Explore the vast range of titles available.

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.

Genome-wide association studies (GWAS) have significantly advanced the identification of genetic susceptibility variants associated with complex diseases. As of 2023, approximately 800 variants predisposing individuals to the risk of type 2 diabetes (T2D) were identified through GWAS, and the majority of studies were predominantly conducted in European populations. Despite the shared nature of the majority of genetic susceptibility loci across diverse ethnic populations, GWAS in non-European populations, including Japanese and East Asian populations, have revealed population-specific T2D loci. Currently, polygenic risk scores (PRSs), encompassing millions of associated variants, can identify individuals with a higher T2D risk than the general population. However, GWAS focusing on microvascular complications of diabetes have identified a limited number of disease-susceptibility loci. Ongoing efforts are crucial to enhance the applicability of PRS for all ethnic groups and unravel the genetic architecture of microvascular complications of diabetes.

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 −8 ) with 115 independent signals ( P  < 5.0 × 10 −6 ), of which 28 loci with 30 signals were novel. Twenty-eight missense variants were in linkage disequilibrium ( r 2  > 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 JPN  > 0.05 versus MAF EUR  < 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). Genome-wide association analyses identify 28 new susceptibility loci for type 2 diabetes in the Japanese population. Transethnic comparisons highlight the key role of beta cell dysfunction in type 2 diabetes across different ancestry groups.

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

PurposeCoronavirus disease 2019 (COVID-19) pandemic changed the dynamics of other community-acquired respiratory viruses (CARVs), however, information regarding the frequency of CARV detection during COVID-19 pandemic in subtropical regions is limited. Additionally, studies comparing the diagnostic accuracy between multiplex and monoplex PCR for the diagnosis of COVID-19 are scarce.MethodsWe evaluated samples collected from patients suspected of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in Okinawa, a subtropical climate in Japan, from March 2020 to March 2021. For SARS-CoV-2, results obtained from monoplex (NIID method) and multiplex (Allplex™ SARS-CoV-2 Assay) PCR were compared.ResultsIn total, 744 samples were collected and 238 viruses were detected in 205 specimens, of which 22 showed viral co-infection. Viral co-infection was more common in patients aged 10 and under than in older patients (p = 0.0054). For CARV, 142 viruses were detected in 127 specimens (17.1%), and human rhinovirus (HRV) was most common. Overall concordance rate for two SARS-CoV-2 assays was 94.1%; 7 and 37 specimens were detected only by NIID and Allplex™ SARS-CoV-2 Assay, respectively. The median cycling threshold values of the 44 samples that were only positive for either the NIID or Allplex™ SARS-CoV-2 Assay were 37.91 for E gene, 38.13 for RdRp/S gene, 38.21 for N gene and 39.16 for N2 gene.ConclusionHRV was continuously detected during COVID-19 pandemic in the subtropical region and viral co-infection was more common in younger patients. For the diagnosis of COVID-19, multiplex PCR was more reliable, especially in samples with low viral load.

Microinflammation has been recognized as an important process for the progression of diabetic nephropathy. Inflammatory cytokines, such as interleukin-6 produced by infiltrating cells or renal cells, play important roles in the pathogenesis of diabetic nephropathy. Although the mechanisms underlying the regulation of these cytokines in the kidneys of patients with diabetes mellitus remain unclear, genetic variations in the genes encoding the inflammatory cytokines might confer susceptibility to the disease by altering their functions or expressions.

Abstract Natural selection signatures across Japanese subpopulations are under-explored. Here we conducted genome-wide selection scans with 622,926 single nucleotide polymorphisms for 20,366 Japanese individuals, who were recruited from the main-islands of Japanese Archipelago (Hondo) and the Ryukyu Archipelago (Ryukyu), representing two major Japanese subpopulations. The integrated haplotype score (iHS) analysis identified several signals in one or both subpopulations. We found a novel candidate locus at IKZF2, especially in Ryukyu. Significant signals were observed in the major histocompatibility complex region in both subpopulations. The lead variants differed and demonstrated substantial allele frequency differences between Hondo and Ryukyu. The lead variant in Hondo tags HLA-A*33:03-C*14:03-B*44:03-DRB1*13:02-DQB1*06:04-DPB1*04:01, a haplotype specific to Japanese and Korean. While in Ryukyu, the lead variant tags DRB1*15:01-DQB1*06:02, which had been recognized as a genetic risk factor for narcolepsy. In contrast, it is reported to confer protective effects against type 1 diabetes and human T lymphotropic virus type 1-associated myelopathy/tropical spastic paraparesis. The FastSMC analysis identified 8 loci potentially affected by selection within the past 20–150 generations, including 2 novel candidate loci. The analysis also showed differences in selection patterns of ALDH2 between Hondo and Ryukyu, a gene recognized to be specifically targeted by selection in East Asian. In summary, our study provided insights into the selection signatures within the Japanese and nominated potential sources of selection pressure.

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 Ryukyu Islands are located in the southernmost part of the Japanese Archipelago and consist of several island groups. Each island group has its own history and culture, which differ from those of mainland Japan. People of the Ryukyu Islands are genetically subdivided; however, their detailed demographic history remains unclear. We report the results of a whole-genome sequencing analysis of a total of 50 Ryukyu islanders, focusing on genetic differentiation between Miyako and Okinawa islanders. We confirmed that Miyako and Okinawa islanders cluster differently in principal component analysis and ADMIXTURE analysis and that there is a population structure among Miyako islanders. The present study supports the hypothesis that population differentiation is primarily caused by genetic drift rather than by differences in the rate of migration from surrounding regions, such as the Japanese main islands or Taiwan. In addition, the genetic cline observed among Miyako and Okinawa islanders can be explained by recurrent migration beyond the bounds of these islands. Our analysis also suggested that the presence of multiple subpopulations during the Neolithic Ryukyu Jomon period is not crucial to explain the modern Ryukyu populations. However, the assumption of multiple subpopulations during the time of admixture with mainland Japanese is necessary to explain the modern Ryukyu populations. Our findings add insights that could help clarify the complex history of populations in the Ryukyu Islands.