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Classification of Type 2 Diabetes Genetic Variants and a Novel Genetic Risk Score Association With Insulin Clearance.

ABSTRACT: CONTEXT:Genome-wide association studies have identified more than 450 single nucleotide polymorphisms (SNPs) for type 2 diabetes (T2D). OBJECTIVE:To facilitate use of these SNPs in future genetic risk score (GRS)-based analyses, we aimed to classify the SNPs based on physiology. We also sought to validate GRS associations with insulin-related traits in deeply phenotyped Mexican Americans. DESIGN, SETTING, AND PARTICIPANTS:A total of 457 T2D SNPs from the literature were assigned physiologic function based on association studies and cluster analyses. All SNPs (All-GRS), beta-cell (BC-GRS), insulin resistance (IR-GRS), lipodystrophy (Lipo-GRS), and body mass index plus lipids (B + L-GRS) were evaluated for association with diabetes and indices of insulin secretion (from oral glucose tolerance test), insulin sensitivity and insulin clearance (from euglycemic clamp), and adiposity and lipid markers in 1587 Mexican Americans. RESULTS:Of the 457 SNPs, 52 were classified as BC, 30 as IR, 12 as Lipo, 12 as B + L, whereas physiologic function of 351 was undefined. All-GRS was strongly associated with T2D. Among nondiabetic Mexican Americans, BC-GRS was associated with reduced insulinogenic index, IR-GRS was associated with reduced insulin sensitivity, and Lipo-GRS was associated with reduced adiposity. B + L-GRS was associated with increased insulin clearance. The latter did not replicate in an independent cohort wherein insulin clearance was assessed by a different method. CONCLUSIONS:Supporting their utility, BC-GRS, IR-GRS, and Lipo-GRS, based on SNPs discovered largely in Europeans, exhibited expected associations in Mexican Americans. The novel association of B + L-GRS with insulin clearance suggests that impaired ability to reduce insulin clearance in compensation for IR may play a role in the pathogenesis of T2D. Whether this applies to other ethnic groups remains to be determined.

SUBMITTER: Goodarzi MO

PROVIDER: S-EPMC7059988 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Classification of Type 2 Diabetes Genetic Variants and a Novel Genetic Risk Score Association With Insulin Clearance.

Goodarzi Mark O MO Palmer Nicholette D ND Cui Jinrui J Guo Xiuqing X Chen Yii-Der I YI Taylor Kent D KD Raffel Leslie J LJ Wagenknecht Lynne E LE Buchanan Thomas A TA Hsueh Willa A WA Rotter Jerome I JI

The Journal of clinical endocrinology and metabolism 20200401 4

<h4>Context</h4>Genome-wide association studies have identified more than 450 single nucleotide polymorphisms (SNPs) for type 2 diabetes (T2D).<h4>Objective</h4>To facilitate use of these SNPs in future genetic risk score (GRS)-based analyses, we aimed to classify the SNPs based on physiology. We also sought to validate GRS associations with insulin-related traits in deeply phenotyped Mexican Americans.<h4>Design, setting, and participants</h4>A total of 457 T2D SNPs from the literature were ass ...[more]

PMID: 31714576

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Project description:BackgroundType 2 diabetes (T2D) is a prevalent chronic disease associated with several comorbidities.ObjectivesThis study investigated whether the risk of T2D varied with genetically predicted insulin (INS), insulin receptor (INS-R), or insulin-like growth factor 1 receptor (IGF-1R) using genetic variants in a Mendelian randomization (MR) study.MethodsA 2-sample MR study was conducted using summary statistics from 2 genome-wide association studies (GWASs). Genetic predictors of the exposures (INS, INS-R, and IGF-1R) were obtained from a publicly available proteomics GWAS of the INTERVAL randomized controlled trial of blood donation in the United Kingdom. For T2D, the study leveraged the DIAbetes Meta-ANalysis of Trans-Ethnic association studies (DIAMANTE) consortium. The estimated associations of INS, INS-R, and IGF-1R proteins with T2D were based on independent single nucleotide polymorphisms (SNPs) strongly (P < 5 × 10-6) predicting each exposure. These SNPs were applied to publicly available genetic associations with T2D from the DIAMANTE case (n = 74,124) and control (n = 824,006) study of people of European descent. SNP-specific Wald estimates were meta-analyzed using inverse variance weighting with multiplicative random effects. Sensitivity analysis was conducted using the weighted median (WM) and MR-Egger.ResultsINS-R (based on 13 SNPs) was associated with a lower risk of T2D (OR: 0.95 per effect size; 95% CI: 0.92, 0.98; P = 0.001), with similar estimates from the WM and MR-Egger. Insulin (8 SNPs) and IGF-1R (10 SNPs) were not associated with T2D. However, 1 of the SNPs for INS-R was from the ABO blood group gene.ConclusionsThis study is consistent with a causally protective association of the INS-R with T2D. INS-R in RBCs regulates glycolysis and thus may affect their functionality and integrity. However, a pleiotropic effect via the blood group ABO gene cannot be excluded. The INS-R may be a target for intervention by repurposing existing therapeutics or otherwise to reduce the risk of T2D.

Project description:BackgroundStrong evidence supports that dietary modifications may decrease incident type 2 diabetes mellitus (T2DM). Numerous diabetes risk models/scores have been developed, but most do not rely specifically on dietary variables or do not fully capture the overall dietary pattern. We prospectively assessed the association of a dietary-based diabetes-risk score (DDS), which integrates optimal food patterns, with the risk of developing T2DM in the SUN ("Seguimiento Universidad de Navarra") longitudinal study.MethodsWe assessed 17,292 participants initially free of diabetes, followed-up for a mean of 9.2 years. A validated 136-item FFQ was administered at baseline. Taking into account previous literature, the DDS positively weighted vegetables, fruit, whole cereals, nuts, coffee, low-fat dairy, fiber, PUFA, and alcohol in moderate amounts; while it negatively weighted red meat, processed meats and sugar-sweetened beverages. Energy-adjusted quintiles of each item (with exception of moderate alcohol consumption that received either 0 or 5 points) were used to build the DDS (maximum: 60 points). Incident T2DM was confirmed through additional detailed questionnaires and review of medical records of participants. We used Cox proportional hazards models adjusted for socio-demographic and anthropometric parameters, health-related habits, and clinical variables to estimate hazard ratios (HR) of T2DM.ResultsWe observed 143 T2DM confirmed cases during follow-up. Better baseline conformity with the DDS was associated with lower incidence of T2DM (multivariable-adjusted HR for intermediate (25-39 points) vs. low (11-24) category 0.43 [95% confidence interval (CI) 0.21, 0.89]; and for high (40-60) vs. low category 0.32 [95% CI: 0.14, 0.69]; p for linear trend: 0.019).ConclusionsThe DDS, a simple score exclusively based on dietary components, showed a strong inverse association with incident T2DM. This score may be applicable in clinical practice to improve dietary habits of subjects at high risk of T2DM and also as an educational tool for laypeople to help them in self-assessing their future risk for developing diabetes.

Dataset Information

Classification of Type 2 Diabetes Genetic Variants and a Novel Genetic Risk Score Association With Insulin Clearance.

Publications

Classification of Type 2 Diabetes Genetic Variants and a Novel Genetic Risk Score Association With Insulin Clearance.

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