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

BMC Medicine

Research Article

Carmy Forney¹  Mehak Chawla¹  Arthur Lynch¹  Daniel Miller¹  Leah C. Kottyan²  Matthew T. Weirauch³  Xuzhe Zhang⁴  Fansheng Kong⁴  Robert M. Rossi⁵  Louis J. Muglia⁶  Li Wang⁷  Bo Jacobsson⁸  Jing Chen⁹  Jilian Runyon^1,10  Ge Zhang^1,11  Xiaoting Chen^1,12 

[1] Center for Autoimmune Genomics and Etiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA;Center for Autoimmune Genomics and Etiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA;Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA;Center for Autoimmune Genomics and Etiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA;Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA;Divisions of Biomedical Informatics and Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA;Center for Prevention of Preterm Birth, Perinatal Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA;Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA;March of Dimes Prematurity Research Center Ohio Collaborative, Cincinnati, OH, USA;Center for Prevention of Preterm Birth, Perinatal Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA;Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA;March of Dimes Prematurity Research Center Ohio Collaborative, Cincinnati, OH, USA;Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA;Center for Prevention of Preterm Birth, Perinatal Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA;Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA;March of Dimes Prematurity Research Center Ohio Collaborative, Cincinnati, OH, USA;Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA;Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA;Center for Prevention of Preterm Birth, Perinatal Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA;Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA;March of Dimes Prematurity Research Center Ohio Collaborative, Cincinnati, OH, USA;Present Address: Department of Biology, Xavier University, Cincinnati, OH, USA;Department of Obstetrics and Gynecology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden;Department of Obstetrics and Gynecology, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden;Department of Genetics and Bioinformatics, Domain of Health Data and Digitalisation, Institute of Public Health, Oslo, Norway;Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA;Divisions of Biomedical Informatics and Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA;Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA;Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA;March of Dimes Prematurity Research Center Ohio Collaborative, Cincinnati, OH, USA;Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA;Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA;March of Dimes Prematurity Research Center Ohio Collaborative, Cincinnati, OH, USA;Center for Autoimmune Genomics and Etiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA;

关键词: Functional studies;    Preterm birth;    Non-coding variant;    AGTR2;   

DOI  :  10.1186/s12916-023-02973-w

 received in 2022-12-15, accepted in 2023-07-05,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundPreterm 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.MethodsTo 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.ResultsOur 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.ConclusionCollectively, 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.

【 授权许可】

CC BY   
© The Author(s) 2023

【 图 表 】

Fig. 2

Fig. 2

Fig. 9

Fig. 6

12888_2023_4994_Article_IEq1.gif

41116_2023_38_Article_IEq190.gif

41116_2023_38_Article_IEq341.gif

41116_2023_38_Article_IEq335.gif