Search

Nephronophthisis (NPHP) 4 gene coding nephrocystin-4 is involved in the development of renal tubules and its congenital mutations cause juvenile end-stage renal disease, NPHP. To investigate the association between single-point single-nucleotide polymorphism (SNP) of NPHP4 gene and renal function, we conducted a cross-sectional study in Japanese population. The subjects of this study were non-diabetic general population consisting of 2604 individuals >40 years in Takahata town, Japan. We genotyped 11 SNPs within NPHP4 gene that displayed frequent minor allele frequencies (>0.1) in Japanese general population. Among 11 SNPs in NPHP4 gene, only rs1287637 that induces amino acid substitution (A (Gln)/T (Leu)), located in the acceptor site of exon 21, showed a significant association with estimated glomerular filtration rate (eGFR; T/T: 81.3±15.6 (n=1886), A/T: 82.0±15.5 (n=652) and A/A: 87.4±21.4 ml min−1 per 1.73m2 (n=66); mean±s.d., P=0.006). This SNP was not in linkage disequilibrium with the surrounding SNPs. The multivariate analysis adjusted with possible confounders showed that the A/T+T/T genotype of rs1287637 was independently associated with reduced renal function (eGFR <90 ml min−1 per 1.73m2; odds ratio (OR) 1.75, 95% confidence interval (CI) 1.05-2.94, P=0.033). These results indicate the novel and independent association between single-point SNP rs1287637 in NPHP4 gene and renal function in non-diabetic Japanese population. [ABSTRACT FROM AUTHOR]

Abstract: The effect of smoking cessation on the rate of decline in lung function in patients with advanced stages of chronic obstructive pulmonary disease (COPD) has not been clarified. Saccharomyces cerevisiae cell division cycle 6 homolog (CDC6) protein possesses the pro-apoptotic properties. We tested our hypothesis that the individual susceptibility to rapid decline in lung function despite smoking cessation in patients with advanced stages of COPD is attributed to the genetic variants in the CDC6 gene. We prospectively followed 82 patients (ex-smokers) during 30months and evaluated the differences among the genotypes in the annual rate of decline in FEV1.0 (%predicted) with ten single nucleotide polymorphisms (SNPs) in and around the CDC6 gene. We found significant differences in SNP5 (National Center for Biotechnology Information SNP reference: rs2077464), SNP6 (rs13706), SNP7 (rs7217852), and SNP8 (rs9904270) with a gene-dosage effect (ANOVA overall-P =0.029–0.030). The individual allele of SNP5G, SNP6A, SNP7G, and SNP8T were associated with rapid decline in FEV1.0 (%predicted) [odds ratio (95% confidence interval)=2.35 (1.19–4.65), P =0.014]. The SNP5G/SNP6A/SNP7G/SNP8T haplotype was associated with an increased risk of deterioration of FEV1.0 (%predicted) (P =0.017). Importantly, SNP6 caused a change in amino acids in CDC6 protein (Val441Ile), immediately upstream of the caspase-3-dependent cleavage site of CDC6 (Asp442) during apoptosis. These results suggest that CDC6 may be one of the susceptibility genes that contribute to rapid decline in lung function despite smoking cessation in these patients with COPD. [Copyright &y& Elsevier]

Abstract: The forced expiratory volume in the first second (FEV1.0)/the forced vital capacity (FVC) is an important index of a single forced expiration. Ectopic expression of the human olfactory receptor (OR) gene family in the lungs has suggested its potential involvement of respiratory physiology. We hypothesized that the individual variability of FEV1.0/FVC value may be attributed to the genetic variance of the OR gene family caused by the nonfunctioning SNPs (nSNPs). We conducted quantitative trait locus (QTL) analyses of population having the 7 OR gene nSNPs and FEV1.0/FVC values by ANOVA, in 2970 samples in the Yamagata Takahata cohort. We found significant association of one nSNP [rs10838851, OR, family 4, subfamily X, member 1 (OR4X1) gene, Tyr273Ter∗] with FEV1.0/FVC (%) (P =0.008). The FEV1.0/FVC value (%) of population having OR4X1 gene nSNP Ter∗/Ter∗, Ter∗/Tyr, and Tyr/Tyr were 78.9±0.2, 78.2±0.2, and 77.7±0.4, respectively. Haplotype-based analysis of the OR4X1 gene with FEV1.0/FVC values demonstrated that two exclusive haplotypes [Hap-1/Hap-2 (frequency 0.669/0.330): SNP1 (rs7106648)T/A-SNP2 (rs871249)G/A-SNP3 (rs713325)G/A-SNP4 (rs10838851)A (Ter∗)/T (Tyr)-SNP5 (rs4752923)G/A-SNP6 (rs960640)G/A] were significantly associated with FEV1.0/FVC values (global P =0.005). These results suggest that OR4X1 may be one of the genes that contribute to the individual variability of FEV1.0/FVC value in pulmonary function test. [Copyright &y& Elsevier]

Synoviolin, also called HRD1, is an E3 ubiquitin ligase and is implicated in endoplasmic reticulum -associated degradation. In mammals, Synoviolin plays crucial roles in various physiological and pathological processes, including embryogenesis and the pathogenesis of arthropathy. However, little is known about the molecular mechanisms of Synoviolin in these actions. To clarify these issues, we analyzed the profile of protein expression in synoviolin-null cells. Here, we report that Synoviolin targets tumor suppressor gene p53 for ubiquitination. Synoviolin sequestrated and metabolized p53 in the cytoplasm and negatively regulated its cellular level and biological functions, including transcription, cell cycle regulation and apoptosis. Furthermore, these p53 regulatory functions of Synoviolin were irrelevant to other E3 ubiquitin ligases for p53, such as MDM2, Pirh2 and Cop1, which form autoregulatory feedback loops. Our results provide novel insights into p53 signaling mediated by Synoviolin. [ABSTRACT FROM AUTHOR]

Abstract: The association of the Ser326Cys polymorphism of the 8-oxoguanine glycosylase 1 (OGG1) gene with type 2 diabetes was examined using a Japanese population (n (M/W): 4585 (2085/2500); age: 62.6±10.9years). HbA1c levels and frequency of diabetic subjects were significantly higher in subjects with genotypes with Cys allele than in those without (p =0.032 and 0.037, respectively). Multiple logistic regression analysis showed that genotypes with Cys allele were significantly associated with diabetes (OR: 1.32, p =0.0289). In subjects whose glucose tolerance was classified by FPG and 2-h PG (n =1.634), the association was more substantial (genotypes with Cys allele vs. without, OR: 1.70, p =0.0059; genotypes Cys/Cys vs. Ser/Ser, OR: 2.19, p =0.0008). In subjects with genotype Ser/Ser, the insulin secretion index, HOMA-β, increased in the subjects with glucose intolerance and decreased in the subjects with diabetes, while, in subjects with genotypes Ser/Cys+Cys/Cys, HOMA-β decreased as the glucose tolerance progressed (p for trend=0.010). [Copyright &y& Elsevier]

Paraoxonase-1 (PON1) is an HDL cholesterol–associated antioxidant enzyme, and some of its polymorphisms are linked with systemic oxidative stress and cardiovascular events. In this study, we genotyped seven single nucleotide polymorphisms (SNPs) within the PON1 gene and determined their association with chronic kidney disease in 2,968 individuals from the general Japanese population. We found that a missense SNP (rs662) with a G-to-A substitution leading to an amino acid substitution (G[Arg]/A[Gln]), was significantly associated with albuminuria and estimated glomerular filtration rate (eGFR), especially in women. The A/A genotype in women had the highest prevalence of albuminuria and the lowest values of adjusted eGFR. In contrast, such relationships were not detected in men. Multivariate regression analysis found that the A/A genotype was an independent and significant factor for albuminuria and renal insufficiency (eGFR less than 60 ml/min/1.73 m2). The serum PON1 activity was lowest in subjects with the A/A genotype. In biopsy specimens, immunohistochemical analysis found increased PON1 expression on the endothelial surface of sclerotic renal arterioles and glomerular capillaries in patients with hypertension or diabetes. Our study shows that this PON1 G-to-A substitution may be a key player in a common pathway to chronic kidney and cardiovascular diseases in women.Kidney International (2009) 76, 183–189; doi:10.1038/ki.2009.97; published online 8 April 2009 [ABSTRACT FROM AUTHOR]

Abstract: The associations of the C825T polymorphism (rs5443) of the G-protein β3 subunit (GNB3) gene and eight adjacent single nucleotide polymorphisms (SNPs) with diabetes were examined using a Japanese population (n (M/W): 2956 (1335/1621); age: 63.0±10.2 years). Fasting plasma glucose (FPG) levels were significantly associated with the C825T polymorphism and two flanking SNPs (rs2301339 and rs5446) (p =0.002, 0.001, and 0.008, respectively). A case-control association study of the C825T polymorphism with diabetes using multiple logistic regression analysis showed a significant association of the genotypes TT+TC with an odds ratio of 0.62 (p =0.008) independent of age, gender, and BMI. The effects of salt consumption on the association were then examined (n =1635). The FPG levels were significantly associated with the C825T polymorphism only in subjects with low salt consumption (<12.44 g/day) (p =0.002). A case-control association study also showed a significant association with diabetes only in subjects with low salt consumption (p =0.006). [Copyright &y& Elsevier]

Abstract: The associations of five SNPs (SNPs1-5: A-5468G, A-3333G, C-1794T, C437T and T9148C) of the class II phosphoinositide 3-kinase γ-subunit (PIK3C2G) gene with type 2 diabetes were examined using a population of the Takahata Study (n (M/W): 2930 (1328/1602); age: 63.3±10.2 years), a Japanese community-based study. Quantitative association study of the SNPs with HbA1c levels showed significant association for SNPs 2 and 4 (p =0.018 and 0.004, respectively). A case-control association study of SNP 4 with diabetes by multiple logistic regression analysis showed a significant association of the genotype TT of the SNP with an odds ratio of 2.21 (p =0.001) independently of age, gender and BMI. In the NGT subjects, serum fasting insulin levels in the at-risk genotype group of SNP 4 were significantly lower than those in the others (TT, TC, and CC, 4.9±2.6, 5.4±3.0, and 5.6±3.4μU/ml, respectively; p =0.029). [Copyright &y& Elsevier]

The association of the FTO gene polymorphism, rs9939609, with obesity was examined using the population of the Takahata study (n (M/F): 2,639 (1,168 / 1,470); age: 63.0 +/- 10.2 years), a Japanese community-based study. The effects of lifestyle-related factors, including nutritional intake and physical activities, on the association were also examined. Body mass index (BMI) was significantly associated with the FTO gene polymorphism (p<0.001). A case-control association study of the FTO gene polymorphism with obesity using multiple logistic regression analysis showed a significant association of the genotype AA (odds ratio, 1.53 [95% confidential interval, 1.04-2.24]) after adjustment for age and gender. Analysis to examine the differences in lifestyle-related factors among the genotype groups showed a significant difference in the energy expenditure for moderate to high-intensity physical activity (PA) (> or = 3.0 METs) (p=0.012) with a significant decrease toward the genotype AA (p=0.027). The effect of energy expenditure for moderate to high-intensity PA on the association of the polymorphism with obesity was then examined using study groups stratified based on the energy expenditure for moderate to high-intensity PA (Low-PA and High-PA). The BMI was significantly higher in the genotype AA in the Low-PA group (p=0.016) but not in the High-PA group (p=0.103). Furthermore, the genotype AA was significantly associated with obesity (odds ratio, 2.39 [95% confidential interval, 1.19-4.80]) in the Low-PA group but not in the High- PA group (p=0.650). The FTO gene, rs9939609, was associated with obesity, and the association was evident in subjects with low-PA, suggesting a PA-dependent association.