Tetsuya Babazono

SNPs in KCNQ1 are associated with susceptibility to type 2 diabetes in East Asian and European populations

We conducted a genome-wide association study using 207,097 SNP markers in Japanese individuals with type 2 diabetes and unrelated controls, and identified KCNQ1 (potassium voltage-gated channel, KQT-like subfamily, member 1) to be a strong candidate for conferring susceptibility to type 2 diabetes. We detected consistent association of a SNP in KCNQ1 (rs2283228) with the disease in several independent case-control studies (additive model P = 3.1 × 10−12; OR = 1.26, 95% CI = 1.18–1.34). Several other SNPs in the same linkage disequilibrium (LD) block were strongly associated with type 2 diabetes (additive model: rs2237895, P = 7.3 × 10−9; OR = 1.32, 95% CI = 1.20–1.45, rs2237897, P = 6.8 × 10−13; OR = 1.41, 95% CI = 1.29–1.55). The association of these SNPs with type 2 diabetes was replicated in samples from Singaporean (additive model: rs2237895, P = 8.5 × 10−3; OR = 1.14, rs2237897, P = 2.4 × 10−4; OR = 1.22) and Danish populations (additive model: rs2237895, P = 3.7 × 10−11; OR = 1.24, rs2237897, P = 1.2 × 10−4; OR = 1.36).

2008 Japanese Society for Dialysis Therapy: guidelines for renal anemia in chronic kidney disease.

The Japanese Society for Dialysis Therapy (JSDT) guideline committee, chaired by Dr Y. Tsubakihara, presents the Japanese guidelines entitled “Guidelines for Renal Anemia in Chronic Kidney Disease.” These guidelines replace the “2004 JSDT Guidelines for Renal Anemia in Chronic Hemodialysis Patients,” and contain new, additional guidelines for peritoneal dialysis (PD), non‐dialysis (ND), and pediatric chronic kidney disease (CKD) patients.

Predictors of the progression of diabetic nephropathy and the beneficial effect of angiotensin-converting enzyme inhibitors in NIDDM patients

Summary A progressive decline in glomerular function occurs in diabetic nephropathy. The predictive effects of progression promoters were examined in 182 non-insulin-dependent diabetic patients from a baseline serum creatinine concentration of 133 μml/l. During a total of 605 person-years follow-up, 107 patients developed end-stage renal failure requiring dialysis. The rate of decline of renal function was highly variable. Urinary protein excretion was the strongest predictor correlated to the rate of decline, followed by diastolic and systolic blood pressure, total cholesterol and platelet count, while the protective effects were seen in serum albumin and haematocrit. Ajustment for urinary protein excretion revealed that diastolic blood pressure, familial predisposition to hypertension, serum albumin, and smoking were independent significant predictors. Angiotensin converting enzyme inhibitors (ACE-I) significantly retarded the development of end-stage renal failure compared to antihypertensives other than ACE-I (mostly nifedipine), and the effect was evident particularly in patients with proteinuria below the median (2.5 g/24 h) (presumably those who responded to ACE-I). A complex effect of proteinuria in association with blood pressure elevation, familial predisposition to hypertension, hypoalbuminaemia, and smoking may play an important role in the progression of nephropathy. [Diabetologia (1997) 40: 405–411]

Association of the Gene Encoding Wingless-Type Mammary Tumor Virus Integration-Site Family Member 5B (WNT5B) with Type 2 Diabetes

Recent reports have suggested that WNT signaling is an important regulator for adipogenesis or insulin secretion and might be involved in the pathogenesis of type 2 diabetes. To investigate possible roles of the WNT genes in conferring susceptibility to type 2 diabetes, we examined the association of the genes that encode members of the WNT family with type 2 diabetes in the Japanese population. First, 40 single-nucleotide polymorphism (SNP) loci within 11 WNT genes were analyzed in 188 subjects with type 2 diabetes (case-1) and 564 controls (control-1). Among them, six SNP loci exhibited a significant difference (P<.05) in the allele and/or genotype distributions between case and control subjects. These SNP loci were further analyzed in another set of case (case-2; n=733) and control (control-2; n=375) subjects to confirm their statistical significance. As a result, one SNP locus in the WNT5B gene was strongly associated with type 2 diabetes ( chi 2=15.6; P=.00008; odds ratio=1.74; 95% confidence interval 1.32-2.29). Expression of the WNT5B gene was detectable in several tissues, including adipose, pancreas, and liver. Subsequent in vitro experiments identified the fact that expression of the Wnt5b gene was increased at an early phase of adipocyte differentiation in mouse 3T3-L1 cells. Furthermore, overexpression of the Wnt5b gene in preadipocytes resulted in the promotion of adipogenesis and the enhancement of adipocytokine-gene expression. These results indicate that the WNT5B gene may contribute to conferring susceptibility to type 2 diabetes and may be involved in the pathogenesis of this disease through the regulation of adipocyte function.

Current status of renal replacement therapy in Japan

The study of the current status of renal replacement therapy in Japan is based on the analysis of data from the registry reports for regular dialysis therapy and kidney transplantation. The total number of patients receiving regular dialysis therapy was 123,926 at the end of 1992: 117,809 (95.1%) on hemodialysis and 6,117 (4.9%) on peritoneal dialysis. The primary diseases of newly accepted patients were chronic glomerulonephritis (42.2%), diabetic nephropathy (28.4%), nephrosclerosis (5.9%), polycystic kidney disease (2.7%), chronic pyelonephritis (1.6%), and others. The number of kidney transplant patients in Japan was 8,384 at the end of 1991: 6,154 (73.4%) received a living donor transplantation and 2,230 (26.9%) received a cadaver donor transplantation. Overall 5-year survival rates of dialysis patients were 60.4%: 69.7% for chronic glomerulonephritis, 41.7% for diabetic nephropathy, 39.6% for nephrosclerosis, 73.6% for diffuse polycystic kidney disease, and 66.6% for chronic pyelonephritis. The causes of death of dialysis patients were heart failure (31.1%), cerebrovascular accident (13.6%), infectious diseases (11.3%), malignancies (7.1%), cachexia/uremia (6.7%), myocardial infarction (5.8%), and others. The gross mortality rate of dialysis patients was increased in cases of less than 4 hours of the average length of each dialysis session, less than 4% and more than 9% of the average weight loss during each dialysis session, less than 1.0 of Kt/V, and less than 0.9 and more than 1.7 g/kg/d of protein catabolic rate. Overall 5-year patient and graft survival rates of kidney transplant patients since 1964 were 82.7% and 60.3%: 84.4% and 65.0% in living donor cases, and 77.4% and 46.2% in cadaver donor case, respectively. Those since 1983 were 90.1% and 68.2%: 91.3% and 72.6% in living donor cases, and 87.8% and 59.3%, respectively. Graft survival rates were superior in cases treated with combined steroid, cyclosporine and azathioprine or mizoribine, to those treated with other immuno-suppressive regimens, and they decreased as the number of HLA-A, -B and -DR increased.

Asymmetric dimethylarginine is closely associated with the development and progression of nephropathy in patients with type 2 diabetes

BACKGROUND Nitric oxide (NO) is thought to play an important role in the pathogenesis of diabetic nephropathy. We conducted a prospective, observational cohort study to explore the relationship between plasma levels of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthase, and the development and progression of nephropathy in patients with type 2 diabetes. METHODS This was a hospital-based observational cohort study in Japanese type 2 diabetic patients with normoalbuminuria [urinary albumin-to-creatinine ratio (ACR) <30 mg/g creatinine] or microalbuminuria (30 < or = ACR <300 mg/g creatinine). The primary endpoint was the development or progression of diabetic nephropathy, based on transition from any given stage to a more advanced stage of albuminuria. RESULTS We studied 225 diabetic patients, 81 women and 144 men, with a mean (+/-SD) age of 64 +/- 10 years. The majority (183) of patients were normoalbuminuric, with the remainder microalbuminuric (42). During the median follow-up period of 5.2 years, 27 normoalbuminuric and 10 microalbuminuric patients reached the primary endpoint. When patients were separated according to the median ADMA level (0.46 mumol/l), patients with higher ADMA levels had a greater incidence of reaching the endpoint (P = 0.014 by the log-rank test). In the multivariate Cox proportional hazard model, the hazard ratio for reaching the endpoint for patients with higher versus lower ADMA levels was 2.72 (95% confidence interval 1.25-5.95; P = 0.012). CONCLUSIONS Higher plasma levels of ADMA may be a novel and potent predictor of the progression of nephropathy in adult Japanese type 2 diabetic patients.

A single nucleotide polymorphism within the acetyl-coenzyme A carboxylase beta gene is associated with proteinuria in patients with type 2 diabetes

It has been suggested that genetic susceptibility plays an important role in the pathogenesis of diabetic nephropathy. A large-scale genotyping analysis of gene-based single nucleotide polymorphisms (SNPs) in Japanese patients with type 2 diabetes identified the gene encoding acetyl-coenzyme A carboxylase beta (ACACB) as a candidate for a susceptibility to diabetic nephropathy; the landmark SNP was found in the intron 18 of ACACB (rs2268388: intron 18 +4139 C > T, p = 1.4×10−6, odds ratio = 1.61, 95% confidence interval [CI]: 1.33–1.96). The association of this SNP with diabetic nephropathy was examined in 9 independent studies (4 from Japan including the original study, one Singaporean, one Korean, and two European) with type 2 diabetes. One case-control study involving European patients with type 1 diabetes was included. The frequency of the T allele for SNP rs2268388 was consistently higher among patients with type 2 diabetes and proteinuria. A meta-analysis revealed that rs2268388 was significantly associated with proteinuria in Japanese patients with type 2 diabetes (p = 5.35×10−8, odds ratio = 1.61, 95% Cl: 1.35–1.91). Rs2268388 was also associated with type 2 diabetes–associated end-stage renal disease (ESRD) in European Americans (p = 6×10−4, odds ratio = 1.61, 95% Cl: 1.22–2.13). Significant association was not detected between this SNP and nephropathy in those with type 1 diabetes. A subsequent in vitro functional analysis revealed that a 29-bp DNA fragment, including rs2268388, had significant enhancer activity in cultured human renal proximal tubular epithelial cells. Fragments corresponding to the disease susceptibility allele (T) had higher enhancer activity than those of the major allele. These results suggest that ACACB is a strong candidate for conferring susceptibility for proteinuria in patients with type 2 diabetes.

Genetic variations in the gene encoding TFAP2B are associated with type 2 diabetes mellitus

AbstractTo search a gene(s) conferring susceptibility to type 2 diabetes mellitus, we genotyped nearly 60,000 gene-based SNPs for Japanese patients and found evidence that the gene at chromosome 6p12 encoding transcription-factor-activating protein 2β (TFAP2B) was a likely candidate in view of significant association of polymorphism in this gene with type 2 diabetes. Extensive analysis of this region identified that several variations within TFAP2B were significantly associated with type 2 diabetes [a variable number of tandem repeat locus: χ2=10.9, P=0.0009; odds ratio=1.57, 95% CI 1.20-2.06, intron 1+774 (G/T); χ2=11.6, P=0.0006; odds ratio=1.60, 95% CI 1.22-2.09, intron 1+2093 (A/C); χ2=12.2, P=0.0004; odds ratio=1.61, 95% CI 1.23-2.11]. The association of TFAP2B with type 2 diabetes was also observed in the UK population. These results suggest that TFAP2B might be a new candidate for conferring susceptibility to type 2 diabetes and contribute to the pathogenesis of type 2 diabetes.

Single nucleotide polymorphisms in the gene encoding Krüppel-like factor 7 are associated with type 2 diabetes

Aims/hypothesisAlthough genetic susceptibility plays an important role in the pathogenesis of type 2 diabetes, most of the genes that influence susceptibility to type 2 diabetes have yet to be identified. Krüppel-like transcription factors are known to play important roles in development and cell differentiation, and have recently been implicated in the pathogenesis of type 2 diabetes. The present study aimed to examine the associations of single nucleotide polymorphisms (SNPs) in genes encoding members of the Krüppel-like-factor (KLF) family with type 2 diabetes in a large cohort of Japanese subjects.MethodsWe genotyped 33 SNP loci found in 12 KLF genes in subjects with type 2 diabetes and in subjects from the general population using the PCR-Invader assay. We also examined the effects of the overexpression of KLF7 on adipogenesis in 3T3-L1 cells.ResultsWe identified a significant association between an SNP in KLF7 and type 2 diabetes (A vs C: p=0.004 after Bonferroni’s correction, odds ratio=1.59, 95% CI 1.27–2.00). The expression of Klf7 decreased in response to the differentiation of 3T3-L1 adipocytes, and the overexpression of KLF7 resulted in significant inhibition of adipogenesis in 3T3-L1 cells.Conclusions/interpretationThese results indicate that the gene encoding KLF7 is a novel candidate for conferring genetic susceptibility to type 2 diabetes.

Effects of icodextrin on glycemic and lipid profiles in diabetic patients undergoing peritoneal dialysis.

Aim: Icodextrin reduces glucose absorption from the peritoneal dialysate. We conducted this prospective, open-labeled, multicenter study to determine the effects of icodextrin on glycemic and lipid parameters in diabetic patients undergoing continuous ambulatory peritoneal dialysis (PD) or automated PD. Methods: Patients were recruited from 15 institutions in Japan, and a total of 51 patients (15 women and 36 men, mean age: 59 ± 10 years, median duration of PD: 13 months) were enrolled. The patients were administered an overnight or daytime dwell of 1.5 or 2.0 l of 7.5% icodextrin-containing solution. At baseline and 3, 6, 9 and 12 months after the start of icodextrin, nonfasting blood was drawn for measurement of glycated hemoglobin (HbA1C) and serum lipids. Results: During icodextrin treatment, there was no change in overall HbA1C levels compared to baseline values; however, for those with baseline HbA1C ≧6.5% (n = 22), significant decreases in HbA1C were observed. Mean total/LDL cholesterol and triglycerides were decreased significantly during icodextrin treatment, with greater decreases for patients with baseline total cholesterol ≧220 mg/dl, LDL cholesterol ≧120 mg/dl or triglycerides ≧150 mg/dl. HDL cholesterol did not differ at any time point; however, values for patients with baseline HDL cholesterol <40 mg/dl tended to increase with marginal significance. Conclusions: In the current study, switching from glucose-containing dialysis solution to icodextrin resulted in improved lipid profiles and possibly a favorable metabolic profile, particularly in patients with poor glycemic control. These hypotheses remain to be proven in controlled clinical trials.