Genome-wide association studies (GWAS) have facilitated a substantial and rapid rise in the number of confirmed genetic susceptibility variants for type 2 diabetes (T2D). Approximately 40 variants ...have been identified so far, many of which were discovered through GWAS. This success has led to widespread hope that the findings will translate into improved clinical care for the increasing numbers of patients with diabetes. Potential areas or clinical translation include risk prediction and subsequent disease prevention, pharmacogenetics, and the development of novel therapeutics. However, the genetic loci so far identified account for only a small fraction (approximately 10%) of the overall heritable risk for T2D. Uncovering the missing heritability is essential to the progress of T2D genetic studies and to the translation of genetic information into clinical practice.
Genome‐wide association studies (GWAS) have facilitated a substantial and rapid increase in the number of confirmed genetic susceptibility variants for complex diseases. Approximately 700 variants ...predisposing individuals to the risk for type 2 diabetes have been identified through GWAS until 2023. From 2018 to 2022, hundreds of type 2 diabetes susceptibility loci with smaller effect sizes were identified through large‐scale GWAS with sample sizes of 200,000 to >1 million. The clinical translation of genetic information for type 2 diabetes includes the development of novel therapeutics and risk predictions. Although drug discovery based on loci identified in GWAS remains challenging owing to the difficulty of functional annotation, global efforts have been made to identify novel biological mechanisms and therapeutic targets by applying multi‐omics approaches or searching for disease‐associated coding variants in isolated founder populations. Polygenic risk scores (PRSs), comprising up to millions of associated variants, can identify individuals with higher disease risk than those in the general population. In populations of European descent, PRSs constructed from base GWAS data with a sample size of approximately 450,000 have predicted the onset of diseases well. However, European GWAS‐derived PRSs have limited predictive performance in non‐European populations. The predictive accuracy of a PRS largely depends on the sample size of the base GWAS data. The results of GWAS meta‐analyses for multi‐ethnic groups as base GWAS data and cross‐population polygenic prediction methodology have been applied to establish a universal PRS applicable to small isolated ethnic populations.
This review summarizes recent advances in the genetics of type 2 diabetes, and discusses the perspective of future investigations for understanding the genetic architecture of type 2 diabetes and its clinical applications.
To understand the genetics of type 2 diabetes in people of Japanese ancestry, we conducted A meta-analysis of four genome-wide association studies (GWAS; 36,614 cases and 155,150 controls of Japanese ...ancestry). We identified 88 type 2 diabetes-associated loci (P < 5.0 × 10
) with 115 independent signals (P < 5.0 × 10
), of which 28 loci with 30 signals were novel. Twenty-eight missense variants were in linkage disequilibrium (r
> 0.6) with the lead variants. Among the 28 missense variants, three previously unreported variants had distinct minor allele frequency (MAF) spectra between people of Japanese and European ancestry (MAF
> 0.05 versus MAF
< 0.01), including missense variants in genes related to pancreatic acinar cells (GP2) and insulin secretion (GLP1R). Transethnic comparisons of the molecular pathways identified from the GWAS results highlight both ethnically shared and heterogeneous effects of a series of pathways on type 2 diabetes (for example, monogenic diabetes and beta cells).
Association of CDKAL1, IGF2BP2, CDKN2A/B, HHEX , SLC30A8, and KCNJ11 With Susceptibility to Type 2 Diabetes in a Japanese Population
Shintaro Omori 1 , 2 ,
Yasushi Tanaka 2 ,
Atsushi Takahashi 3 ,
...Hiroshi Hirose 4 ,
Atsunori Kashiwagi 5 ,
Kohei Kaku 6 ,
Ryuzo Kawamori 7 ,
Yusuke Nakamura 8 and
Shiro Maeda 1
1 Laboratory for Diabetic Nephropathy, SNP Research Center, RIKEN, Yokohama, Kanagawa, Japan
2 Department of Internal Medicine, Division of Metabolism and Endocrinology, St. Marianna University School of Medicine, Kawasaki,
Kanagawa, Japan
3 Laboratory for Statistical Analysis, SNP Research Center, RIKEN, Tokyo, Japan
4 Health Center, Keio University School of Medicine, Tokyo, Japan
5 Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan
6 Division of Endocrinology and Metabolism, Department of Internal Medicine, Kawasaki Medical School, Kurashiki, Okayama, Japan
7 Department of Medicine, Metabolism and Endocrinology, School of Medicine, Juntendo University, Tokyo, Japan
8 Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan
Address correspondence and reprint requests to Shiro Maeda, Laboratory for Diabetic Nephropathy, SNP Research Center, RIKEN,
1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan. E-mail: smaeda{at}src.riken.jp
Abstract
OBJECTIVE —Recently, several genes have been shown to be associated with an increased risk of type 2 diabetes by genome-wide association
studies in white populations. To further investigate the involvement of these polymorphisms in conferring susceptibility to
type 2 diabetes, we examined the association of 14 single nucleotide polymorphisms (SNPs) within 11 candidate loci with type
2 diabetes in a Japanese population.
RESEARCH DESIGN AND METHODS —We analyzed 14 SNPs (rs4402960 in IGF2BP2 , rs10811661 in CDKN2A/B , rs1111875 and rs7923837 in HHEX , rs13266634 in SLC30A8 , rs1113132 and rs11037909 in EXT2 , rs9939609 and rs8050136 in FTO , rs7756992 in CDKAL1 , rs1801282 in PPARG Pro12Ara, rs5219 in KCNJ11 Glu23Lys, rs7480010 in LOC387761 , and rs9300039 in Ch11) in 1,630 Japanese subjects with type 2 diabetes and in 1,064 control subjects by using an invader
assay or a TaqMan assay.
RESULTS —Among the 11 loci examined, 6 were significantly associated with type 2 diabetes in our population by a logistic regression
analysis, similar to previously reported results (rs4402960, P = 0.00009; rs10811661, P = 0.0024; rs5219, P = 0.0034; rs1111875, P = 0.0064; rs13266634, P = 0.0073; rs7756992, P = 0.0363). In this population, the remaining five loci were not significantly associated with type 2 diabetes. In addition,
we identified significant association of the SNPs in FTO gene with BMI in the control subjects.
CONCLUSIONS —We have identified 6 of the 11 loci that were identified by genome-wide association studies in white populations, and these
loci are considered strong candidates for type 2 diabetes susceptibility across different ethnicities.
SNP, single nucleotide polymorphism
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 27 December 2007. DOI: 10.2337/db07-0979.
Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db07-0979 .
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received July 14, 2007.
Accepted December 12, 2007.
DIABETES
Type 2 diabetes (T2D) is a complex, polygenic disease affecting nearly 300 million people worldwide. T2D is primarily characterized by insulin resistance, and growing evidence has indicated the ...causative link between adipose tissue inflammation and the development of insulin resistance. Genetic association studies have successfully revealed a number of important genes consistently associated with T2D to date. However, these robust T2D-associated genes do not fully elucidate the mechanisms underlying the development and progression of the disease. Here, we report an alternative approach, gene expression-based genome-wide association study (eGWAS): searching for genes repeatedly implicated in functional microarray experiments (often publicly available). We performed an eGWAS across 130 independent experiments (totally 1,175 T2D case-control microarrays) to find additional genes implicated in the molecular pathogenesis of T2D and identified the immune-cell receptor CD44 as our top candidate (P = 8.5 x 10–20). We found CD44 deficiency in a diabetic mouse model ameliorates insulin resistance and adipose tissue inflammation and also found that anti-CD44 antibody treatment decreases blood glucose levels and adipose tissue macrophage accumulation in a high-fat, diet-fed mouse model. Further, in humans, we observed CD44 is expressed in inflammatory cells in obese adipose tissue and discovered serum CD44 levels were positively correlated with insulin resistance and glycemic control. CD44 likely plays a causative role in the development of adipose tissue inflammation and insulin resistance in rodents and humans. Genes repeatedly implicated in publicly available experimental data may have unique functionally important roles in T2D and other complex diseases.
Aims/hypothesis
Nitric oxide (NO) is synthesised not only from
l
-arginine by NO synthases (NOSs), but also from its inert metabolites, nitrite and nitrate. Green leafy vegetables are abundant in ...nitrate, but whether or not a deficiency in dietary nitrite/nitrate spontaneously causes disease remains to be clarified. In this study, we tested our hypothesis that long-term dietary nitrite/nitrate deficiency would induce the metabolic syndrome in mice.
Methods
To this end, we prepared a low-nitrite/nitrate diet (LND) consisting of an amino acid-based low-nitrite/nitrate chow, in which the contents of
l
-arginine, fat, carbohydrates, protein and energy were identical with a regular chow, and potable ultrapure water. Nitrite and nitrate were undetectable in both the chow and the water.
Results
Three months of the LND did not affect food or water intake in wild-type C57BL/6J mice compared with a regular diet (RD). However, in comparison with the RD, 3 months of the LND significantly elicited visceral adiposity, dyslipidaemia and glucose intolerance. Eighteen months of the LND significantly provoked increased body weight, hypertension, insulin resistance and impaired endothelium-dependent relaxations to acetylcholine, while 22 months of the LND significantly led to death mainly due to cardiovascular disease, including acute myocardial infarction. These abnormalities were reversed by simultaneous treatment with sodium nitrate, and were significantly associated with endothelial NOS downregulation, adiponectin insufficiency and dysbiosis of the gut microbiota.
Conclusions/interpretation
These results provide the first evidence that long-term dietary nitrite/nitrate deficiency gives rise to the metabolic syndrome, endothelial dysfunction and cardiovascular death in mice, indicating a novel pathogenetic role of the exogenous NO production system in the metabolic syndrome and its vascular complications.
The carbapenem inactivation method (CIM) and modified CIM (mCIM) are simple and economical phenotypic screening methods for detecting carbapenemase production in Gram-negative bacteria. Although the ...mCIM has been recommended by the Clinical and Laboratory Standards Institute, both the CIM and mCIM have limitations. This study describes another modified CIM, called CIMTris, in which carbapenemase was extracted from bacteria with 0.5 M Tris-HCl (pH 7.6) buffer. The ability of the CIMTris to detect carbapenemase production was examined in
and
species. The CIMTris had an overall sensitivity of 97.6% and an overall specificity of 92.6%, whereas the mCIM had a sensitivity of 45.1% and a specificity of 100% for the isolates tested. These findings indicate that the CIMTris is useful for detecting carbapenemase production in
and
species.
Although over 60 loci for type 2 diabetes (T2D) have been identified, there still remains a large genetic component to be clarified. To explore unidentified loci for T2D, we performed a genome-wide ...association study (GWAS) of 6 209 637 single-nucleotide polymorphisms (SNPs), which were directly genotyped or imputed using East Asian references from the 1000 Genomes Project (June 2011 release) in 5976 Japanese patients with T2D and 20 829 nondiabetic individuals. Nineteen unreported loci were selected and taken forward to follow-up analyses. Combined discovery and follow-up analyses (30 392 cases and 34 814 controls) identified three new loci with genome-wide significance, which were MIR129-LEP rs791595; risk allele = A; risk allele frequency (RAF) = 0.080; P = 2.55 × 10(-13); odds ratio (OR) = 1.17, GPSM1 rs11787792; risk allele = A; RAF = 0.874; P = 1.74 × 10(-10); OR = 1.15 and SLC16A13 (rs312457; risk allele = G; RAF = 0.078; P = 7.69 × 10(-13); OR = 1.20). This study demonstrates that GWASs based on the imputation of genotypes using modern reference haplotypes such as that from the 1000 Genomes Project data can assist in identification of new loci for common diseases.
Aims/Introduction
We evaluated the efficacy of multifactorial intensive treatment (IT) on renal outcomes in patients with type 2 diabetes and advanced‐stage diabetic kidney disease (DKD).
Materials ...and Methods
The Diabetic Nephropathy Remission and Regression Team Trial in Japan (DNETT‐Japan) is a multicenter, open‐label, randomized controlled trial with a 5‐year follow‐up period. We randomly assigned 164 patients with advanced‐stage diabetic kidney disease (urinary albumin‐to‐creatinine ratio ≥300 mg/g creatinine, serum creatinine level 1.2–2.5 mg/dL in men and 1.0–2.5 mg/dL in women) to receive either IT or conventional treatment. The primary composite outcome was end‐stage kidney failure, doubling of serum creatinine or death from any cause, which was assessed in the intention‐to‐treat population.
Results
The IT tended to reduce the risk of primary end‐points as compared with conventional treatment, but the difference between treatment groups did not reach the statistically significant level (hazard ratio 0.69, 95% confidence interval 0.43–1.11; P = 0.13). Meanwhile, the decrease in serum low‐density lipoprotein cholesterol level and the use of statin were significantly associated with the decrease in primary outcome (hazard ratio 1.14; 95% confidence interval 1.05–1.23, P < 0.001 and hazard ratio 0.53, 95% confidence interval 0.28–0.998, P < 0.05, respectively). The incidence of adverse events was not different between treatment groups.
Conclusions
The risk of kidney events tended to decrease by IT, although it was not statistically significant. Lipid control using statin was associated with a lower risk of adverse kidney events. Further follow‐up study might show the effect of IT in patients with advanced diabetic kidney disease.
The Diabetic Nephropathy Remission and Regression Team Trial in Japan was designed to clarify the beneficial effects of multifactorial intensified intervention by the team approach with medical staffs at each institution. There was an overall trend toward a lower risk on the development of kidney events in the intensive treatment group than in the conventional treatment group in this trial, but the benefit of intensive treatment could not be confirmed statistically. Lipid control by statin was associated with lower risk of kidney events in addition to strict control of blood glucose and blood pressure.
Several studies have demonstrated that polymorphisms within the fat-mass and obesity-associated gene (FTO) are associated with type 2 diabetes (T2D). However, whether the effects of the FTO locus on ...T2D susceptibility are independent of fat-mass increases remains controversial. To investigate this issue, we examined the association of FTO variants with T2D and various aspects of BMI history during adult life in a Japanese population.
We genotyped SNPs within FTO (rs1121980 and rs1558902) in 760 Japanese patients with T2D who had reached a lifetime maximum BMI (BMImax) before or at the time of diagnosis and 693 control individuals with information regarding their BMImax.
The BMImax showed the strongest association with T2D risk among the BMIs evaluated in this study. In the sex-combined analysis, FTO SNPs were not associated with any of the BMI variables or with T2D, but in sex-stratified analyses, both SNPs were significantly associated with the BMImax and rs1558902 was associated with T2D in men. The association of the SNPs with T2D remained significant after adjustments for the current BMI and age, whereas the T2D association of the SNP was no longer significant after adjustments for BMImax and age.
These results suggest that the effects of FTO polymorphisms on T2D susceptibility in Japanese men are mediated through their effect on increasing the BMImax before or at the time of diagnosis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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