network; Network of Investigator Networks: The emergence of networks in human genome epidemiology: challenges and opportunities. Epidemiology 2007;18:1–8.
47.
Menon R, Fortunato SJ, Thorsen P, Williams S: Genetic associations in preterm birth: a primer of marker selection, study design, and data analysis. J Soc Gynecol Investig 2006;13:531–541.
48.
Menon R, Velez DR, Thorsen P, Vogel I, Jacobsson B, Williams SM, Fortunato SJ: Ethnic differences in key candidate genes for spontaneous preterm birth: TNF-alpha and its receptors. Hum Hered 2006;62:107–118.
49.
Velez DR, Menon R, Thorsen P, Jiang L, Simhan H, Morgan N, Fortunato SJ, Williams SM: Ethnic differences in interleukin 6 (IL-6) and IL6 receptor genes in spontaneous preterm birth and effects on amniotic fluid protein levels. Ann Hum Genet 2007;71:586–600.
50.
Wilcox AJ, Skjaerven R, Lie RT: Familial patterns of preterm delivery: maternal and fetal contributions. Am J Epidemiol 2008;167:474–479.
51.
Ioannidis JP, Gwinn M, Little J, Higgins JP, Bernstein JL, Boffetta P, Bondy M, Bray MS, Brenchley PE, Buffler PA, Casas JP, Chokkalingam A, Danesh J, Smith GD, Dolan S, Duncan R, Gruis NA, Hartge P, Hashibe M, Hunter DJ, Jarvelin MR, Malmer B, Maraganore DM, Newton-Bishop JA, O’Brien TR, Petersen G, Riboli E, Salanti G, Seminara D, Smeeth L, Taioli E, Timpson N, Uitterlinden AG, Vineis P, Wareham N, Winn DM, Zimmern R, Khoury MJ: A road map for efficient and reliable human genome epidemiology. Nat Genet 2006;38:3–5.
52.
Chaves JH, Babayan A, Bezerra Cde M, Linhares IM, Witkin SS: Maternal and neonatal interleukin-1 receptor antagonist genotype and pregnancy outcome in a population with a high rate of pre-term birth. Am J Reprod Immunol 2008;60:312–317.
53.
Landau R, Xie HG, Dishy V, Stein CM, Wood AJJ, Moore JH, Emala CW, Smiley RM: Beta2-adrenergic receptor genotype and preterm delivery. Am J Obstet Gynecol 2002;187:1294–1298.
54.
Kocher O, Cirovic C, Malynn E, Rowland CM, Bare LA, Young BA, Henslee JG, Laffler TG, Huff JB, Kruskall MS, Wong G, Bauer KA: Obstetric complications in patients with hereditary thrombophilia identified using the LCx microparticle enzyme immunoassay: a controlled study of 5,000 patients. Am J Clin Pathol 2007;127:68–75.
55.
Valdez LL, Quintero A, Garcia E, Olivares N, Celis A, Rivas F Jr, Rivas F: Thrombophilic polymorphisms in preterm delivery. Blood Cells Mol Dis 2004;33:51–56.
56.
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;143:1990–1996.
57.
Gibson CS, MacLennan AH, Dekker GA, Goldwater PN, Dambrosia JM, Munroe DJ, Tsang S, Stewart C, Nelson KB: Genetic polymorphisms and spontaneous preterm birth. Obstet Gynecol 2007;109:384–391.
58.
Hartel C, von Otte S, Koch J, Ahrens P, Kattner E, Segerer H, Moller J, Diedrich K, Gopel W: Polymorphisms of haemostasis genes as risk factors for preterm delivery. Thromb Haemost 2005;94:88–92.
59.
Resch B, Gallistl S, Kutschera J, Mannhalter C, Muntean W, Mueller WD: Thrombophilic polymorphisms – Factor V Leiden, prothrombin G20210A, and methylenetetrahydrofolate reductase C677T mutations – and preterm birth. Wien Klin Wochenschr 2004;116:622–626.
60.
Gopel W, Kim D, Gortner L: Prothrombotic mutations as a risk factor for preterm birth. Lancet 1999;353:1411–1412.
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