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An Ancient Fecundability-Associated Polymorphism Switches a Repressor into an Enhancer of Endometrial TAP2 Expression.

ABSTRACT: Variation in female reproductive traits, such as fertility, fecundity, and fecundability, is heritable in humans, but identifying and functionally characterizing genetic variants associated with these traits has been challenging. Here, we explore the functional significance and evolutionary history of a T/C polymorphism of SNP rs2071473, which we have previously shown is an eQTL for TAP2 and significantly associated with fecundability (time to pregnancy). We replicated the association between the rs2071473 genotype and TAP2 expression by using GTEx data and demonstrated that TAP2 is expressed by decidual stromal cells at the maternal-fetal interface. Next, we showed that rs2071473 is located within a progesterone-responsive cis-regulatory element that functions as a repressor with the T allele and an enhancer with the C allele. Remarkably, we found that this polymorphism arose before the divergence of modern and archaic humans, segregates at intermediate to high frequencies across human populations, and has genetic signatures of long-term balancing selection. This variant has also previously been identified in genome-wide association studies of immune-related disease, suggesting that both alleles are maintained as a result of antagonistic pleiotropy.

SUBMITTER: Mika KM

PROVIDER: S-EPMC5097936 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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An Ancient Fecundability-Associated Polymorphism Switches a Repressor into an Enhancer of Endometrial TAP2 Expression.

Mika Katelyn M KM Lynch Vincent J VJ

American journal of human genetics 20161013 5

Variation in female reproductive traits, such as fertility, fecundity, and fecundability, is heritable in humans, but identifying and functionally characterizing genetic variants associated with these traits has been challenging. Here, we explore the functional significance and evolutionary history of a T/C polymorphism of SNP rs2071473, which we have previously shown is an eQTL for TAP2 and significantly associated with fecundability (time to pregnancy). We replicated the association between th ...[more]

PMID: 27745831

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Project description:BACKGROUND:Peroxisome proliferator-activated receptor gamma (PPAR?) is a major regulator in sepsis. Our previous study identified the enhancer polymorphism rs10865710C/G to be associated with susceptibility to sepsis in trauma patients. We performed two-stage cohort studies integrating biological experiments of potential functional variants that modify susceptibility to traumatic sepsis. METHODS:Improved multiplex ligation detection reaction (iMLDR) was used to genotype rs10865710 in 797 Han Chinese trauma patients in Chongqing. Clinical relevance was validated in 334 patients in Guizhou. The potential function of rs10865710 in transcriptional regulation was explored through a dual luciferase reporter assay and electrophoretic mobility shift assay (EMSA). Expression of PPAR? was assessed by expression quantitative trait locus (e-QTL) and western blot analyses. RESULTS:The association results confirmed rs10865710 to be significantly strongly associated with sepsis risk in trauma patients of the Chongqing and Guizhou cohorts (OR?=?1.41 (1.11-1.79), P?=?0.004 and OR?=?1.45 (1.01-2.09), P?=?0.046, both for allele-dose effect, respectively). A meta-analysis of both cohorts and a previous study indicated strong evidence for this association (OR?=?1.41 (1.17-1.71), P?=?0.0004 for the dominant model, OR?=?1.78 (1.34-2.36), P?<?0.0001 for the recessive model and OR?=?1.38 (1.20-1.58), P?<?0.0001 for the allelic model). Functional experiments verified that rs10865710 was a causative variant influencing enhancer activity (G vs. C, 0.068?±?0.004 vs. 0.096?±?0.002, P?=?0.0005) and CREB2 binding. Expression analysis also indicatevd rs10865710 genotypes to be associated with levels of PPAR? expression (P?=?9.2?×?10-5 for dominant effect and P?=?0.005 for recessive effect). CONCLUSIONS:Our study provides evidence that the enhancer-region polymorphism rs10865710 might influence transcription factor binding and regulate PPAR? expression, thus conferring susceptibility to traumatic sepsis. TRIAL REGISTRATION:ClinicalTrials.gov, NCT01713205. Registered 18 October 2012, retrospectively registered.

Dataset Information

An Ancient Fecundability-Associated Polymorphism Switches a Repressor into an Enhancer of Endometrial TAP2 Expression.

Publications

An Ancient Fecundability-Associated Polymorphism Switches a Repressor into an Enhancer of Endometrial TAP2 Expression.

Similar Datasets

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