Dataset Information

Stratification of Type 2 Diabetes by Age of Diagnosis in the UK Biobank Reveals Subgroup-Specific Genetic Associations and Causal Risk Profiles.

ABSTRACT: The pathogenesis of type 2 diabetes (T2D) might change with increasing age. Here, we used a stratification based on age of diagnosis to gain insight into the genetics and causal risk factors of T2D across different age-groups. We performed genome-wide association studies (GWAS) on T2D and T2D subgroups based on age of diagnosis (<50, 50-60, 60-70, and >70 years) (total of 24,986 cases). As control subjects, participants were at least 70 years of age at the end of follow-up without developing T2D (N =187,130). GWAS identified 208 independent lead single nucleotide polymorphism (SNPs) mapping to 69 loci associated with T2D (P < 1.0e-8). Among others, SNPs mapped to CDKN2B-AS1 and multiple independent SNPs mapped to TCF7L2 were more strongly associated with cases diagnosed after age 70 years than with cases diagnosed before age 50 years. Based on the different case groups, we performed two-sample Mendelian randomization. Most notably, we observed that of the investigated risk factors, the association between BMI and T2D attenuated with increasing age of diagnosis. Collectively, our results indicate that stratification of T2D based on age of diag-nosis reveals subgroup-specific genetics and causal determinants, supporting the hypothesis that the pathogenesis of T2D changes with increasing age.

SUBMITTER: Noordam R

PROVIDER: S-EPMC8571356 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Stratification of Type 2 Diabetes by Age of Diagnosis in the UK Biobank Reveals Subgroup-Specific Genetic Associations and Causal Risk Profiles.

Noordam Raymond R Läll Kristi K Smit Roelof A J RAJ Laisk Triin T Metspalu Andres A Esko Tõnu T Milani Lili L Loos Ruth J F RJF Mägi Reedik R Willems van Dijk Ko K van Heemst Diana D

Diabetes 20210510 8

The pathogenesis of type 2 diabetes (T2D) might change with increasing age. Here, we used a stratification based on age of diagnosis to gain insight into the genetics and causal risk factors of T2D across different age-groups. We performed genome-wide association studies (GWAS) on T2D and T2D subgroups based on age of diagnosis (<50, 50-60, 60-70, and >70 years) (total of 24,986 cases). As control subjects, participants were at least 70 years of age at the end of follow-up without developing T2D ...[more]

PMID: 33972266

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Project description:Aims/hypothesisThe aim of the study was to examine the association of retinal vessel morphometry with BP, body composition and biochemistry, and to determine whether these associations differ by diabetes status.MethodsThe UK Biobank ocular assessment included 68,550 participants aged 40-70 years who underwent non-mydriatic retinal photography, BP and body composition measurements, and haematological analysis. A fully automated image analysis program provided measurements of retinal vessel diameter and tortuosity. The associations between retinal vessel morphology and cardiometabolic risk factors by diabetes status were examined using multilevel linear regression, to provide absolute differences in vessel diameter and percentage differences in tortuosity (allowing for within-person clustering).ResultsA total of 50,233 participants (a reduction from 68,550) were included in these analyses. Overall, those with diabetes had significantly more tortuous venules and wider arteriolar diameters compared with those without. Associations between venular tortuosity and cardiometabolic risk factors differed according to diabetes status (p interaction <0.01) for total fat mass index, HbA1c, C-reactive protein, white cell count and granulocyte count. For example, a unit rise in white cell count was associated with a 0.18% increase (95% CI 0.05, 0.32%) in venular tortuosity for those without diabetes and a 1.48% increase (95% CI 0.90, 2.07%) among those with diabetes. For arteriolar diameter, significant interactions were evident for systolic BP, diastolic BP, mean arterial pressure (MAP) and LDL-cholesterol. For example, a 10 mmHg rise in systolic BP was associated with a -0.92 μm difference (95% CI -0.96 to -0.88 μm) in arteriolar diameter for those without diabetes, and a -0.58 μm difference (95% CI -0.76 to -0.41 μm) among those with diabetes. No interactions were observed for arteriolar tortuosity or venular diameters.Conclusions/interpretationWe provide clear evidence of the modifying effect of diabetes on cardiometabolic risk factor associations with retinal microvascular architecture. These observations suggest the occurrence of preclinical disease processes, and may be a sign of impaired autoregulation due to hyperglycaemia, which has been suggested to play a pivotal role in the development of diabetes-related microvascular complications.Data availabilityThe data supporting the results reported here are available through the UK Biobank ( https://www.ukbiobank.ac.uk/enable-your-research/apply-for-access ).

Dataset Information

Stratification of Type 2 Diabetes by Age of Diagnosis in the UK Biobank Reveals Subgroup-Specific Genetic Associations and Causal Risk Profiles.

Publications

Stratification of Type 2 Diabetes by Age of Diagnosis in the UK Biobank Reveals Subgroup-Specific Genetic Associations and Causal Risk Profiles.

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