Human Genetics

, Volume 131, Issue 3, pp 341–351 | Cite as

Associations between gene polymorphisms in fatty acid metabolism pathway and preterm delivery in a US urban black population

  • Xin Liu
  • Guoying Wang
  • Xiumei Hong
  • Hui-Ju Tsai
  • Rong Liu
  • Shanchun Zhang
  • Hongjian Wang
  • Colleen Pearson
  • Katherin Ortiz
  • Deli Wang
  • Emmet Hirsch
  • Barry Zuckerman
  • Xiaobin Wang
Original Investigation


There is increasing evidence suggesting that higher intakes of fish or n-3 polyunsaturated fatty acids supplements may decrease the risk of preterm delivery (PTD). We hypothesized that genetic variants of the enzymes critical to fatty acids biosynthesis and metabolism may be associated with PTD. We genotyped 231 potentially functional single nucleotide polymorphisms (SNPs) and tagSNPs in 9 genes (FADS1, FADS2, PTGS1, PTGS2, ALOX5, ALOX5AP, PTGES, PTGES2, and PTGES3) among 1,110 black mothers, including 542 mothers who delivered preterm (<37 weeks gestation) and 568 mothers who delivered full-term babies (≥37 weeks gestation) at Boston Medical Center. After excluding SNPs that are in complete linkage disequilibrium or have lower minor allele frequency (<1%) or call rate (<90%), we examined the association of 206 SNPs with PTD using multiple logistic regression models. We also imputed 190 HapMap SNPs via program MACH and examined their associations with PTD. Finally, we explored gene-level and pathway-level associations with PTD using the adaptive rank truncated product (ARTP) methods. A total of 21 SNPs were associated with PTD (p value ranging from 0.003 to 0.05), including 3 imputed SNPs. Gene-level ARTP statistics indicated that the gene PTGES2 was significantly associated with PTD with a gene-based p value equal to 0.01. No pathway-based association was found. In this large and comprehensive candidate gene study, we found a modest association of genes in fatty acid metabolism pathway with PTD. Further investigation of these gene polymorphisms jointly with fatty acid measures and other genetic factors would help better understand the pathogenesis of PTD.


Complete Linkage Disequilibrium Black Mother Impute SNPs Infant Gender Fatty Acid Metabolism Pathway 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



We thank all of the participating mothers and their families enrolled in the Boston Medical Center Cohort study; their efforts have helped further our understanding of the causes of preterm delivery. We thank the nursing staff of Labor and Delivery at Boston Medical Center for their continuous support and assistance to the study, as well as Lingling Fu for data management and Ann Ramsay for administrative support. We thank Dr. Kai Yu from the NCI for his helpful instruction on ARTP methods, and also Dr. Fuhong He from the Beijing Institute of Genomics, Chinese Academy of Sciences for her help on bioinformatics analyses. We thank Tami R. Bartell for English editing. The study was supported in part by grants from the National Institutes of Health (R01 HD041702, R01ES11682, R21ES11666, and R21HD066471), and March of Dimes Birth Defects Foundation (20-FY98-0701, 20-FY02-56).

Conflict of interest

None of the authors have a conflict of interest pertaining to this work.

Supplementary material

439_2011_1079_MOESM1_ESM.doc (1.3 mb)
Supplementary material 1 (DOC 1361 kb)


  1. Allen KG, Harris MA (2001) The role of n-3 fatty acids in gestation and parturition. Exp Biol Med (Maywood) 226:498–506Google Scholar
  2. Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21:263–265. doi: 10.1093/bioinformatics/bth457 PubMedCrossRefGoogle Scholar
  3. Bazan NG (2007) Omega-3 fatty acids, pro-inflammatory signaling and neuroprotection. Curr Opin Clin Nutr Metab Care 10:136–141PubMedCrossRefGoogle Scholar
  4. Bhangale TR, Rieder MJ, Nickerson DA (2008) Estimating coverage and power for genetic association studies using near-complete variation data. Nat Genet 40:841–843PubMedCrossRefGoogle Scholar
  5. Bonham MP, Duffy EM, Wallace JM, Robson PJ, Myers GJ, Davidson PW, Clarkson TW, Shamlaye CF, Strain JJ (2008) Habitual fish consumption does not prevent a decrease in LCPUFA status in pregnant women (the Seychelles Child Development Nutrition Study). Prostaglandins Leukot Essent Fatty Acids 78:343–350PubMedCrossRefGoogle Scholar
  6. Calder PC (2009) Polyunsaturated fatty acids and inflammatory processes: new twists in an old tale. Biochimie. doi: 10.1016/j.biochi.2009.01.008
  7. Coletta JM, Bell SJ, Roman AS (2010) Omega-3 Fatty acids and pregnancy. Rev Obstet Gynecol 3:163–171PubMedGoogle Scholar
  8. Crider KS, Whitehead N, Buus RM (2005) Genetic variation associated with preterm birth: a HuGE review. Genet Med 7:593–604PubMedCrossRefGoogle Scholar
  9. de Bakker PI, Yelensky R, Pe’er I, Gabriel SB, Daly MJ, Altshuler D (2005) Efficiency and power in genetic association studies. Nat Genet 37:1217–1223PubMedCrossRefGoogle Scholar
  10. Decsi T (2009) Effects of supplementing LCPUFA to the diet of pregnant women: data from RCT. Adv Exp Med Biol 646:65–69. doi: 10.1007/978-1-4020-9173-5_7 PubMedCrossRefGoogle Scholar
  11. Fischer A, Grallert H, Bohme M, Gieger C, Boomgaarden I, Heid I, Wichmann HE, Doring F, Illig T (2009) Association analysis between the prostaglandin E synthase 2 R298H polymorphism and body mass index in 8079 participants of the KORA study cohort. Genet Test Mol Biomarkers 13:223–226. doi: 10.1089/gtmb.2008.0111 PubMedCrossRefGoogle Scholar
  12. Fisher E, Nitz I, Lindner I, Rubin D, Boeing H, Mohlig M, Hampe J, Schreiber S, Schrezenmeir J, Doring F (2007) Candidate gene association study of type 2 diabetes in a nested case–control study of the EPIC-Potsdam cohort—role of fat assimilation. Mol Nutr Food Res 51:185–191. doi: 10.1002/mnfr.200600162 PubMedCrossRefGoogle Scholar
  13. Glaser C, Heinrich J, Koletzko B (2010) Role of FADS1 and FADS2 polymorphisms in polyunsaturated fatty acid metabolism. Metabolism 59:993–999. doi: 10.1016/j.metabol.2009.10.022 PubMedCrossRefGoogle Scholar
  14. Gomez LM, Sammel MD, Appleby DH, Elovitz MA, Baldwin DA, Jeffcoat MK, Macones GA, Parry S (2010) Evidence of a gene–environment interaction that predisposes to spontaneous preterm birth: a role for asymptomatic bacterial vaginosis and DNA variants in genes that control the inflammatory response. Am J Obstet Gynecol 202:386e1–6. doi: 10.1016/j.ajog.2010.01.042 Google Scholar
  15. Greenberg JA, Bell SJ, Ausdal WV (2008) Omega-3 fatty acid supplementation during pregnancy. Rev Obstet Gynecol 1:162–169PubMedGoogle Scholar
  16. Guldner L, Monfort C, Rouget F, Garlantezec R, Cordier S (2007) Maternal fish and shellfish intake and pregnancy outcomes: a prospective cohort study in Brittany, France. Environ Health 6:33. doi: 10.1186/1476-069X-6-33 PubMedCrossRefGoogle Scholar
  17. Gupta M, Mestan KK, Martin CR, Pearson C, Ortiz K, Fu L, Stubblefield P, Cerda S, Kasznica JM, Wang X (2007) Impact of clinical and histologic correlates of maternal and fetal inflammatory response on gestational age in preterm births. J Matern Fetal Neonatal Med 20:39–46PubMedCrossRefGoogle Scholar
  18. Hao K, Wang X, Niu T, Xu X, Li A, Chang W, Wang L, Li G, Laird N, Xu X (2004) A candidate gene association study on preterm delivery: application of high-throughput genotyping technology and advanced statistical methods. Hum Mol Genet 13:683–691PubMedCrossRefGoogle Scholar
  19. Hara S, Kamei D, Sasaki Y, Tanemoto A, Nakatani Y, Murakami M (2010) Prostaglandin E synthases: understanding their pathophysiological roles through mouse genetic models. Biochimie 92:651–659. doi: 10.1016/j.biochi.2010.02.007 PubMedCrossRefGoogle Scholar
  20. Horvath A, Koletzko B, Szajewska H (2007) Effect of supplementation of women in high-risk pregnancies with long-chain polyunsaturated fatty acids on pregnancy outcomes and growth measures at birth: a meta-analysis of randomized controlled trials. Br J Nutr 98:253–259PubMedCrossRefGoogle Scholar
  21. Jania LA, Chandrasekharan S, Backlund MG, Foley NA, Snouwaert J, Wang IM, Clark P, Audoly LP, Koller BH (2009) Microsomal prostaglandin E synthase-2 is not essential for in vivo prostaglandin E2 biosynthesis. Prostaglandins Other Lipid Mediat 88:73–81. doi: 10.1016/j.prostaglandins.2008.10.003 PubMedCrossRefGoogle Scholar
  22. Jones NM, Holzman C, Friderici KH, Jernigan K, Chung H, Wirth J, Fisher R (2010) Interplay of cytokine polymorphisms and bacterial vaginosis in the etiology of preterm delivery. J Reprod Immunol 87:82–89. doi: 10.1016/j.jri.2010.06.158 PubMedCrossRefGoogle Scholar
  23. Kesmodel U, Olsen SF, Salvig JD (1997) Marine n-3 fatty acid and calcium intake in relation to pregnancy induced hypertension, intrauterine growth retardation, and preterm delivery. A case–control study. Acta Obstet Gynecol Scand 76:38–44PubMedCrossRefGoogle Scholar
  24. King DC, Taylor J, Elnitski L, Chiaromonte F, Miller W, Hardison RC (2005) Evaluation of regulatory potential and conservation scores for detecting cis-regulatory modules in aligned mammalian genome sequences. Genome Res 15:1051–1060. doi: 10.1101/gr.3642605 PubMedCrossRefGoogle Scholar
  25. Li M, Li C, Guan W (2008) Evaluation of coverage variation of SNP chips for genome-wide association studies. Eur J Hum Genet 16:635–643PubMedCrossRefGoogle Scholar
  26. Li Y, Willer C, Sanna S, Abecasis G (2009) Genotype imputation. Annu Rev Genomics Hum Genet 10:387–406. doi: 10.1146/annurev.genom.9.081307.164242 PubMedCrossRefGoogle Scholar
  27. Li Y, Willer CJ, Ding J, Scheet P, Abecasis GR (2010) MaCH: using sequence and genotype data to estimate haplotypes and unobserved genotypes. Genet Epidemiol 34:816–834. doi: 10.1002/gepi.20533 Google Scholar
  28. Lindner I, Helwig U, Rubin D, Fischer A, Marten B, Schreiber S, Doring F, Schrezenmeir J (2007) Prostaglandin E synthase 2 (PTGES2) Arg298His polymorphism and parameters of the metabolic syndrome. Mol Nutr Food Res 51:1447–1451. doi: 10.1002/mnfr.200700144 PubMedCrossRefGoogle Scholar
  29. Lovejoy JC, Champagne CM, Smith SR, de Jonge L, Xie H (2001) Ethnic differences in dietary intakes, physical activity, and energy expenditure in middle-aged, premenopausal women: the Healthy Transitions Study. Am J Clin Nutr 74:90–95PubMedGoogle Scholar
  30. Macones GA, Parry S, Elkousy M, Clothier B, Ural SH, Strauss JF, 3rd (2004) 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 190:1504–1508 (discussion 3A)Google Scholar
  31. Makrides M, Duley L, Olsen SF (2006) Marine oil, and other prostaglandin precursor, supplementation for pregnancy uncomplicated by pre-eclampsia or intrauterine growth restriction. Cochrane Database Syst Rev 3:CD003402Google Scholar
  32. Martin JA, Osterman MJ, Sutton PD (2010) Are preterm births on the decline in the United States? Recent data from the National Vital Statistics System. NCHS Data Brief 39:1–8Google Scholar
  33. Merino DM, Ma DW, Mutch DM (2010) Genetic variation in lipid desaturases and its impact on the development of human disease. Lipids Health Dis 9:63. doi: 10.1186/1476-511X-9-63 PubMedCrossRefGoogle Scholar
  34. Murakami M, Kudo I (2004) Recent advances in molecular biology and physiology of the prostaglandin E2-biosynthetic pathway. Prog Lipid Res 43:3–35 pii: S0163782703000377PubMedCrossRefGoogle Scholar
  35. Nitz I, Fisher E, Grallert H, Li Y, Gieger C, Rubin D, Boeing H, Spranger J, Lindner I, Schreiber S, Rathmann W, Gohlke H, Doring A, Wichmann HE, Schrezenmeir J, Doring F, Illig T (2007) Association of prostaglandin E synthase 2 (PTGES2) Arg298His polymorphism with type 2 diabetes in two German study populations. J Clin Endocrinol Metab 92:3183–3188. doi: 10.1210/jc.2006-2550 PubMedCrossRefGoogle Scholar
  36. Nukui T, Day RD, Sims CS, Ness RB, Romkes M (2004) Maternal/newborn GSTT1 null genotype contributes to risk of preterm, low birthweight infants. Pharmacogenetics 14:569–576PubMedCrossRefGoogle Scholar
  37. Oken E, Kleinman KP, Olsen SF, Rich-Edwards JW, Gillman MW (2004) Associations of seafood and elongated n-3 fatty acid intake with fetal growth and length of gestation: results from a US pregnancy cohort. Am J Epidemiol 160:774–783. doi: 10.1093/aje/kwh282 PubMedCrossRefGoogle Scholar
  38. Olsen SF, Secher NJ (2002) Low consumption of seafood in early pregnancy as a risk factor for preterm delivery: prospective cohort study. BMJ 324:447PubMedCrossRefGoogle Scholar
  39. Olsen SF, Olsen J, Frische G (1990) Does fish consumption during pregnancy increase fetal growth? A study of the size of the newborn, placental weight and gestational age in relation to fish consumption during pregnancy. Int J Epidemiol 19:971–977PubMedCrossRefGoogle Scholar
  40. Olsen SF, Hansen HS, Sommer S, Jensen B, Sorensen TI, Secher NJ, Zachariassen P (1991) Gestational age in relation to marine n-3 fatty acids in maternal erythrocytes: a study of women in the Faroe Islands and Denmark. Am J Obstet Gynecol 164:1203–1209PubMedGoogle Scholar
  41. Olsen SF, Hansen HS, Secher NJ, Jensen B, Sandstrom B (1995) Gestation length and birth weight in relation to intake of marine n-3 fatty acids. Br J Nutr 73:397–404PubMedCrossRefGoogle Scholar
  42. Plunkett J, Muglia LJ (2008) Genetic contributions to preterm birth: implications from epidemiological and genetic association studies. Ann Med 40:167–195PubMedCrossRefGoogle Scholar
  43. Pontes PV, Torres AG, Trugo NM, Fonseca VM, Sichieri R (2006) n-6 and n-3 Long-chain polyunsaturated fatty acids in the erythrocyte membrane of Brazilian preterm and term neonates and their mothers at delivery. Prostaglandins Leukot Essent Fatty Acids 74:117–123PubMedCrossRefGoogle Scholar
  44. Reece MS, McGregor JA, Allen KG, Harris MA (1997) Maternal and perinatal long-chain fatty acids: possible roles in preterm birth. Am J Obstet Gynecol 176:907–914PubMedCrossRefGoogle Scholar
  45. Romero R, Velez Edwards DR, Kusanovic JP, Hassan SS, Mazaki-Tovi S, Vaisbuch E, Kim CJ, Chaiworapongsa T, Pearce BD, Friel LA, Bartlett J, Anant MK, Salisbury BA, Vovis GF, Lee MS, Gomez R, Behnke E, Oyarzun E, Tromp G, Williams SM, Menon R (2010) Identification of fetal and maternal single nucleotide polymorphisms in candidate genes that predispose to spontaneous preterm labor with intact membranes. Am J Obstet Gynecol 202:431e1–34. doi: 10.1016/j.ajog.2010.03.026 Google Scholar
  46. Schaid DJ, Rowland CM, Tines DE, Jacobson RM, Poland GA (2002) Score tests for association between traits and haplotypes when linkage phase is ambiguous. Am J Hum Genet 70:425–434PubMedCrossRefGoogle Scholar
  47. Suh YJ, Ha EH, Park H, Kim YJ, Kim H, Hong YC (2008) GSTM1 polymorphism along with PM10 exposure contributes to the risk of preterm delivery. Mutat Res 656:62–67. doi: 10.1016/j.mrgentox.2008.07.006 PubMedGoogle Scholar
  48. Szajewska H, Horvath A, Koletzko B (2006) Effect of n-3 long-chain polyunsaturated fatty acid supplementation of women with low-risk pregnancies on pregnancy outcomes and growth measures at birth: a meta-analysis of randomized controlled trials. Am J Clin Nutr 83:1337–1344PubMedGoogle Scholar
  49. Tsai HJ, Liu X, Mestan K, Yu Y, Zhang S, Fang Y, Pearson C, Ortiz K, Zuckerman B, Bauchner H, Cerda S, Stubblefield PG, Xu X, Wang X (2008) Maternal cigarette smoking, metabolic gene polymorphisms, and preterm delivery: new insights on G × E interactions and pathogenic pathways. Hum Genet 123:359–369PubMedCrossRefGoogle Scholar
  50. Wang X, Zuckerman B, Pearson C, Kaufman G, Chen C, Wang G, Niu T, Wise PH, Bauchner H, Xu X (2002) Maternal cigarette smoking, metabolic gene polymorphism, and infant birth weight. JAMA 287:195–202PubMedCrossRefGoogle Scholar
  51. Yashodhara BM, Umakanth S, Pappachan JM, Bhat SK, Kamath R, Choo BH (2009) Omega-3 fatty acids: a comprehensive review of their role in health and disease. Postgrad Med J 85:84–90PubMedCrossRefGoogle Scholar
  52. Yeo GW, Coufal NG, Liang TY, Peng GE, Fu XD, Gage FH (2009) An RNA code for the FOX2 splicing regulator revealed by mapping RNA–protein interactions in stem cells. Nat Struct Mol Biol 16:130–137. doi: 10.1038/nsmb.1545 PubMedCrossRefGoogle Scholar
  53. Yu K, Li Q, Bergen AW, Pfeiffer RM, Rosenberg PS, Caporaso N, Kraft P, Chatterjee N (2009a) Pathway analysis by adaptive combination of P-values. Genet Epidemiol 33:700–709. doi: 10.1002/gepi.20422 PubMedCrossRefGoogle Scholar
  54. Yu Y, Tsai HJ, Liu X, Mestan K, Zhang S, Pearson C, Ortiz K, Xu X, Zuckerman B, Wang X (2009b) The joint association between F5 gene polymorphisms and maternal smoking during pregnancy on preterm delivery. Hum Genet 124:659–668PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Xin Liu
    • 1
  • Guoying Wang
    • 1
  • Xiumei Hong
    • 1
  • Hui-Ju Tsai
    • 1
    • 2
  • Rong Liu
    • 1
  • Shanchun Zhang
    • 1
    • 3
  • Hongjian Wang
    • 1
  • Colleen Pearson
    • 4
  • Katherin Ortiz
    • 4
  • Deli Wang
    • 5
  • Emmet Hirsch
    • 6
    • 7
  • Barry Zuckerman
    • 4
  • Xiaobin Wang
    • 1
  1. 1.Mary Ann and J. Milburn Smith Child Health Research Program, Children’s Memorial Hospital, Children’s Memorial Research Center, Department of Pediatrics, Feinberg School of Medicine Northwestern UniversityChicagoUSA
  2. 2.Division of Biostatistics and BioinformaticsInstitute of Population Health Sciences, National Health Research InstitutesZhunanTaiwan
  3. 3.Department of Epidemiology and Health Statistics, School of MedicineZhejiang UniversityHangzhouChina
  4. 4.Department of Pediatrics, Boston Medical CenterBoston University School of Medicine BostonUSA
  5. 5.Biostatistics Research Core, Children’s Memorial Research CenterFeinberg School of Medicine, Northwestern UniversityChicagoUSA
  6. 6.Department of Obstetrics and GynecologyNorthShore University HealthSystemEvanstonUSA
  7. 7.Department of Obstetrics and Gynecology, Pritzker School of MedicineUniversity of ChicagoChicagoUSA

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