X-chromosome variants are associated with aldosterone producing adenomas

Ravi Kumar Dutta,Thomas Arnesen,Peter Söderkvist,Martin Walz,Anette Heie,Oliver Gimm,Piero Alesina,Malin Larsson

doi:10.1038/s41598-021-89986-8

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.

Highlights

Aldosterone-producing adenomas (APAs) are a major cause of primary aldosteronism (PA) and are characterized by constitutively producing aldosterone, which leads to hypertension
Somatic mutations in KCNJ5, ATP2B3, ATP1A1, CACNA1D, or CLCN2 have been found in a majority of A PAs2,9–13
The frequency of the risk allele was higher in patients with APAs than in controls with an odds ratio (OR) of 6.1 (CI 3.5–10.6, p < 0.0005)

Summary

Introduction

Aldosterone-producing adenomas (APAs) are a major cause of primary aldosteronism (PA) and are characterized by constitutively producing aldosterone, which leads to hypertension. 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. The binding of angiotensin II to its receptor blocks the potassium channels and causes depolarization of the cell membrane This generates an action potential that opens voltage-gated Ca2+ channels, which leads to an influx of Ca2+. Somatic mutations in KCNJ5, ATP2B3, ATP1A1, CACNA1D, or CLCN2 have been found in a majority of A PAs2,9–13 All mutations in these genes result in chronic depolarization of the cell membrane, the opening of voltage-gated Ca2+ channels, cellular Ca2+ influx, and aldosterone production. Green dots show the 100 most significant SNPs in the region of the susceptibility loci

Methods

Results

Conclusion