A functional mechanism for a non-coding variant near AGTR2 associated with risk for preterm birth
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 E...
| Main Authors: | , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2023-07-01
|
| Series: | BMC Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12916-023-02973-w |
| _version_ | 1797774176956710912 |
|---|---|
| author | Li Wang Robert M. Rossi Xiaoting Chen Jing Chen Jilian Runyon Mehak Chawla Daniel Miller Carmy Forney Arthur Lynch Xuzhe Zhang Fansheng Kong Bo Jacobsson Leah C. Kottyan Matthew T. Weirauch Ge Zhang Louis J. Muglia |
| author_facet | Li Wang Robert M. Rossi Xiaoting Chen Jing Chen Jilian Runyon Mehak Chawla Daniel Miller Carmy Forney Arthur Lynch Xuzhe Zhang Fansheng Kong Bo Jacobsson Leah C. Kottyan Matthew T. Weirauch Ge Zhang Louis J. Muglia |
| author_sort | Li Wang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-12T22:17:12Z |
| format | Article |
| id | doaj.art-be5cdb1ceca847a8807404f5cbf105e9 |
| institution | Directory Open Access Journal |
| issn | 1741-7015 |
| language | English |
| last_indexed | 2024-03-12T22:17:12Z |
| publishDate | 2023-07-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Medicine |
| spelling | doaj.art-be5cdb1ceca847a8807404f5cbf105e92023-07-23T11:16:45ZengBMCBMC Medicine1741-70152023-07-0121111210.1186/s12916-023-02973-wA functional mechanism for a non-coding variant near AGTR2 associated with risk for preterm birthLi Wang0Robert M. Rossi1Xiaoting Chen2Jing Chen3Jilian Runyon4Mehak Chawla5Daniel Miller6Carmy Forney7Arthur Lynch8Xuzhe Zhang9Fansheng Kong10Bo Jacobsson11Leah C. Kottyan12Matthew T. Weirauch13Ge Zhang14Louis J. Muglia15Center for Prevention of Preterm Birth, Perinatal Institute, Cincinnati Children’s Hospital Medical CenterCenter for Prevention of Preterm Birth, Perinatal Institute, Cincinnati Children’s Hospital Medical CenterMarch of Dimes Prematurity Research Center Ohio CollaborativeDepartment of Pediatrics, University of Cincinnati College of MedicineDivision of Human Genetics, Cincinnati Children’s Hospital Medical CenterCenter for Autoimmune Genomics and Etiology, Cincinnati Children’s Hospital Medical CenterCenter for Autoimmune Genomics and Etiology, Cincinnati Children’s Hospital Medical CenterCenter for Autoimmune Genomics and Etiology, Cincinnati Children’s Hospital Medical CenterCenter for Autoimmune Genomics and Etiology, Cincinnati Children’s Hospital Medical CenterCenter for Prevention of Preterm Birth, Perinatal Institute, Cincinnati Children’s Hospital Medical CenterCenter for Prevention of Preterm Birth, Perinatal Institute, Cincinnati Children’s Hospital Medical CenterDepartment of Obstetrics and Gynecology, Institute of Clinical Sciences, Sahlgrenska Academy, University of GothenburgCenter for Autoimmune Genomics and Etiology, Cincinnati Children’s Hospital Medical CenterCenter for Autoimmune Genomics and Etiology, Cincinnati Children’s Hospital Medical CenterDivision of Human Genetics, Cincinnati Children’s Hospital Medical CenterCenter for Prevention of Preterm Birth, Perinatal Institute, Cincinnati Children’s Hospital Medical CenterAbstract 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.https://doi.org/10.1186/s12916-023-02973-wFunctional studiesPreterm birthNon-coding variantAGTR2 |
| spellingShingle | Li Wang Robert M. Rossi Xiaoting Chen Jing Chen Jilian Runyon Mehak Chawla Daniel Miller Carmy Forney Arthur Lynch Xuzhe Zhang Fansheng Kong Bo Jacobsson Leah C. Kottyan Matthew T. Weirauch Ge Zhang Louis J. Muglia A functional mechanism for a non-coding variant near AGTR2 associated with risk for preterm birth BMC Medicine Functional studies Preterm birth Non-coding variant AGTR2 |
| title | A functional mechanism for a non-coding variant near AGTR2 associated with risk for preterm birth |
| title_full | A functional mechanism for a non-coding variant near AGTR2 associated with risk for preterm birth |
| title_fullStr | A functional mechanism for a non-coding variant near AGTR2 associated with risk for preterm birth |
| title_full_unstemmed | A functional mechanism for a non-coding variant near AGTR2 associated with risk for preterm birth |
| title_short | A functional mechanism for a non-coding variant near AGTR2 associated with risk for preterm birth |
| title_sort | functional mechanism for a non coding variant near agtr2 associated with risk for preterm birth |
| topic | Functional studies Preterm birth Non-coding variant AGTR2 |
| url | https://doi.org/10.1186/s12916-023-02973-w |
| work_keys_str_mv | AT liwang afunctionalmechanismforanoncodingvariantnearagtr2associatedwithriskforpretermbirth AT robertmrossi afunctionalmechanismforanoncodingvariantnearagtr2associatedwithriskforpretermbirth AT xiaotingchen afunctionalmechanismforanoncodingvariantnearagtr2associatedwithriskforpretermbirth AT jingchen afunctionalmechanismforanoncodingvariantnearagtr2associatedwithriskforpretermbirth AT jilianrunyon afunctionalmechanismforanoncodingvariantnearagtr2associatedwithriskforpretermbirth AT mehakchawla afunctionalmechanismforanoncodingvariantnearagtr2associatedwithriskforpretermbirth AT danielmiller afunctionalmechanismforanoncodingvariantnearagtr2associatedwithriskforpretermbirth AT carmyforney afunctionalmechanismforanoncodingvariantnearagtr2associatedwithriskforpretermbirth AT arthurlynch afunctionalmechanismforanoncodingvariantnearagtr2associatedwithriskforpretermbirth AT xuzhezhang afunctionalmechanismforanoncodingvariantnearagtr2associatedwithriskforpretermbirth AT fanshengkong afunctionalmechanismforanoncodingvariantnearagtr2associatedwithriskforpretermbirth AT bojacobsson afunctionalmechanismforanoncodingvariantnearagtr2associatedwithriskforpretermbirth AT leahckottyan afunctionalmechanismforanoncodingvariantnearagtr2associatedwithriskforpretermbirth AT matthewtweirauch afunctionalmechanismforanoncodingvariantnearagtr2associatedwithriskforpretermbirth AT gezhang afunctionalmechanismforanoncodingvariantnearagtr2associatedwithriskforpretermbirth AT louisjmuglia afunctionalmechanismforanoncodingvariantnearagtr2associatedwithriskforpretermbirth AT liwang functionalmechanismforanoncodingvariantnearagtr2associatedwithriskforpretermbirth AT robertmrossi functionalmechanismforanoncodingvariantnearagtr2associatedwithriskforpretermbirth AT xiaotingchen functionalmechanismforanoncodingvariantnearagtr2associatedwithriskforpretermbirth AT jingchen functionalmechanismforanoncodingvariantnearagtr2associatedwithriskforpretermbirth AT jilianrunyon functionalmechanismforanoncodingvariantnearagtr2associatedwithriskforpretermbirth AT mehakchawla functionalmechanismforanoncodingvariantnearagtr2associatedwithriskforpretermbirth AT danielmiller functionalmechanismforanoncodingvariantnearagtr2associatedwithriskforpretermbirth AT carmyforney functionalmechanismforanoncodingvariantnearagtr2associatedwithriskforpretermbirth AT arthurlynch functionalmechanismforanoncodingvariantnearagtr2associatedwithriskforpretermbirth AT xuzhezhang functionalmechanismforanoncodingvariantnearagtr2associatedwithriskforpretermbirth AT fanshengkong functionalmechanismforanoncodingvariantnearagtr2associatedwithriskforpretermbirth AT bojacobsson functionalmechanismforanoncodingvariantnearagtr2associatedwithriskforpretermbirth AT leahckottyan functionalmechanismforanoncodingvariantnearagtr2associatedwithriskforpretermbirth AT matthewtweirauch functionalmechanismforanoncodingvariantnearagtr2associatedwithriskforpretermbirth AT gezhang functionalmechanismforanoncodingvariantnearagtr2associatedwithriskforpretermbirth AT louisjmuglia functionalmechanismforanoncodingvariantnearagtr2associatedwithriskforpretermbirth |