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Rare Genetic Variants of Large Effect Influence Risk of Type 1 Diabetes.

ABSTRACT: Most replicated genetic determinants for type 1 diabetes are common (minor allele frequency [MAF] >5%). We aimed to identify novel rare or low-frequency (MAF <5%) single nucleotide polymorphisms with large effects on risk of type 1 diabetes. We undertook deep imputation of genotyped data followed by genome-wide association testing and meta-analysis of 9,358 type 1 diabetes case and 15,705 control subjects from 12 European cohorts. Candidate variants were replicated in a separate cohort of 4,329 case and 9,543 control subjects. Our meta-analysis identified 27 independent variants outside the MHC, among which 3 were novel and had MAF <5%. Three of these variants replicated with P _replication < 0.05 and P _combined < P _discovery In silico analysis prioritized a rare variant at 2q24.3 (rs60587303 [C], MAF 0.5%) within the first intron of STK39, with an effect size comparable with those of common variants in the INS and PTPN22 loci (combined [from the discovery and replication cohorts] estimate of odds ratio [OR_combined] 1.97, 95% CI 1.58-2.47, P _combined = 2.9 × 10^-9). Pharmacological inhibition of Stk39 activity in primary murine T cells augmented effector responses through enhancement of interleukin 2 signaling. These findings provide insight into the genetic architecture of type 1 diabetes and have identified rare variants having a large effect on disease risk.

SUBMITTER: Forgetta V

PROVIDER: S-EPMC7085253 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Rare Genetic Variants of Large Effect Influence Risk of Type 1 Diabetes.

Forgetta Vincenzo V Manousaki Despoina D Istomine Roman R Ross Stephanie S Tessier Marie-Catherine MC Marchand Luc L Li Min M Qu Hui-Qi HQ Bradfield Jonathan P JP Grant Struan F A SFA Hakonarson Hakon H Paterson Andrew D AD Piccirillo Ciriaco C Polychronakos Constantin C Richards J Brent JB

Diabetes 20200131 4

Most replicated genetic determinants for type 1 diabetes are common (minor allele frequency [MAF] >5%). We aimed to identify novel rare or low-frequency (MAF <5%) single nucleotide polymorphisms with large effects on risk of type 1 diabetes. We undertook deep imputation of genotyped data followed by genome-wide association testing and meta-analysis of 9,358 type 1 diabetes case and 15,705 control subjects from 12 European cohorts. Candidate variants were replicated in a separate cohort of 4,329 ...[more]

PMID: 32005708

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Project description:Type 2 diabetes mellitus incidence is increased in HIV-infected persons. We examined the associations of diabetes mellitus with known diabetes mellitus-risk alleles from the general population in the context of HIV infection, and explored effect modification by combination antiretroviral therapy (cART).The Women's Interagency HIV Study is a prospective cohort of HIV-infected women. Seventeen European-derived diabetes mellitus-risk polymorphisms were genotyped in the eligible participants of the Women's Interagency HIV Study. Analyses were run separately for non-African Americans (Whites, Hispanics, Asians, and other; n?=?378, 49 with incident diabetes mellitus) and African Americans (n?=?591, 49 with incident diabetes mellitus). Cox proportional-hazards models were fit to estimate hazard ratios for diabetes mellitus overall and within strata of cART.In non-African Americans, heterogeneity across cART regimen was observed for nine of the 14 polymorphisms (phet?<?0.05). One polymorphism was statistically significantly inversely associated with diabetes mellitus risk among women taking two nucleotide reverse transcriptase inhibitors (NRTIs) + non-nucleotide reverse transcriptase inhibitor (NNRTI). Five polymorphisms were statistically significantly associated with diabetes mellitus among women treated with at least two NRTIs?+?at least one protease inhibitor and one polymorphism was associated with diabetes mellitus among those treated with at least three NRTIs?±?NNRTI. The hazard ratio per risk allele for IGF2BP2 rs1470579 was 2.67 (95% confidence interval 1.67-4.31) for women taking cART with at least two NRTIs?+?at least one protease inhibitor and 2.45 (95% confidence interval 1.08-5.53) in women taking at least three NRTIs?±?NNRTI (phet?=?2.50?×?10?³). No such associations were observed in the African Americans.Genetic susceptibility to diabetes mellitus, based on the variants studied, is substantially elevated among HIV-infected women using cART containing three or more NRTI/protease inhibitor components. A personalized medicine approach to cART selection may be indicated for HIV-infected persons carrying these diabetes mellitus-risk variants.

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Rare Genetic Variants of Large Effect Influence Risk of Type 1 Diabetes.

Publications

Rare Genetic Variants of Large Effect Influence Risk of Type 1 Diabetes.

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