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

Study question: What is the genetic basis of preeclampsia in Andean families residing at high altitudes? Summary answer: A 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 already: Preeclampsia, 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, duration: To 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, methods: We 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 chance: A 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<6x10-6) 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 caution: Our 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 findings: These 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.