To further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and ...83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry. We observed a significant excess in the directional consistency of T2D risk alleles across ancestry groups, even at SNPs demonstrating only weak evidence of association. By following up the strongest signals of association from the trans-ethnic meta-analysis in an additional 21,491 cases and 55,647 controls of European ancestry, we identified seven new T2D susceptibility loci. Furthermore, we observed considerable improvements in the fine-mapping resolution of common variant association signals at several T2D susceptibility loci. These observations highlight the benefits of trans-ethnic GWAS for the discovery and characterization of complex trait loci and emphasize an exciting opportunity to extend insight into the genetic architecture and pathogenesis of human diseases across populations of diverse ancestry.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
In Chinese populations, middle cerebral artery (MCA) stenosis is the most commonly identified intracranial vascular lesion, and has been shown to be associated with an increased risk of secondary ...stroke mortality, but has yet to be reported for primary events. We assess whether asymptomatic MCA stenosis is associated with mortality in Chinese type 2 diabetic patients.
The presence of MCA stenosis was determined by transcranial Doppler and mortality data were collated in the Hong Kong Death Registry. Cox proportional hazards regression was used to determine if the MCA stenosis (n = 272, 53.7% 2-vessel disease) in 2,197 diabetics was associated with all-cause or vascular disease mortality, including after adjustment for conventional vascular risk factors. Anthropometric and fasting biochemical parameters were compared between diabetic patients with MCA stenosis and without evidence of stenosis.
A total of 191 deaths were identified (30.9% of vascular disease origin) during a follow-up of 18,279 patient years over 8.32 years. After adjustment for age, gender and diabetes duration, the hazard ratios for vascular mortality for 1- and 2-vessel disease were 2.47 (95% CI = 1.13-5.38) and 4.47 (95% CI = 2.24-8.82), p < 0.001 for trend, for increasing vascular mortality with increasing severity of cerebrovascular involvement, but 0.81 (95% CI = 0.45-1.47) and 2.23 (95% CI = 1.45-1.47), p = 0.001 for trend, for all-cause mortality. For vascular mortality, further adjustments for anthropometric and fasting biochemical parameters, or existing disease and treatment history increased the hazard ratios for 1-vessel disease slightly but attenuated the risk for 2-vessel disease evidently, 2.81 (95% CI = 1.10-7.16) and 2.85 (95% = CI 1.11-7.33), p = 0.026.
The presence of MCA stenoses was an independent predictor of vascular mortality in these diabetics. More aggressive treatment of risk factors in these subjects merits further evaluation.
Abstract Aim Dyslipidaemia may be a risk factor for diabetic kidney disease. We examined prospectively association between the use of statins and development of renal dysfunction in type 2 diabetes. ...Methods A consecutive cohort of 5264 diabetic patient recruited between 1996 and 2005 underwent detailed assessments. Renal dysfunction was defined as first estimated glomerular filtration rate <60 ml/min/1.73 m2 , or, the first hospitalisation with a diagnosis of renal disease as coded by the International Classification of Disease, Ninth Revision. Drug use was quantified using the proportion of exposure time from baseline to event/death/censored time, as appropriate. Results In this cohort (male: 47.3%, median age: 55 years, median duration of diabetes: 6.0 years), none had renal dysfunction at baseline. During a median follow-up period of 4.9 (quartiles: 2.77, 7.04) years, 703 patients (13.4%) developed renal dysfunction, 1275 patients (22.2%) were exposed to statins. After controlling for baseline risk factors, multivariable adjusted hazard ratio of statin use for development of renal dysfunction was 0.32 (95% CI 0.21–0.50, p < 0.0001). Conclusion Use of statins was associated with reduced risk of developing renal dysfunction in type 2 diabetes and this association was independent of baseline risk factors.
In the past two decades, we have acquired an enormous amount of knowledge regarding the epidemiology, diagnosis, pathophysiology and treatment of type 2 diabetes and its comorbidities. In addition to ...the earlier landmark blood lipid and blood pressure lowering trials, the latest blood glucose lowering megatrials represent the zenith of this global effort to prevent and control diabetes, and its devastating consequences. Although many of these latter trials have yielded negative results and have shown the narrow risk‐benefit ratio of intensive treatment in patients with advanced disease, the exceedingly low event rates in these high‐risk patients who were carefully monitored and intensively managed made possible in these clinical trial settings have not been emphasized enough. The heterogeneity of the clinical outcomes in these studies further highlight the complexity of diabetes, which is more than managing a disease, but the multiple needs of a patient with multisystem dysfunction. In the final analysis, what transpires from these megatrials is the need to translate the key components of these studies, namely, protocol, team, documentation and monitoring, into our daily clinical practice to enable the care team to stratify risk, define needs, individualize therapy, monitor progress and reinforce compliance in order to achieve positive outcomes. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00063.x, 2010)
Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes
and molecular mechanisms that are often specific to cell type
. Here, to characterize the ...genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P < 5 × 10
) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores
in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.
In a series of 31 cases of renal impairment with renal biopsies showing deposits of tubular calcium phosphate, the risk was highest among patients with preexisting renal impairment, elderly patients, ...and patients with hypertension or concurrent use of ACE inhibitor or angiotensin receptor blocker (ARB). The U.S. Food and Drug Administration has recently issued an alert advising against the use of OSP products in patients with kidney disease, impaired renal function or perfusion, dehydration, or uncorrected electrolyte abnormalities.
Introduction & Objectives: Monogenic diabetes are caused by rare mutations in genes usually implicated in β-cell reserve/function. Whether their common variants could jointly influence risk of YOD ...diagnosed before 40 years and CV-kidney events is underexplored. We hypothesized a positive association of a weighted PRS derived from common variants of MDG with these outcomes. Methods: We constructed three weighted PRS with common variants (minor allele frequency>0.01) of 34 MDG based on three r2 thresholds (0.2, 0.4, 0.6) of linkage disequilibrium (LD), from a discovery cohort of adults with n=453, median age (interquartile range) = 40.0 (35.0-47.0) and without n=405, age=56.7 (50.3-61.0) YOD who had whole exome sequencing data followed by validation in an independent cohort with array-based genotyping. We further tested association of the best performer with incident CV-kidney events in a cohort of type 2 diabetes (T2D). Results: 135 single nucleotide polymorphisms were used to construct the PRS based on LD r2 threshold 0.2 which performed the best at validation in an independent cohort (920 YOD + 4909 non-YOD) where per standard deviation (SD) rise in PRS was associated with 8% increased risk of YOD after adjusting sex and BMI (OR 1.08, p=0.047). In an independent cohort of T2D free of CV-kidney events at baseline n=2313, age = 53.4 (45.4-61.7), disease duration = 4.0 (1.0-9.0), per SD rise in PRS was associated with 16%, 9% and 10% increased risk of incident CV (HR 1.16, p<0.001), kidney (HR 1.09, p=0.011) and CV-kidney events (HR 1.10, p=0.003) respectively after adjusting sex, baseline age and metabolic control. Those at top 20% PRS and baseline diabetes duration (DD) 5 to <10 years had higher hazards of incident CV-kidney events than those at bottom 20% PRS and DD ≥10 years (HR 1.66, p=0.019) by direct comparison. Conclusion: Common variants of MDG jointly affected the risk of YOD and CV-kidney complications. Disclosure C. O: Other Relationship; Novo Nordisk. B. Fan: None. S.T.F. Tsoi: None. C.H. Tam: None. R. Wan: None. E.S.H. Lau: None. M. Shi: None. C.K.P. Lim: None. E. Chow: Research Support; Merck KGaA. Speaker's Bureau; AstraZeneca. Advisory Panel; Boehringer-Ingelheim. Research Support; Medtronic. Speaker's Bureau; Zuellig Pharma Holdings Pte. Ltd., Abbott. A.P. Kong: Speaker's Bureau; Abbott. Advisory Panel; Merck Sharp & Dohme Corp. Speaker's Bureau; Boehringer-Ingelheim, Bayer Inc., AstraZeneca. Other Relationship; Dexcom, Inc. Speaker's Bureau; Eli Lilly and Company, Novo Nordisk, Sanofi. Advisory Panel; Kyowa Kirin Co., Ltd., Abbott. R.C. Ma: Advisory Panel; AstraZeneca. Other Relationship; Bayer Inc., Boehringer-Ingelheim. Advisory Panel; Merck & Co., Inc. Other Relationship; Roche Diagnostics, Novo Nordisk. Advisory Panel; Takeda Pharmaceutical Company Limited. Other Relationship; GemVCare Ltd. A. Luk: Research Support; Novo Nordisk, Amgen Inc., Merck Sharp & Dohme Corp., Roche Pharmaceuticals, Biogen, Boehringer-Ingelheim, Shanghai Junshi Biosciences CO.Ltd. J.C. Chan: Research Support; AstraZeneca, Hua Medicine. Consultant; Sanofi. Research Support; Servier Laboratories. Consultant; Viatris Inc. Research Support; Merck & Co., Inc. Stock/Shareholder; GemVCare Ltd. Board Member; Asia Diabetes Foundation. Speaker's Bureau; Zuellig Pharma Holdings Pte. Ltd. Advisory Panel; Bayer Inc. Speaker's Bureau; Boehringer-Ingelheim. Funding Health and Medical Research Fund, Health Bureau, the HKSAR Government (CFS-CUHK2); Research Impact Fund, the Research Grants Council Hong Kong (R4012-18); Hong Kong Genome Institute
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