Association of candidate gene polymorphisms with chronic kidney disease in Japanese individuals with hypertension

Abstract

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) o60 ml min À1 per 1.73 m 2 ) and 2439 controls (1476 men, 963 women; eGFRX60 ml min À1 per 1.73 m 2 ). The genotypes for 30 polymorphisms of 26 candidate genes were determined. An initial screening of allele frequencies by the v 2 -test revealed that eight polymorphisms were significantly (false discovery rate o0.05) 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 À681C-G polymorphism of PPARG (rs10865710), the T-C (Cys1367Arg) polymorphism of WRN (rs1346044), the À850C-T polymorphism of TNF (rs1799724), the À219G-T polymorphism of APOE (rs405509), the C-T polymorphism of PTGS1 (rs883484) and the 41A-G (Glu14Gly) polymorphism of ACAT2 (rs9658625) were significantly (Po0.05) 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.

Genetics of vesicoureteral reflux

“…Data regarding linkage with regions identified in this study on chromosomes 2, 3, 4, 10, 13, 16 and 20 were supported by smaller linkage studies or studies of chromosomal rearrangements associated with vur, usually in association with other urinary tract malformations. 22,[127][128][129][130][131][132][133] For example, the second highest linkage peak in this study was in chromo some 10q26, with the linkage peak clearly distal to potential candidate genes FGFR2 and PAX2. a study of 10 patients with monosomy of 10q26 and urinary anomalies (such as vur and hypoplastic kidney) with or without genital anomalies provided evidence for a gene or genes involved in kidney development in the same region.…”

“…the esrD study also revealed evidence for linkage at 10q26, 1q25, 6q24 and 4p15.32, 130 all of which are close to or overlapping with regions identified by Kelly et al the CKD candidate gene study provided support for loci identified by Kelly et al at 6q24-q25, 16q24.3, and 20p11.2. 133 these results indicate that the study of the genetics of vur has wider implications than the understanding of vur alone, and is likely to be important to the understanding of chronic renal disease and renal failure.…”

“…131 special attention should be drawn to the region on chromosome 13q32-q33, which was not the highest peak in the study by Kelly et al 47 but received support from two other linkage studies 22,127 and a study of chromo somal rearrangements. 132 it is particularly noteworthy that a genome-wide linkage scan for end-stage renal disease (esrD) 130 and a candidate gene association study for chronic kidney disease (CKD) 133 provide further data to support a role for this region in renal disease or CaKut. the esrD study also revealed evidence for linkage at 10q26, 1q25, 6q24 and 4p15.32, 130 all of which are close to or overlapping with regions identified by Kelly et al the CKD candidate gene study provided support for loci identified by Kelly et al at 6q24-q25, 16q24.3, and 20p11.2.…”

Association of genetic variants with chronic kidney disease in Japanese individuals with or without hypertension or diabetes mellitus

“…a total of 150 polymorphisms (data not shown) were selected by genome-wide association studies of ischemic stroke and myocardial infarction (p-value for allele frequency <1.0x10 -7 ) with the use of the Genechip human mapping 500K array Set (affymetrix, Santa clara, ca, uSa) (14). the relationship of these polymorphisms to cKd was not previously examined in our studies (9)(10)(11)(12)15,16).…”

“…In addition, given ethnic differences in lifestyle and environmental factors as well as in genetic background and renal function, it is necessary to examine genetic variants related to cKd in each ethnic group. We previously showed that genetic variants that confer susceptibility to cKd differ between individuals with or without metabolic syndrome (9), with or without type 2 diabetes mellitus (10), with or without hypertension (11), or with different lipid profiles (12). To further examine whether the association of polymorphisms with CKD is influenced by the absence or presence of hypertension or diabetes mellitus, we performed an association study for 150 polymorphisms of…”