Download PDF
Am J Perinatol 2017; 34(11): 1041-1047
DOI: 10.1055/s-0037-1603508
Original Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Evolutionary Triangulation to Refine Genetic Association Studies of Spontaneous Preterm Birth

Tracy A. Manuck
1   Department of Obstetrics & Gynecology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
,
Minjun Huang
2   Department of Molecular and Systems Biology, Dartmouth College, Hanover, New Hampshire
,
Louis Muglia
3   Department of Pediatrics, Cincinnati Children's Hospital, Cincinnati, Ohio
,
Scott M. Williams
4   Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio
› Author Affiliations
Further Information

Publication History

19 April 2017

20 April 2017

Publication Date:
22 May 2017 (online)

    Permissions and Reprints

Abstract

Objective The objective of this study was to apply evolutionary triangulation, a novel technique exploiting evolutionary differentiation among three populations with variable disease prevalence, to spontaneous preterm birth (PTB) genetic association studies.

Study Design Single nucleotide polymorphism (SNP) allele frequency data were obtained from HapMap for CEU, GIH/MEX, and YRI/ASW populations. Evolutionary triangulation SNPs, then genes, were selected according to the overlaps of genetic population differences (CEU = outlier). Evolutionary triangulation genes were then compared with three PTB gene lists: (1) top maternal and fetal genes from a large genome-wide association study of PTB, (2) 640 genes from the database for PTB, and (3) 118 genes from a recent systematic review. Empirical p-values were calculated to determine whether evolutionary triangulation enriched for putative PTB associating genes compared with randomly selected sample genes.

Results Evolutionary triangulation identified 5/17 maternal genes and 8/16 fetal genes from PTB gene list 1. From list 2, 79/640 were identified by CEU_GIH_YRI evolutionary triangulation, and 57/640 were identified by CEU_ASW_MEX evolutionary triangulation. Finally, 20/118 genes were identified by evolutionary triangulation from gene list 3. For all analyses, p < 0.001 except CEU_ASW_MEX analysis of list 3 where p = 0.002.

Conclusion Genes identified in prior PTB association studies confirmed by evolutionary triangulation should be prioritized for further genetic prematurity research.

Keywords

preterm birth - evolutionary triangulation - genetic - susceptibility - racial disparity

Condensation

Evolutionary triangulation, a novel bioinformatics approach, provides independent support for multiple genes previously associated with PTB and presents an alternate filtering metric for genetic analyses using evolutionary history.


Note

This study was presented in part at the Society for Maternal Fetal Medicine's 37th Annual Meeting 2017 (Las Vegas, NV), as an oral concurrent presentation (1/26/17), final abstract ID #11.


 

  • References

  • 1 Smid MC, Stringer EM, Stringer JS. A worldwide epidemic: the problem and challenges of preterm birth in low- and middle-income countries. Am J Perinatol 2016; 33 (03) 276-289
    Article in Thieme ConnectPubMedGoogle Scholar
  • 2 Russell RB, Green NS, Steiner CA. , et al. Cost of hospitalization for preterm and low birth weight infants in the United States. Pediatrics 2007; 120 (01) e1-e9
    CrossrefPubMedGoogle Scholar
  • 3 Hamilton BE, Martin JA, Osterman MJ, Curtin SC, Matthews TJ. Births: final data for 2014. Natl Vital Stat Rep 2015; 64 (12) 1-64
    PubMedGoogle Scholar
  • 4 DeFranco EA, Hall ES, Muglia LJ. Racial disparity in previable birth. Am J Obstet Gynecol 2016; 214 (03) 394.e1-394.e7
    CrossrefPubMedGoogle Scholar
  • 5 Huang M, Graham BE, Zhang G. , et al. Evolutionary triangulation: informing genetic association studies with evolutionary evidence. BioData Min 2016; 9: 12 . Doi: 10.1186/s13040-016-0091-7
    CrossrefPubMedGoogle Scholar
  • 6 Zhang W, Ng HW, Shu M. , et al. Comparing genetic variants detected in the 1000 genomes project with SNPs determined by the International HapMap Consortium. J Genet 2015; 94 (04) 731-740
    CrossrefPubMedGoogle Scholar
  • 7 International HapMap Consortium. The International HapMap Project. Nature 2003; 426 (6968): 789-796
    CrossrefPubMedGoogle Scholar
  • 8 Wang C, Zhan X, Bragg-Gresham J. , et al; FUSION Study. Ancestry estimation and control of population stratification for sequence-based association studies. Nat Genet 2014; 46 (04) 409-415
    CrossrefPubMedGoogle Scholar
  • 9 Altshuler DM, Gibbs RA, Peltonen L. , et al; International HapMap 3 Consortium. Integrating common and rare genetic variation in diverse human populations. Nature 2010; 467 (7311): 52-58
    CrossrefPubMedGoogle Scholar
  • 10 Bhatia G, Patterson N, Sankararaman S, Price AL. Estimating and interpreting FST: the impact of rare variants. Genome Res 2013; 23 (09) 1514-1521
    CrossrefPubMedGoogle Scholar
  • 11 Elhaik E. Empirical distributions of F(ST) from large-scale human polymorphism data. PLoS One 2012; 7 (11) e49837 . Doi: 10.1371/journal.pone.0049837
    CrossrefPubMedGoogle Scholar
  • 12 Cockerham CC, Weir BS. Covariances of relatives stemming from a population undergoing mixed self and random mating. Biometrics 1984; 40 (01) 157-164
    CrossrefPubMedGoogle Scholar
  • 13 Zhang H, Baldwin DA, Bukowski RK. , et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Genomic and Proteomic Network for Preterm Birth Research (GPN-PBR). A genome-wide association study of early spontaneous preterm delivery. Genet Epidemiol 2015; 39 (03) 217-226
    CrossrefPubMedGoogle Scholar
  • 14 Uzun A, Laliberte A, Parker J. , et al. dbPTB: a database for preterm birth. Database (Oxford) 2012; 2012: bar069 . Doi: 10.1093/database/bar069
    PubMedGoogle Scholar
  • 15 Uzun A, Sharma S, Padbury J. A bioinformatics approach to preterm birth. Am J Reprod Immunol 2012; 67 (04) 273-277
    CrossrefPubMedGoogle Scholar
  • 16 Sheikh IA, Ahmad E, Jamal MS. , et al. Spontaneous preterm birth and single nucleotide gene polymorphisms: a recent update. BMC Genomics 2016; 17 (Suppl. 09) 759 . Doi: 10.1186/s12864-016-3089-0
    CrossrefPubMedGoogle Scholar
  • 17 Szklarczyk D, Franceschini A, Wyder S. , et al. STRING v10: protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res 2015; 43 (Database issue): D447-D452
    CrossrefPubMedGoogle Scholar
  • 18 Menon R, Fortunato SJ. Infection and the role of inflammation in preterm premature rupture of the membranes. Best Pract Res Clin Obstet Gynaecol 2007; 21 (03) 467-478
    CrossrefPubMedGoogle Scholar
  • 19 Wu W, Clark EA, Stoddard GJ. , et al. Effect of interleukin-6 polymorphism on risk of preterm birth within population strata: a meta-analysis. BMC Genet 2013; 14: 30 . Doi: 10.1186/1471-2156-14-30
    PubMedGoogle Scholar
  • 20 Nguyen DP, Genc M, Vardhana S, Babula O, Onderdonk A, Witkin SS. Ethnic differences of polymorphisms in cytokine and innate immune system genes in pregnant women. Obstet Gynecol 2004; 104 (02) 293-300
    CrossrefPubMedGoogle Scholar
  • 21 Jaffe S, Normand N, Jayaram A. , et al. Unique variation in genetic selection among black North American women and its potential influence on pregnancy outcome. Med Hypotheses 2013; 81 (05) 919-922
    CrossrefPubMedGoogle Scholar
  • 22 Fettweis JM, Brooks JP, Serrano MG. , et al; Vaginal Microbiome Consortium. Differences in vaginal microbiome in African American women versus women of European ancestry. Microbiology 2014; 160 (Pt 10): 2272-2282
    CrossrefPubMedGoogle Scholar
  • 23 Menon R, Dunlop AL, Kramer MR, Fortunato SJ, Hogue CJ. An overview of racial disparities in preterm birth rates: caused by infection or inflammatory response?. Acta Obstet Gynecol Scand 2011; 90 (12) 1325-1331
    CrossrefPubMedGoogle Scholar
  • 24 Plunkett J, Doniger S, Orabona G. , et al. An evolutionary genomic approach to identify genes involved in human birth timing. PLoS Genet 2011; 7 (04) e1001365 . Doi: 10.1371/journal.pgen.1001365
    CrossrefPubMedGoogle Scholar
  • 25 Enquobahrie DA, Williams MA, Qiu C. , et al. Early pregnancy peripheral blood gene expression and risk of preterm delivery: a nested case control study. BMC Pregnancy Childbirth 2009; 9: 56 . Doi: 10.1186/1471-2393-9-56
    CrossrefPubMedGoogle Scholar
  • 26 Lyttle B, Chai J, Gonzalez JM, Xu H, Sammel M, Elovitz MA. The negative regulators of the host immune response: an unexplored pathway in preterm birth. Am J Obstet Gynecol 2009; 201 (03) 284.e1-284.e7
    CrossrefPubMedGoogle Scholar
  • 27 Buxton IL, Singer CA, Tichenor JN. Expression of stretch-activated two-pore potassium channels in human myometrium in pregnancy and labor. PLoS One 2010; 5 (08) e12372 . Doi: 10.1371/journal.pone.0012372
    CrossrefPubMedGoogle Scholar
  • 28 Andraweera PH, Dekker GA, Thompson SD, North RA, McCowan LM, Roberts CT. ; SCOPE Consortium. The interaction between the maternal BMI and angiogenic gene polymorphisms associates with the risk of spontaneous preterm birth. Mol Hum Reprod 2012; 18 (09) 459-465
    CrossrefPubMedGoogle Scholar
  • 29 Andraweera PH, Dekker GA, Laurence JA, Roberts CT. Placental expression of VEGF family mRNA in adverse pregnancy outcomes. Placenta 2012; 33 (06) 467-472
    CrossrefPubMedGoogle Scholar
  • 30 Yoshie M, Tamura K, Hara T, Kogo H. Expression of stathmin family genes in the murine uterus during early pregnancy. Mol Reprod Dev 2006; 73 (02) 164-172
    CrossrefPubMedGoogle Scholar
  • 31 Wu X, Blanck A, Norstedt G, Sahlin L, Flores-Morales A. Identification of genes with higher expression in human uterine leiomyomas than in the corresponding myometrium. Mol Hum Reprod 2002; 8 (03) 246-254
    CrossrefPubMedGoogle Scholar
  • 32 Gargano JW, Holzman CB, Senagore PK. , et al. Polymorphisms in thrombophilia and renin-angiotensin system pathways, preterm delivery, and evidence of placental hemorrhage. Am J Obstet Gynecol 2009; 201 (03) 317.e1-317.e9
    CrossrefPubMedGoogle Scholar
  • 33 Yong HE, Murthi P, Borg A. , et al. Increased decidual mRNA expression levels of candidate maternal pre-eclampsia susceptibility genes are associated with clinical severity. Placenta 2014; 35 (02) 117-124
    CrossrefPubMedGoogle Scholar
  • 34 Haas DM, Lai D, Sharma S. , et al. Steroid pathway genes and neonatal respiratory distress after betamethasone use in anticipated preterm birth. Reprod Sci 2016; 23 (05) 680-686
    CrossrefPubMedGoogle Scholar
  • 35 Luo YJ, Wen XZ, Ding P. , et al. Interaction between maternal passive smoking during pregnancy and CYP1A1 and GSTs polymorphisms on spontaneous preterm delivery. PLoS One 2012; 7 (11) e49155 . Doi: 10.1371/journal.pone.0049155
    CrossrefPubMedGoogle Scholar
  • 36 Frey HA, Stout MJ, Pearson LN. , et al. Genetic variation associated with preterm birth in African-American women. Am J Obstet Gynecol 2016; 215 (02) 235.e1-235.e8
    CrossrefPubMedGoogle Scholar
  • 37 Chun S, Plunkett J, Teramo K, Muglia LJ, Fay JC. Fine-mapping an association of FSHR with preterm birth in a Finnish population. PLoS One 2013; 8 (10) e78032 . Doi: 10.1371/journal.pone.0078032
    CrossrefPubMedGoogle Scholar
  • 38 Suh YJ, Kim YJ, Park H, Park EA, Ha EH. Oxidative stress-related gene interactions with preterm delivery in Korean women. Am J Obstet Gynecol 2008; 198 (05) 541.e1-541.e7
    CrossrefPubMedGoogle Scholar
  • 39 Suh YJ, Ha EH, Park H, Kim YJ, Kim H, Hong YC. GSTM1 polymorphism along with PM10 exposure contributes to the risk of preterm delivery. Mutat Res 2008; 656 (1-2): 62-67
    CrossrefPubMedGoogle Scholar
  • 40 Gibson CS, MacLennan AH, Dekker GA. , et al. Genetic polymorphisms and spontaneous preterm birth. Obstet Gynecol 2007; 109 (2 Pt 1): 384-391
    CrossrefPubMedGoogle Scholar
  • 41 Langmia IM, Apalasamy YD, Omar SZ, Mohamed Z. Interleukin 1 receptor type 2 gene polymorphism is associated with reduced risk of preterm birth. J Matern Fetal Neonatal Med 2016; 29 (20) 3347-3350
    PubMedGoogle Scholar
  • 42 Chaemsaithong P, Romero R, Docheva N. , et al. Comparison of rapid MMP-8 and interleukin-6 point-of-care tests to identify intra-amniotic inflammation/infection and impending preterm delivery in patients with preterm labor and intact membranes. J Matern Fetal Neonatal Med 2017; DOI: 10.1080/14767058.2017.1281904.
    PubMedGoogle Scholar
  • 43 Sundtoft I, Uldbjerg N, Steffensen R, Sommer S, Christiansen OB. Polymorphisms in genes coding for cytokines, mannose-binding lectin, collagen metabolism and thrombophilia in women with cervical insufficiency. Gynecol Obstet Invest 2016; 81 (01) 15-22
    CrossrefPubMedGoogle Scholar
  • 44 Zhong X, Jiang YZ, Liu P. , et al. Toll-like 4 receptor /NFκB inflammatory/miR-146a pathway contributes to the ART-correlated preterm birth outcome. Oncotarget 2016; 7 (45) 72475-72485
    CrossrefPubMedGoogle Scholar
  • 45 Sundrani DP, Reddy US, Joshi AA. , et al. Differential placental methylation and expression of VEGF, FLT-1 and KDR genes in human term and preterm preeclampsia. Clin Epigenetics 2013; 5 (01) 6 . Doi: 10.1186/1868-7083-5-6
    CrossrefPubMedGoogle Scholar
  • 46 Grisaru-Granovsky S, Altarescu G, Finci S. , et al. Prostanoid DP receptor (PTGDR) variants in mothers with post-coital associated preterm births: preliminary observations. J Perinatol 2010; 30 (01) 33-37
    CrossrefPubMedGoogle Scholar
  • 47 Day LJ, Schaa KL, Ryckman KK. , et al. Single-nucleotide polymorphisms in the KCNN3 gene associate with preterm birth. Reprod Sci 2011; 18 (03) 286-295
    CrossrefPubMedGoogle Scholar
  • 48 Mann PC, Cooper ME, Ryckman KK. , et al. Polymorphisms in the fetal progesterone receptor and a calcium-activated potassium channel isoform are associated with preterm birth in an Argentinian population. J Perinatol 2013; 33 (05) 336-340
    CrossrefPubMedGoogle Scholar
  • 49 Abrahams VM, Potter JA, Bhat G, Peltier MR, Saade G, Menon R. Bacterial modulation of human fetal membrane Toll-like receptor expression. Am J Reprod Immunol 2013; 69 (01) 33-40
    CrossrefPubMedGoogle Scholar