Clotting factor genes are associated with preeclampsia in high altitude pregnant women in the Peruvian Andes

Abstract

AbstractStudy questionWhat is the genetic basis of preeclampsia in Andean families residing at high altitudes?Summary answerA top candidate region associated with preeclampsia containing clotting factor genes PROZ, F7 and F10 was found on chromosome 13 of the fetal genome in affected Andean families.What is known alreadyPreeclampsia, a multi-organ complication of pregnancy, is a leading cause of maternal morbidity and mortality worldwide. Diagnosed by the onset of maternal hypertension and proteinuria after 20 weeks of gestation, this disorder is a common cause of preterm delivery and affects approximately 5-7% of global pregnancies. The heterogeneity of preeclampsia has posed a challenge in understanding its etiology and molecular basis. However, risk for the condition is known to increase in high altitude regions such as the Peruvian Andes.Study design, size, durationTo investigate the genetic basis of preeclampsia in a high-altitude resident population, we characterized genetic diversity in a cohort of Andean families (N=883) from Puno, Peru, a high-altitude city above 3,500 meters. Our study collected DNA samples and medical records from case-control trios and duos between 2011-2016, thus allowing for measurement of maternal, paternal, and fetal genetic factors influencing preeclampsia risk.Participants/materials, setting, methodsWe generated high-density genotype data for 439,314 positions across the genome, determined ancestry patterns and mapped associations between genetic variants and preeclampsia phenotype. We also conducted fine mapping of potential causal variants in a subset of family participants and tested ProZ protein levels in post-partum maternal and cord blood plasma by ELISA.Main results and the role of chanceA transmission disequilibrium test (TDT) revealed variants near genes of biological importance in pregnancy physiology for placental and blood vessel function. The most significant SNP in this cluster, rs5960 (p<6×10−6) is a synonymous variant in the clotting factor F10. Two other members of the coagulation cascade, F7 and PROZ, are also in the top associated region. However, we detected no difference of PROZ levels in maternal or umbilical cord plasma.Limitations, reasons for cautionOur genome-wide association analysis (GWAS) was limited by a small sample size and lack of functional follow up. Our ELISA was limited to post-natal blood sampling (only samples collected immediately after birth). But, despite a small sample size, our family based GWAS design permits identification of novel significant and suggestive associations with preeclampsia. Further longitudinal studies could analyze clotting factor levels and activity in other pregnant cohorts in Peru to assess the impact of thrombosis in preeclampsia risk among Andean highlanders.Wider implications of the findingsThese findings support previous evidence suggesting that coagulation plays an important role in the pathology of preeclampsia and potentially underlies susceptibility to other pregnancy disorders exacerbated at high altitudes. This discovery of a novel association related to a functional pathway relevant to pregnancy biology in an understudied population of Native American origin demonstrates the increased power of family-based study design and underscores the importance of conducting genetic research in diverse populations.Study funding/competing interest(s)This work was supported in part by the National Science Foundation (NSF) Graduate Research Fellowship Program Grant No. DGE–1147470 awarded to K.M.B.R. (fellow no. 2014187481); NSF SBE Postdoctoral Research Fellowship Award No. 1711982 awarded to M.N.C.; an A.P. Giannini Foundation postdoctoral fellowship, a Stanford Child Health Research Institute postdoctoral award, and a Stanford Dean’s Postdoctoral Fellowship awarded to E.T.Z.; the Chan Zuckerberg Biohub Investigator Award to C.D.B; a Burroughs Welcome Prematurity Initiative Award to J.C.B.; the George Rosenkranz Prize for Health Care Research in Developing Countries, and the International Center for Genetic Engineering and Biotechnology (ICGEB, Italy) grant CRP/ MEX15-04_EC, and Mexico’s CONACYT grant FONCICYT/50/2016, each awarded to A.M.E. Further funding was provided by the Sandler Family Foundation, the American Asthma Foundation, the RWJF Amos Medical Faculty Development Program, Harry Wm. and Diana V. Hind Distinguished Professor in Pharmaceutical Sciences II, National Institutes of Health, National Heart, Lung, and Blood Institute Awards R01HL117004, R01HL128439, R01HL135156, R01HL141992, National Institute of Health and Environmental Health Sciences Awards R01ES015794, R21ES24844, the National Institute on Minority Health and Health Disparities Awards R01MD010443, and R56MD013312, and the National Human Genome Research Institute Award U01HG009080, each awarded to E.G.B. Author J.W.C. is currently a full-time employee at Genentech, Inc. and hold stocks in Roche Holding AG. Author E.G.B. reports grants from the National Institute of Health, Lung, Blood Institute, the National Institute of Health, General Medical Sciences, the National Institute on Minority Health and Health Disparities, the Tobacco-Related Disease Research Program, the Food and Drug Administration, and the Sandler Family Foundation, during the conduct of the study.Trial registration numberN/A*for MESH terms see PubMed at http://www.ncbi.nlm.nih.gov/pubmed/