X-chromosome variants are associated with aldosterone producing adenomas

Abstract Aldosterone-producing adenomas (APAs) are a major cause of primary aldosteronism (PA) and are characterized by constitutively producing aldosterone, which leads to hypertension. Several mutations have been identified in ion channels or ion channel-associated genes that result in APAs. To da...

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Main Authors: Ravi Kumar Dutta, Malin Larsson, Thomas Arnesen, Anette Heie, Martin Walz, Piero Alesina, Oliver Gimm, Peter Söderkvist
Format: Article
Language:English
Published: Nature Publishing Group 2021-05-01
Series:Scientific Reports
Online Access:https://doi.org/10.1038/s41598-021-89986-8
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spelling doaj-4f78aad9b98748638c71ffa0c79235012021-05-23T11:34:13ZengNature Publishing GroupScientific Reports2045-23222021-05-011111810.1038/s41598-021-89986-8X-chromosome variants are associated with aldosterone producing adenomasRavi Kumar Dutta0Malin Larsson1Thomas Arnesen2Anette Heie3Martin Walz4Piero Alesina5Oliver Gimm6Peter Söderkvist7Division of Cell Biology, Department of Biomedical and Clinical Sciences, Linköping UniversityScience for Life Laboratory, Department of Physics, Chemistry and Biology, Linköping UniversityDepartment of Surgery, Haukeland University HospitalDepartment of Surgery, Haukeland University HospitalKlinik Für Chirurgie and Zentrum Für Minimal Invasive Chirurgie, Klinikum Essen-MitteKlinik Für Chirurgie and Zentrum Für Minimal Invasive Chirurgie, Klinikum Essen-MitteDepartment of Surgery and Department of Biomedical and Clinical Sciences, Linköping UniversityDivision of Cell Biology, Department of Biomedical and Clinical Sciences, Linköping UniversityAbstract Aldosterone-producing adenomas (APAs) are a major cause of primary aldosteronism (PA) and are characterized by constitutively producing aldosterone, which leads to hypertension. Several mutations have been identified in ion channels or ion channel-associated genes that result in APAs. To date, no studies have used a genome-wide association study (GWAS) approach to search for predisposing loci for APAs. Thus, we investigated Scandinavian APA cases (n = 35) and Swedish controls (n = 60) in a GWAS and discovered a susceptibility locus on chromosome Xq13.3 (rs2224095, OR = 7.9, 95% CI = 2.8–22.4, P = 1 × 10–7) in a 4-Mb region that was significantly associated with APA. Direct genotyping of sentinel SNP rs2224095 in a replication cohort of APAs (n = 83) and a control group (n = 740) revealed persistently strong significance (OR = 6.1, 95% CI = 3.5–10.6, p < 0.0005). We sequenced an adjacent gene, MAGEE1, of the sentinel SNP and identified a rare variant in one APA, p.Gly327Glu, which is complementary to other mutations in our primary cohort. Expression quantitative trait loci (eQTL) were investigated on the X-chromosome, and 24 trans-eQTL were identified. Some of the genes identified by trans-eQTL point towards a novel mechanistic explanation for the association of the SNPs with APAs. In conclusion, our study provides further insights into the genetic basis of APAs.https://doi.org/10.1038/s41598-021-89986-8
collection DOAJ
language English
format Article
sources DOAJ
author Ravi Kumar Dutta
Malin Larsson
Thomas Arnesen
Anette Heie
Martin Walz
Piero Alesina
Oliver Gimm
Peter Söderkvist
spellingShingle Ravi Kumar Dutta
Malin Larsson
Thomas Arnesen
Anette Heie
Martin Walz
Piero Alesina
Oliver Gimm
Peter Söderkvist
X-chromosome variants are associated with aldosterone producing adenomas
Scientific Reports
author_facet Ravi Kumar Dutta
Malin Larsson
Thomas Arnesen
Anette Heie
Martin Walz
Piero Alesina
Oliver Gimm
Peter Söderkvist
author_sort Ravi Kumar Dutta
title X-chromosome variants are associated with aldosterone producing adenomas
title_short X-chromosome variants are associated with aldosterone producing adenomas
title_full X-chromosome variants are associated with aldosterone producing adenomas
title_fullStr X-chromosome variants are associated with aldosterone producing adenomas
title_full_unstemmed X-chromosome variants are associated with aldosterone producing adenomas
title_sort x-chromosome variants are associated with aldosterone producing adenomas
publisher Nature Publishing Group
series Scientific Reports
issn 2045-2322
publishDate 2021-05-01
description Abstract Aldosterone-producing adenomas (APAs) are a major cause of primary aldosteronism (PA) and are characterized by constitutively producing aldosterone, which leads to hypertension. Several mutations have been identified in ion channels or ion channel-associated genes that result in APAs. To date, no studies have used a genome-wide association study (GWAS) approach to search for predisposing loci for APAs. Thus, we investigated Scandinavian APA cases (n = 35) and Swedish controls (n = 60) in a GWAS and discovered a susceptibility locus on chromosome Xq13.3 (rs2224095, OR = 7.9, 95% CI = 2.8–22.4, P = 1 × 10–7) in a 4-Mb region that was significantly associated with APA. Direct genotyping of sentinel SNP rs2224095 in a replication cohort of APAs (n = 83) and a control group (n = 740) revealed persistently strong significance (OR = 6.1, 95% CI = 3.5–10.6, p < 0.0005). We sequenced an adjacent gene, MAGEE1, of the sentinel SNP and identified a rare variant in one APA, p.Gly327Glu, which is complementary to other mutations in our primary cohort. Expression quantitative trait loci (eQTL) were investigated on the X-chromosome, and 24 trans-eQTL were identified. Some of the genes identified by trans-eQTL point towards a novel mechanistic explanation for the association of the SNPs with APAs. In conclusion, our study provides further insights into the genetic basis of APAs.
url https://doi.org/10.1038/s41598-021-89986-8
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