Search

Objective: To evaluate whether high glucose levels in the normoglycemic range and higher have a causal genetic effect on risk of retinopathy, neuropathy, nephropathy, chronic kidney disease (CKD), peripheral arterial disease (PAD), and myocardial infarction (MI; positive control) in the general population.Research Design and Methods: This study applied observational and one-sample Mendelian randomization (MR) analyses to individual-level data from 117,193 Danish individuals, and validation by two-sample MR analyses on summary-level data from 133,010 individuals from the Meta-Analyses of Glucose and Insulin-Related Traits Consortium (MAGIC), 117,165 from the CKDGen Consortium, and 452,264 from the UK Biobank.Results: Observationally, glucose levels in the normoglycemic range and higher were associated with high risks of retinopathy, neuropathy, diabetic nephropathy, PAD, and MI (all P for trend <0.001). In genetic causal analyses, the risk ratio for a 1 mmol/L higher glucose level was 2.01 (95% CI 1.18-3.41) for retinopathy, 2.15 (1.38-3.35) for neuropathy, 1.58 (1.04-2.40) for diabetic nephropathy, 0.97 (0.84-1.12) for estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2, 1.19 (0.90-1.58) for PAD, and 1.49 (1.02-2.17) for MI. Summary-level data from the MAGIC, the CKDGen Consortium, and the UK Biobank gave a genetic risk ratio of 4.55 (95% CI 2.26-9.15) for retinopathy, 1.48 (0.83-2.66) for peripheral neuropathy, 0.98 (0.94-1.01) for eGFR <60 mL/min/1.73 m2, and 1.23 (0.57-2.67) for PAD per 1 mmol/L higher glucose level.Conclusions: Glucose levels in the normoglycemic range and higher were prospectively associated with a high risk of retinopathy, neuropathy, diabetic nephropathy, eGFR <60 mL/min/1.73 m2, PAD, and MI. These associations were confirmed in genetic causal analyses for retinopathy, neuropathy, diabetic nephropathy, and MI, but they could not be confirmed for PAD and seemed to be refuted for eGFR <60 mL/min/1.73 m2. [ABSTRACT FROM AUTHOR]

OBJECTIVE Mortality is increased in patients with hereditary hemochromatosis, in individuals from the general population with increased transferrin saturation (TS), and also in patients with type 1 diabetes and increased TS from a highly specialized diabetes clinic. Thus, we have recommended targeted screening for TS in specialized diabetes clinics. Whether mortality is also increased in individuals from the general population with diabetes and increased TS is unknown. RESEARCH DESIGN AND METHODS In two Danish population studies (N = 84,865), we examined mortality according to baseline levels of TS and hemochromatosis genotype (HFE) G → A substitution at nucleotide 845 in codon 282 (C282Y/C282Y) in individuals with diabetes (type 1, N = 118; type 2, N = 3,228; total, N = 3,346). RESULTS The cumulative survival rate was reduced in individuals with diabetes with TS ≥50% vs. <50% (log-rank; P < 0.0001), with median survival ages of 66 and 79 years, respectively. The hazard ratio (HR) for TS ≥50% vs. <50% was 2.0 (95% CI 1.3-2.8; P = 0.0004) for total mortality overall (and similar for men and women separately); 2.6 (1.3-5.4; P = 0.008) for neoplasms; and 3.4 (2.0-6.0; P = 0.00002) for endocrinological causes. A stepwise increased risk of total mortality was observed for stepwise increasing TS (log-rank test, P= 0.0001), with an HR for TS ≥70% vs. TS <20% of 4.8 (2.0-12; P = 0.0006). The HR for total mortality in individuals with diabetes for C282Y/C282Y versus wild type/wild type was 3.3 (1.04-10; P = 0.04), and for C282Y/C282Y and TS ≥50% versus wild type/wild type and TS <50% was 6.0 (1.5-24; P = 0.01). Six percent of these premature deaths can possibly be avoided by early screening for TS or HFE genotype. CONCLUSIONS Individuals with diabetes, ascertained in the general population, with increased TS or HFE genotype have a twofold to sixfold increased risk of premature death. [ABSTRACT FROM AUTHOR]

OBJECTIVE--It is not known to what extent iron overload predicts prognosis in patients with diabetes after diagnosis or whether iron overload is a risk factor independent of the geno-HFE type. We investigated total and cause-specific mortality according to increased transferrin saturation (≥50 vs. <50%), whether mortality is driven by the genotype, and whether early HFE measurement of transferrin saturation helps to predict mortality outcome. RESEARCH DESIGN AND METHODS--Cohort 1 included patients with late-onset type 1 diabetes (n = 716) with a cross-sectional measurement of transferrin saturation and HFE genotype. Cohort 2 included consecutively recruited patients with any diabetes (n = 6,120), transferrin saturation measurement at referral, and genotype if transferrin saturation HFE was above 50%. RESULTS--In cohort 1, the hazard ratio for total mortality was 2.3 (95% CI 1.3-3.9; P = 0.002) and for cause-specific mortality by neoplasms was 5.8 (2.4-14; P = 0.00007) in patients with transferrin saturation ≥50 vs. <50%. Excluding genotypes C282Y/C282Y and C282Y/H63D gave similar results. The hazard ratio for total mortality was 4.0 (1.2-13; P = 0.01) and for cause-specific mortality by neoplasms was 13 (3.6-49; P = 0.0001) in patients with C282Y/C282Y versus wild type. In cohort 2, total mortality was not different in patients with transferrin saturation ≥50 vs. <50%. In patients with late-onset type 1 diabetes and transferrin saturation ≥50%, the hazard ratio for total mortality was 0.4 (0.2-0.9; P = 0.03) in cohort 2 versus cohort 1. CONCLUSIONS--Increased transferrin saturation and genotype C282Y/C282Y predict HFE total mortality in patients with late-onset type 1 diabetes, and increased transferrin saturation after diagnosis is an independent risk factor. Early measurement of transferrin saturation in these patients leading to early intervention improves life expectancy. [ABSTRACT FROM AUTHOR]

Objective: Alterations of pancreatic β-cell cholesterol content may contribute to β-cell dysfunction. Two important determinants of intracellular cholesterol content are the ATP-binding cassette (ABC) transporters A1 (ABCA1) and -G1 (ABCG1). Whether genetic variation in ABCA1 and ABCG1 predicts risk of type 2 diabetes in the general population is unknown.Research Design and Methods: We tested whether genetic variation in the promoter and coding regions of ABCA1 and ABCG1 predicted risk of type 2 diabetes in the general population. Twenty-seven variants, identified by previous resequencing of both genes, were genotyped in the Copenhagen City Heart Study (CCHS) (n = 10,185). Two loss-of-function mutations (ABCA1 N1800H and ABCG1 g.-376C>T) (n = 322) and a common variant (ABCG1 g.-530A>G) were further genotyped in the Copenhagen General Population Study (CGPS) (n = 30,415).Results: Only one of the variants examined, ABCG1 g.-530A>G, predicted a decreased risk of type 2 diabetes in the CCHS (P for trend = 0.05). Furthermore, when validated in the CGPS or in the CCHS and CGPS combined (n = 40,600), neither the two loss-of-function mutations (ABCA1 N1800H, ABCG1 g.-376C>T) nor ABCG1 g.-530A>G were associated with type 2 diabetes (P values >0.57 and >0.30, respectively).Conclusions: Genetic variations in ABCA1 and ABCG1 were not associated with increased risk of type 2 diabetes in the general population. These data were obtained in general population samples harboring the largest number of heterozygotes for loss-of-function mutations in ABCA1 and ABCG1. [ABSTRACT FROM AUTHOR]

OBJECTIVE-Alterations of pancreatic β-cell cholesterol content may contribute to β-cell dysfunction. Two important determinants of intracellular cholesterol content are the ATPbinding cassette (ABC) transporters A1 (ABCA1) and -G1 (ABCG1).Whether genetic variation in ABCA1 and ABCG1 predicts risk of type 2 diabetes in the general population is unknown. RESEARCH DESIGN AND METHOD-We tested whether genetic variation in the promoter and coding regions of ABCA1 and ABCG1 predicted risk of type 2 diabetes in the general population. Twenty-seven variants, identified by previous resequencing of both genes, were genotyped in the Copenhagen City Heart Study (CCHS) (n = 10,185). Two loss-of-function mutations (ABCA1 N1800H and ABCG1 g.-376C>T) (n = 322) and a common variant (ABCG1 g.-530A>G) were further genotyped in the Copenhagen General Population Study (CGPS) (n = 30,415). RESULT-Only one of the variants examined, ABCG1 g.-530A>G, predicted a decreased risk of type 2 diabetes in the CCHS (P for trend = 0.05). Furthermore, when validated in the CGPS or in the CCHS and CGPS combined (n = 40,600), neither the two loss-of-function mutations (ABCA1 N1800H, ABCG1 g.-376C>T) nor ABCG1 g.-530A>G were associated with type 2 diabetes (P values >0.57 and >0.30, respectively). CONCLUSION-Genetic variations in ABCA1 and ABCG1 were not associated with increased risk of type 2 diabetes in the general population. These data were obtained in general population samples harboring the largest number of heterozygotes for loss-of-function mutations in ABCA1 and ABCG1 [ABSTRACT FROM AUTHOR]

Objective: We tested the hypothesis that elevated transferrin saturation is associated with an increased risk of any form of diabetes, as well as type 1 or type 2 diabetes separately.Research Design and Methods: We used two general population studies, The Copenhagen City Heart Study (CCHS, N = 9,121) and The Copenhagen General Population Study (CGPS, N = 24,195), as well as a 1:1 age- and sex-matched population-based case-control study with 6,129 patients with diabetes from the Steno Diabetes Centre and 6,129 control subjects, totaling 8,535 patients with diabetes and 37,039 control subjects.Results: In the combined studies, odds ratios in those with transferrin saturation ≥50% vs. <50% were 2.1 (95% CI 1.3-3.4; P = 0.003) for any form of diabetes; 2.6 (1.2-5.6; P = 0.01) for type 1 diabetes; and 1.7 (1.4-2.1; P = 0.001) for type 2 diabetes.Conclusions: Elevated transferrin saturation confers a two- to threefold increased risk of developing any form of diabetes, as well as type 1 and type 2 diabetes separately. [ABSTRACT FROM AUTHOR]