A functional mechanism for a non-coding variant near AGTR2 associated with risk for preterm birth

Author:

Wang LiORCID,Rossi Robert M.,Chen Xiaoting,Chen Jing,Runyon Jilian,Chawla Mehak,Miller Daniel,Forney Carmy,Lynch Arthur,Zhang Xuzhe,Kong Fansheng,Jacobsson Bo,Kottyan Leah C.,Weirauch Matthew T.,Zhang Ge,Muglia Louis J.

Abstract

Abstract Background Preterm birth (PTB), defined as delivery before 37 gestational weeks, imposes significant public health burdens. A recent maternal genome-wide association study of spontaneous PTB identified a noncoding locus near the angiotensin II receptor type 2 (AGTR2) gene. Genotype-Tissue Expression data revealed that alleles associated with decreased AGTR2 expression in the uterus were linked to an increased risk of PTB and shortened gestational duration. We hypothesized that a causative variant in this locus modifies AGTR2 expression by altering transcription factor (TF) binding. Methods To investigate this hypothesis, we performed bioinformatics analyses and functional characterizations at the implicated locus. Potential causal single nucleotide polymorphisms (SNPs) were prioritized, and allele-dependent binding of TFs was predicted. Reporter assays were employed to assess the enhancer activity of the top PTB-associated non-coding variant, rs7889204, and its impact on TF binding. Results Our analyses revealed that rs7889204, a top PTB-associated non-coding genetic variant is one of the strongest eQTLs for the AGTR2 gene in uterine tissue samples. We observed differential binding of CEBPB (CCAAT enhancer binding protein beta) and HOXA10 (homeobox A10) to the alleles of rs7889204. Reporter assays demonstrated decreased enhancer activity for the rs7889204 risk “C” allele. Conclusion Collectively, these results demonstrate that decreased AGTR2 expression caused by reduced transcription factor binding increases the risk for PTB and suggest that enhancing AGTR2 activity may be a preventative measure in reducing PTB risk.

Funder

March of Dimes Prematurity Research Center Ohio Collaborative

Bill and Melinda Gates Foundation

NIH/NICHD

NIH

Burroughs Wellcome Fund

Cincinnati Children's Hospital Medical Center

Publisher

Springer Science and Business Media LLC

Subject

General Medicine

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