X-chromosome variants are associated with aldosterone producing adenomas [Elektronisk resurs]

• 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=1x10(-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. 

Ämnesord

Medical and Health Sciences  (hsv)

Basic Medicine  (hsv)

Medical Genetics  (hsv)

Medicin och hälsovetenskap  (hsv)

Medicinska och farmaceutiska grundvetenskaper  (hsv)

Medicinsk genetik  (hsv)

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government publication  (marcgt)