Identification of risk loci for primary aldosteronism in genome-wide association studies

Floch, Édith Le; Cosentino, Teresa; Larsen, Casper K.; Beuschlein, Felix; Reincke, Martín; Amar, Laurence; Rossi, Gianpaolo; Sousa, Kelly De; Baron, Stéphanie; Chantalat, Sophie; Saintpierre, Benjamin; Lenzini, Livia; Frouin, Arthur; Giscos-Douriez, Isabelle; Ferey, Matthis; Abdellatif, Alaa B; Méatchi, Tchao; Empana, Jean‐Philippe; Jouven, Xavier; Gieger, Christian; Waldenberger, Mélanie; Peters, Annette; Cusi, Daniele; Touvier, Mathilde; Deschasaux, Mélanie; Druesne-Pecollo, Nathalie; Boulkroun, Sheerazed; Fernandes-Rosa, Fábio Luiz; Deleuze, Jean-François; Jeunemaı̂tre, Xavier; Zennaro, Maria-Christina

doi:10.1038/s41467-022-32896-8

Cited by 27 publications

(27 citation statements)

References 91 publications

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“…Le Floch et al revealed that RXFP2 and CASZ1 expressed in the adrenal gland and their overexpression in adrenocortical cells could modify the basal and stimulated mineralocorticoid output. 39 Considering our findings that the PA association signals strongly colocalized with the RXFP2 eQTL effects in the adrenal gland, this would support the hypothesis that its risk variant might have a causative effect on PA through the overexpression of RXFP2 . Although they reported the stronger association of the RFXP2 locus with BAH than with APA, there was no apparent heterogeneity between the subtypes in our study.…”

Section: Discussionsupporting

confidence: 73%

“…Recently, Le Floch et al published a GWAS of PA in a European cohort. 39 They reported the robust association of 2 loci mapped to RXFP2 (13q12) and CASZ1 (1p36) and also suggested the association of 2 loci mapped to NDP (Xp11) and LSP1 (11p15) in discovery analysis and meta-analysis, respectively. RXFP2 and LSP1 were overlapped with the loci identified in this study, which enhances the reliability of their association with PA.…”

Section: Discussionmentioning

confidence: 97%

“…Recently, Le Floch et al published a GWAS of PA in a European cohort. 39 They reported the robust association of 2 loci mapped to RXFP2 (13q12) and CASZ1 (1p36) and also suggested the association of 2 loci mapped to B, The plot represents −log 10 (P value) of the case-case association analysis between PA and hypertension with the adjustment for BP in the Japanese cohort. The vertical axis shows −log 10 (P value), with the higher risk effects on PA and hypertension shown at the above and below the horizontal axis, respectively.…”

Section: Discussionmentioning

confidence: 99%

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Genetic Risk of Primary Aldosteronism and Its Contribution to Hypertension: A Cross-Ancestry Meta-Analysis of Genome-Wide Association Studies

et al. 2023

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BACKGROUND: Hypertension imposes substantial health and economic burden worldwide. Primary aldosteronism (PA) is one of the most common causes of secondary hypertension, causing cardiovascular events at higher risk compared with essential hypertension. However, the germline genetic contribution to the susceptibility of PA has not been well elucidated. METHOD: We conducted a genome-wide association analysis of PA in the Japanese population and a cross-ancestry meta-analysis combined with UK Biobank and FinnGen cohorts (816 PA cases and 425 239 controls) to identify genetic variants that contribute to PA susceptibility. We also performed a comparative analysis for the risk of 42 previously established blood pressure–associated variants between PA and hypertension with the adjustment of blood pressure. RESULTS: In the Japanese genome-wide association study, we identified 10 loci that presented suggestive evidence for the association with the PA risk ( P <1.0×10 −6 ). In the meta-analysis, we identified 5 genome-wide significant loci (1p13, 7p15, 11p15, 12q24, and 13q12; P <5.0×10 −8 ), including 3 of the suggested loci in the Japanese genome-wide association study. The strongest association was observed at rs3790604 (1p13), an intronic variant of WNT2B (odds ratio, 1.50 [95% CI, 1.33−1.69]; P =5.2×10 −11 ). We further identified 1 nearly genome-wide significant locus (8q24, CYP11B2 ), which presented a significant association in the gene-based test ( P =7.2×10 −7 ). Of interest, all of these loci were known to be associated with blood pressure in previous studies, presumably because of the prevalence of PA among individuals with hypertension. This assumption was supported by the observation that they had a significantly higher risk effect on PA than on hypertension. We also revealed that 66.7% of the previously established blood pressure–associated variants had a higher risk effect for PA than for hypertension. CONCLUSIONS: This study demonstrates the genome-wide evidence for a genetic predisposition to PA susceptibility in the cross-ancestry cohorts and its significant contribution to the genetic background of hypertension. The strongest association with the WNT2B variants reinforces the implication of the Wnt/β-catenin pathway in the PA pathogenesis.

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Section: Discussionsupporting

confidence: 73%

Section: Discussionmentioning

confidence: 97%

“…Recently, Le Floch et al published a GWAS of PA in a European cohort. 39 They reported the robust association of 2 loci mapped to RXFP2 (13q12) and CASZ1 (1p36) and also suggested the association of 2 loci mapped to B, The plot represents −log 10 (P value) of the case-case association analysis between PA and hypertension with the adjustment for BP in the Japanese cohort. The vertical axis shows −log 10 (P value), with the higher risk effects on PA and hypertension shown at the above and below the horizontal axis, respectively.…”

Section: Discussionmentioning

confidence: 99%

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Genetic Risk of Primary Aldosteronism and Its Contribution to Hypertension: A Cross-Ancestry Meta-Analysis of Genome-Wide Association Studies

et al. 2023

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“…SNPs in the exonic region have the potential to affect the coding sequence of CYP11B2 and, ultimately, its function. Other reports have identified specific genomic loci at chromosomes 1 and 13 that are associated with an increased risk of excessive aldosterone production [ 42 ]. Excessive aldosterone is usually associated with hypertension.…”

Section: Discussionmentioning

confidence: 99%

Serum Androgen Metabolites Correlate with Clinical Variables in African and European American Men with Localized, Therapy Naïve Prostate Cancer

et al. 2023

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Dihydrotestosterone (DHT) and testosterone (T), which mediate androgen receptor nuclear translocation and target gene transcription, are crucial androgens and essential molecular triggers required for the proliferation and survival of prostate cancer cells. Therefore, androgen metabolism is commonly targeted in the treatment of prostate cancer. Using a high-pressure liquid chromatographic assay with tandem mass spectral detection, we determined the serum levels of metabolites produced during DHT/T biosynthesis in African American (AA) and European American (EA) men with localized, therapy naïve prostate cancer. Serum progesterone and related metabolites were significantly lower in AA men than in EA men, and these differences were associated with rapid disease progression. Multivariate analysis revealed significant differences between a subset of intermediate androgen metabolites between AA and EA men and between men with <=3 + 4 and >=4 + 3 Gleason score disease. AA men have a significantly higher frequency of single nucleotide polymorphisms in CYP11B1 and CYP11B2, enzymes that regulate corticosterone-aldosterone conversion. Finally, higher levels of T and pregnenolone were associated with a lower risk of progression-free survival only in AA men. This work provides new insight into androgen metabolism and racial disparities in prostate cancer by presenting evidence of dysregulated androgen biosynthesis in therapy naïve disease that correlates with clinical variables.

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“…These studies were performed by focusing on the identification, not of PA-causing genes, but of the genetic background (i. e., single nucleotide polymorphisms, SNPs) contributing to the increased susceptibility to the development of an APA or BAH. One of these studies, performed in a large, multi-center cohort of PA patients 30 , showed a genetic link between PA and RH. In fact, the SNPs associated with PA development clustered near three genes ( CASZ1 , LSP1 , and RXFP2) that were already associated with RH in previous studies in populations from Iceland, from the UK Biobank, and from the eMERGE and the CHARGE consortium studies 31 .…”

Section: Introductionmentioning

confidence: 99%

Primary Aldosteronism and Drug Resistant Hypertension: A “Chicken-Egg” Story

Lenzini

Pintus

Seccia

et al. 2023

Exp Clin Endocrinol Diabetes

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Drug-resistant arterial hypertension (RH) is a major risk factor for cardiovascular disease. However, it is often due to underlying causes, the identification of which poses significant clinical challenges because interfering drugs are used by definition in RH patients. In this setting, primary aldosteronism (PA) is a frequent cause of RH and its prevalence in RH patients is likely higher than 20%. The pathophysiological link between PA and the development and maintenance of RH involves target organ damage and the cellular and extracellular effects of aldosterone excess that promote pro-inflammatory and pro-fibrotic changes in the kidney and vasculature. The feasibility of adrenal vein sampling in RH patients, who have PA, and the clinical benefit achieved by adrenalectomy further emphasize the need of implementing the systematic screening for this common form of secondary hypertension in the management of a high-risk population as RH patients. We herein review the current knowledge of the factors that contribute to the RH phenotype with a focus on PA, and discuss the issues regarding the screening for PA in the setting of RH, and the therapeutical approaches (surgical and medical) aimed at resolving RH caused by PA.

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Identification of risk loci for primary aldosteronism in genome-wide association studies

Cited by 27 publications

References 91 publications

Genetic Risk of Primary Aldosteronism and Its Contribution to Hypertension: A Cross-Ancestry Meta-Analysis of Genome-Wide Association Studies

Genetic Risk of Primary Aldosteronism and Its Contribution to Hypertension: A Cross-Ancestry Meta-Analysis of Genome-Wide Association Studies

Serum Androgen Metabolites Correlate with Clinical Variables in African and European American Men with Localized, Therapy Naïve Prostate Cancer

Primary Aldosteronism and Drug Resistant Hypertension: A “Chicken-Egg” Story

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