Japanese Kidney Disease Research Articles

P1542Identification of 13 novel susceptibility loci for early-onset myocardial infarction, hypertension, or chronic kidney disease in Japanese

Abstract Background Early-onset cardiovascular and renal diseases have a strong genetic component. Purpose To identify genetic variants that confer susceptibility to early-onset myocardial infarction (MI), hypertension, or chronic kidney disease (CKD) in Japanese. We have performed exome-wide association studies (EWASs) in subjects with early-onset forms of these diseases. Methods A total of 8093 individuals aged ≤65 years was enrolled in the study. The EWASs for MI, hypertension, and CKD were conducted with 6926 subjects (1152 cases, 5774 controls), 8080 subjects (3444 cases, 4636 controls), and 2556 subjects (1051 cases, 1505 controls), respectively. Genotyping of single nucleotide polymorphisms (SNPs) was performed with Illumina Human Exome-12 DNA Analysis BeadChip or Infinium Exome-24 BeadChip arrays. The relation of allele frequencies for 31,245, 31,276, or 31,514 SNPs that passed quality control to MI, hypertension, and CKD, respectively, was examined with Fisher's exact test. Bonferroni's correction for statistical significance of association was applied to compensate for multiple comparisons of genotypes with MI, hypertension, or CKD. Results The EWASs of allele frequencies revealed that 25, 11, and 11 SNPs were significantly associated with MI (P<1.60 × 10–6), hypertension (P<1.60 × 10–6), or CKD (P<1.59 × 10–6), respectively. Multivariable logistic regression analysis with adjustment for covariates showed that all 25, 11, and 11 SNPs were significantly related to MI (P<0.0005), hypertension (P<0.0011), or CKD (P<0.0011), respectively. After examination of results from previous genome-wide association studies and linkage disequilibrium of the identified SNPs, we newly identified 11 loci (TMOD4, COL6A3, ADGRL3-CXCL8-MARCH1, OR52E4, TCHP-GIT2, CCDC63, 12q24.1, OAS3, PLCB2-VPS33B, GOSR2, ZNF77), six loci (MOB3C-TMOD4, COL6A3, COL6A5, CXCL8-MARCH1, NFKBIL1-6p21.3-NCR3, PLCB2-VPS33B), and seven loci (MOB3C-TMOD4, COL6A3, COL6A5, ADGRL3-CXCL8-MARCH1, MUC17, PLCB2-VPS33B, ZNF77) that were significantly associated with MI, hypertension, or CKD, respectively. Furthermore, six genes (TMOD4, COL6A3, CXCL8, MARCH1, PLCB2, VPS33B) were significantly associated with MI, hypertension, and CKD; two genes (ADGRL3, ZNF77) with MI and CKD; and two genes (COL6A5, MOB3C) with hypertension and CKD. Network analysis showed that the 13, 10, or 11 genes associated with MI, hypertension, or CKD, respectively, in the present study had direct or indirect interactions with the corresponding sets of 50 genes previously shown to be associated with MI, hypertension, or CKD. Conclusion We newly identified 13 loci (MOB3C-TMOD4, COL6A3, ADGRL3-CXCL8-MARCH1, OR52E4, TCHP-GIT2, CCDC63, 12q24.1, OAS3, PLCB2-VPS33B, ZNF77, COL6A5, NFKBIL1-NCR3, MUC17) that confer susceptibility to early-onset MI, hypertension, or CKD. Determination of genotypes for the SNPs at these loci may prove informative for assessment of the genetic risk for MI, hypertension, or CKD in Japanese.

Polymorphisms of genes involved in lipid metabolism and risk of chronic kidney disease in Japanese - cross-sectional data from the J-MICC study.

BackgroundChronic kidney disease (CKD) is known to be one of the causes of cardiovascular disease and end-stage renal disease. Among the several treatable risk factors of CKD, that of dyslipidemia is relatively controversial. To clarify the association of polymorphisms in genes involved in lipid metabolism with the risk of CKD in the Japanese population, we used cross-sectional data from the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study.MethodsA total of 3,268 men and women, aged 35–69 years, were selected from J-MICC Study participants for inclusion in this study. Twenty-eight candidate single nucleotide polymorphisms (SNPs) were selected in 17 genes associated with the risk of lipid metabolism disorders, and genotyping of the subjects was conducted using the multiplex PCR-based invader assay. The prevalence of CKD was determined for stages 3–5 (defined as estimated glomerular filtration rate <60 ml/min/1.73 m2).ResultsLogistic regression analysis revealed that SNPs APOA5 T − 1131C (rs662799), APOA5 T1259C (rs2266788), TOMM40 A/G (rs157580), and CETP TaqIB (rs708272) were significantly associated with CKD risk in those individuals genotyped, with age- and sex-adjusted odds ratios (ORs) per minor allele (and 95% confidence intervals (CIs)) of OR 1.22 (95% CI: 1.06–1.39), 1.19 (1.03–1.37), 1.27 (1.12–1.45), and 0.81 (0.71–0.92), respectively. Analysis of the gene–environment interaction revealed that body mass index (BMI) was a significant effect modifier for APOA5 T − 1131C (rs662799) and a marginally significant effect modifier for APOA5 T/C (rs2266788), with the interaction between BMI ≥30 and individuals with at least one minor allele of each genotype of OR 10.43 (95% CI: 1.29–84.19) and 3.36 (0.87–13.01), respectively.ConclusionsFour polymorphisms in APOA5, TOMM40, and CETP were shown to be significantly associated with CKD risk, and a significant interaction between the two APOA5 SNPs and BMI on CKD risk was also demonstrated. This suggests the future possibility of personalized risk estimation for this life-limiting disease.Electronic supplementary materialThe online version of this article (doi:10.1186/1476-511X-13-162) contains supplementary material, which is available to authorized users.

MTHFR, MTR and MTRR polymorphisms and risk of chronic kidney disease in Japanese: cross-sectional data from the J-MICC Study

Chronic kidney disease (CKD) is well known as a strong risk factor for both of end-stage renal disease and cardiovascular disease. To clarify the associations of MTHFR, MTR, and MTRR polymorphisms with the risk of CKD in Japanese, we examined this association among Japanese subjects using cross-sectional data. The subjects for this analysis were 3,318 participants consecutively selected from the Japan Multi-institutional Collaborative Cohort (J-MICC) Study. The polymorphisms were genotyped by a multiplex polymerase chain reaction-based Invader assay. Age- and sex-adjusted odds ratio (aOR) of CKD with stage 3-5 was calculated for each genotype. When those with MTHFR C677T C/C were defined as references, those with MTHFR C677T C/T and T/T demonstrated the aORs for CKD of 1.14 (95 % CI 0.93-1.40) and 1.39 (1.06-1.82), respectively. Marginally significantly decreased risk of CKD with increasing number of MTR A2756G G allele (p = 0.058) was observed. Stratified analyses by plasma folate low (<7.4 ng/ml) or high (≥7.4 ng/ml) suggested significantly higher OR of CKD for those with MTHFR C677T T/T and low serum folate with the aOR of 2.07 (95 % CI 1.30-3.31) compared with that for those with MTHFR C677T T/T and high serum folate. The present study found a significant association between the subjects with the T/T genotype of MTHFR C677T polymorphism and the elevated risk of CKD, which may suggest the possibility of the risk evaluation and prevention of this potentially life-threatening disease based on genetic traits in the near future.

Polymorphisms in genes encoding antioxidant enzymes (SOD2, CAT, GPx, TXNRD, SEPP1, SEP15 and SELS) and risk of chronic kidney disease in Japanese - cross-sectional data from the J-MICC study

Chronic kidney disease (CKD) is well known as a strong risk factor for both of end-stage renal disease and cardiovascular disease. To clarify the association of polymorphisms in the genes encoding antioxidant enzymes (SOD2, CAT, GPx, TXNRD, SEPP1, SEP15 and SELS) with the risk of CKD in Japanese, we examined this association using the cross-sectional data of Japan Multi-Institutional Collaborative Cohort (J-MICC) Study. The subjects were 3,285 men and women, aged 35–69 years, selected from J-MICC Study participants for whom genotyping were conducted by multiplex polymerase chain reaction-based Invader assay. The prevalence of CKD was determined for CKD stages 3–5 (eGFR <60 ml/min/1.73 m2). When those with CAT C-262T C/C were defined as reference, those with CAT C-262T C/T demonstrated the OR for CKD of 0.67 (95% CI 0.43–1.06) with the marginally significant trend for decreased odds ratio with increasing numbers of T allele (p = 0.070). There were no significant associations between the other polymorphisms with CKD risk. The present study found a marginally significant trend of the decreased risk of CKD with increasing numbers of T allele of CAT, which may suggest the possibility of personalized risk estimation of this life-limiting disease in the near future.

Association between Obesity and Chronic Kidney Disease in Japanese: Differences in Gender and Hypertensive Status?

Obesity is a known risk factor for hypertension and diabetes, both of which ultimately promote renal dysfunction. In the current study, we investigated the association between body mass index (BMI) and chronic kidney disease (CKD) in 8,168 Japanese individuals (2,924 women, 5,244 men) who underwent general health screening. CKD was diagnosed if the estimated glomerular filtration rate (eGFR) was less than 60 mL/min/1.73 m(2) (designated as low eGFR) and/or if the urinary albumin/creatinine value was equal to or greater than 30 mg/g (designated as albuminuria). Logistic regression analysis adjusted for age, systolic blood pressure, fasting glucose, and smoking habits showed that, in men, both overweight (BMI 25-29 kg/m(2)) and obesity (BMI >or=30 kg/m(2)) were associated with increased prevalence of low eGFR and albuminuria, whereas, in women, obesity was associated with albuminuria, but neither overweight nor obesity was associated with low eGFR. After multivariate adjustment, logistic regression analysis showed that BMI had a graded association with both low eGFR and albuminuria in men. On the other hand, in women, the second and third BMI quartiles were associated with a lower prevalence of albuminuria in comparison with the first BMI quartile. Essentially the same results were obtained when the subjects were subdivided according to the presence and absence of hypertension. Our data showed that overweight and obesity were associated with increased risk for CKD in Japanese individuals undergoing a general health screening, irrespective of the presence or absence of hypertension, although there was a gender difference in these associations.

Genotypes of autosomal dominant polycystic kidney disease in Japanese.

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common hereditary disorders. The prevalence of the ADPKD genotype in the Caucasian and Latin populations has been reported. Here, we used linkage analysis to demonstrate the prevalence of the genotype and the correlation between phenotypes and genotypes among 21 Japanese ADPKD families consisting of 96 individuals and including 57 affected members. Six polymorphic markers, each linked to either the polycystic kidney disease 1 (PKD1) or polycystic kidney disease 2 (PKD2) gene, were used for polymerase chain reaction analysis. Seventeen families (81%) showed linkage to PKD1, two families (10%) showed linkage to PKD2, and two families did not show linkage to either PKD1 or PKD2. One of the PKD1-linked families was indicated to have different mutations of PKD1 gene in the same family. PKD2-linked families did not have milder symptoms than PKD1-linked families.