Yoshida Tetsuro, Kato Kimihiko, Yokoi Kiyoshi, Watanabe Sachiro, Metoki Norifumi, Satoh Kei, Aoyagi Yukitoshi, Nishigaki Yutaka, Nozawa Yoshinori, Yamada Yoshiji
Department of Cardiovascular Medicine, Inabe General Hospital, Inabe, Japan.
Hypertens Res. 2009 May;32(5):411-8. doi: 10.1038/hr.2009.22. Epub 2009 Mar 13.
Although hypertension has been recognized as a risk factor for chronic kidney disease (CKD), the genetic factors for predisposition to CKD in individuals with hypertension remain largely unknown. The purpose of this study was to identify the genetic variants that confer susceptibility to CKD among individuals with hypertension. The study population comprised 3696 Japanese individuals with hypertension (2265 men, 1431 women), including 1257 individuals (789 men, 468 women) with CKD (estimated glomerular filtration rate (eGFR) <60 ml min(-1) per 1.73 m(2)) and 2439 controls (1476 men, 963 women; eGFR >or=60 ml min(-1) per 1.73 m(2)). The genotypes for 30 polymorphisms of 26 candidate genes were determined. An initial screening of allele frequencies by the chi(2)-test revealed that eight polymorphisms were significantly (false discovery rate <0.05) associated with the prevalence of CKD in hypertensive individuals. Subsequent multivariable logistic regression analysis with adjustment for covariates as well as a stepwise forward selection procedure revealed that the T --> C (Val591Ala) polymorphism of APOB (rs679899), the -681C --> G polymorphism of PPARG (rs10865710), the T --> C (Cys1367Arg) polymorphism of WRN (rs1346044), the -850C --> T polymorphism of TNF (rs1799724), the -219G --> T polymorphism of APOE (rs405509), the C --> T polymorphism of PTGS1 (rs883484) and the 41A --> G (Glu14Gly) polymorphism of ACAT2 (rs9658625) were significantly (P<0.05) associated with the prevalence of CKD. Our results suggest that APOB, WRN, ACAT2, APOE, PPARG, TNF and PTGS1 are susceptibility loci for CKD among Japanese individuals with hypertension. Determination of the genotypes for these polymorphisms may prove informative for the assessment of genetic risk for CKD among such individuals.
尽管高血压已被公认为慢性肾脏病（CKD）的一个危险因素，但高血压患者易患CKD的遗传因素仍 largely unknown。本研究的目的是确定在高血压患者中赋予CKD易感性的基因变异。研究人群包括3696名日本高血压患者（2265名男性，1431名女性），其中包括1257名CKD患者（估计肾小球滤过率（eGFR）<60 ml·min⁻¹/1.73 m²）（789名男性，468名女性）和2439名对照者（1476名男性，963名女性；eGFR≥60 ml·min⁻¹/1.73 m²）。测定了26个候选基因的30个多态性的基因型。通过卡方检验对等位基因频率进行初步筛选，发现8个多态性与高血压患者中CKD的患病率显著相关（错误发现率<0.05）。随后进行多变量逻辑回归分析，并对协变量进行调整以及逐步向前选择程序，结果显示，载脂蛋白B（APOB）的T→C（Val591Ala）多态性（rs679899）、过氧化物酶体增殖物激活受体γ（PPARG）的-681C→G多态性（rs10865710）、沃纳综合征蛋白（WRN）的T→C（Cys1367Arg）多态性（rs1346044）、肿瘤坏死因子（TNF）的-850C→T多态性（rs1799724）、载脂蛋白E（APOE）的-219G→T多态性（rs405509）、环氧化酶-1（PTGS1）的C→T多态性（rs883484）以及酰基辅酶A胆固醇酰基转移酶2（ACAT2）的41A→G（Glu14Gly）多态性（rs9658625）与CKD的患病率显著相关（P<0.05）。我们的结果表明，APOB、WRN、ACAT2 APOE、PPARG、TNF和PTGS1是日本高血压患者中CKD的易感基因座。测定这些多态性的基因型可能对评估此类个体中CKD的遗传风险具有参考价值。
