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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.

DNA methylation and demethylation regulate the transcription of genes. DNA methylation-associated gene expression of adrenal steroidogenic enzymes may regulate cortisol production in cortisol-producing adenoma (CPA). We aimed to determine the DNA methylation levels of all genes encoding steroidogenic enzymes involved in CPA. Additionally, the aims were to clarify the DNA methylation-associated gene expression and evaluate the difference of CPA genotype from others using DNA methylation data. Twenty-five adrenal CPA and six nonfunctioning adrenocortical adenoma (NFA) samples were analyzed. RNA sequencing and DNA methylation array were performed. The methylation levels at 118 methylation sites of the genes were investigated, and their methylation and mRNA levels were subsequently integrated. Among all the steroidogenic enzyme genes studied, CYP17A1 gene was mainly found to be hypomethylated in CPA compared to that in NFA, and the Benjamini-Hochberg procedure demonstrated that methylation levels at two sites in the CYP17A1 gene body were statistically significant. PRKACA mutant CPAs predominantly exhibited hypomethylation of CYP17A1 gene compared with the GNAS mutant CPAs. Inverse associations between CYP17A1 methylation in three regions of the gene body and its mRNA levels were observed in the NFAs and CPAs. In applying clustering analysis using CYP17A1 methylation and mRNA levels, CPAs with PRKACA mutation were differentiated from NFAs and CPAs with a GNAS mutation. We demonstrated that CPAs exhibited hypomethylation of the CYP17A1 gene body in CPA, especially in the PRKACA mutant CPAs. Methylation of CYP17A1 gene may influence its transcription levels.

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吉田 里穂 1) 稲見 光浩 1) 大田垣 裕 1) 濱岡 彩 1) 藤原 典子 1) 稲垣 早織 1) 宮原 弥恵 1) 岡信 秀治 2) 柿沢 秀明 3) 亀井 望 1) 要 旨 83 歳，男性．65 歳で 2 型糖尿病を指摘され，78 歳時にボグリボース 0.9 mg内服を開始．全身倦怠感と食欲低 下で受診し，腸管囊胞性気腫症(pneumatosis cystoides intestinalis：PCI)と診断．3 年前のCT(computed tomography)検査，2 年前の下部消化管内視鏡検査でもPCIの所見を認めていた．ボグリボース中止と保存的加 療で気腫は消失．α-グルコシダーゼ阻害薬(α-glucosidase inhibitor：α-GI)によるPCIの報告はあまり多くな いが，実際は無症状で経過し見逃されている例が多数存在すると考えられる． 〔日内会誌 110：2426～2433，2021〕 ポイント・ PCIの症状は非特異的であり，無症状のまま経過する症例も多く，診断にはCT等の画像診断 が有用である． ・PCIの原因にα-GIの服用がある． ・自己免疫性疾患やステロイド使用例へのα-GI使用ではPCIのリスクが高まる． ・ α-GIによるPCIが診断されるまでの服薬期間は報告により 7 日～12 年と幅があり，診断さ れないまま経過している症例が多く存在する可能性がある．