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The effect of diabetes and the common diabetogenic TBC1D4 p.Arg684Ter variant on cardiovascular risk in Inuit in Greenland

ABSTRACT: Cardiovascular disease (CVD) is a well-known complication of diabetes, but the association has not been studied among Inuit in Greenland. The aim was to examine the association between diabetes and incident CVD among Inuit in Greenland and determine if the common diabetogenic TBC1D4 variant confers increased risk of CVD. We followed an initial study population of 4127 adults in Greenland who had participated in at least one population-based health survey, in national registers. We used Poisson regression to calculate incidence rate ratios (IRR) of cardiovascular endpoints, comparing participants with and without diabetes and comparing homozygous TBC1D4 carriers with heterozygous carriers and non-carriers combined. Close to 10% had diabetes and age range was 18–96 years (45% male). Of the 3924 participants without prior CVD, 362 (~?9%) had CVD events during a median follow-up of 10 years. Multivariate IRR for the effect of diabetes on CVD was 1.12 (95% CI: 0.80, 1.57) p?=?0.50. Using a recessive genetic model, we compared homozygous TBC1D4 carriers with wildtype and heterozygous carriers combined, with a multivariate IRR of 1.20 (95% CI: 0.69, 2.11) p?=?0.52. Neither diabetes nor the TBC1D4 variant significantly increased CVD risk among Inuit in Greenland in adjusted models.

SUBMITTER: Overvad M

PROVIDER: S-EPMC7745023 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Skeletal muscle proteome analysis of Inuit homozygous carriers of the common Greenlandic TBC1D4 p.Arg684Ter variant

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A common missense variant in the ATP receptor P2X7 is associated with reduced risk of cardiovascular events.

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| S-EPMC3360776 | biostudies-literature

A novel splice-affecting <i>HNF1A</i> variant with large population impact on diabetes in Greenland.

Project description:BackgroundThe genetic disease architecture of Inuit includes a large number of common high-impact variants. Identification of such variants contributes to our understanding of the genetic aetiology of diseases and improves global equity in genomic personalised medicine. We aimed to identify and characterise novel variants in genes associated with Maturity Onset Diabetes of the Young (MODY) in the Greenlandic population.MethodsUsing combined data from Greenlandic population cohorts of 4497 individuals, including 448 whole genome sequenced individuals, we screened 14 known MODY genes for previously identified and novel variants. We functionally characterised an identified novel variant and assessed its association with diabetes prevalence and cardiometabolic traits and population impact.FindingsWe identified a novel variant in the known MODY gene HNF1A with an allele frequency of 1.9% in the Greenlandic Inuit and absent elsewhere. Functional assays indicate that it prevents normal splicing of the gene. The variant caused lower 30-min insulin (β = -232 pmol/L, βSD = -0.695, P = 4.43 × 10-4) and higher 30-min glucose (β = 1.20 mmol/L, βSD = 0.441, P = 0.0271) during an oral glucose tolerance test. Furthermore, the variant was associated with type 2 diabetes (OR 4.35, P = 7.24 × 10-6) and HbA1c (β = 0.113 HbA1c%, βSD = 0.205, P = 7.84 × 10-3). The variant explained 2.5% of diabetes variance in Greenland.InterpretationThe reported variant has the largest population impact of any previously reported variant within a MODY gene. Together with the recessive TBC1D4 variant, we show that close to 1 in 5 cases of diabetes (18%) in Greenland are associated with high-impact genetic variants compared to 1-3% in large populations.FundingNovo Nordisk Foundation, Independent Research Fund Denmark, and Karen Elise Jensen's Foundation.

| S-EPMC9832271 | biostudies-literature

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