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Few studies have demonstrated reproducible gene-diet interactions (GDIs) impacting metabolic disease risk factors, likely due in part to measurement error in dietary intake estimation and insufficient capture of rare genetic variation. We aimed to identify GDIs across the genetic frequency spectrum impacting the macronutrient-glycemia relationship in genetically and culturally diverse cohorts. We analyzed 33,187 participants free of diabetes from 10 National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine program cohorts with whole-genome sequencing, self-reported diet, and glycemic trait data. We fit cohort-specific, multivariable-adjusted linear mixed models for the effect of diet, modeled as an isocaloric substitution of carbohydrate for fat, and its interactions with common and rare variants genome-wide. In main effect meta-analyses, participants consuming more carbohydrate had modestly lower glycemic trait values (e.g., for glycated hemoglobin [HbA1c], -0.013% HbA1c/250 kcal substitution). In GDI meta-analyses, a common African ancestry-enriched variant (rs79762542) reached study-wide significance and replicated in the UK Biobank cohort, indicating a negative carbohydrate-HbA1c association among major allele homozygotes only. Simulations revealed that >150,000 samples may be necessary to identify similar macronutrient GDIs under realistic assumptions about effect size and measurement error. These results generate hypotheses for further exploration of modifiable metabolic disease risk in additional cohorts with African ancestry., Article Highlights: We aimed to identify genetic modifiers of the dietary macronutrient-glycemia relationship using whole-genome sequence data from 10 Trans-Omics for Precision Medicine program cohorts. Substitution models indicated a modest reduction in glycemia associated with an increase in dietary carbohydrate at the expense of fat. Genome-wide interaction analysis identified one African ancestry-enriched variant near the FRAS1 gene that may interact with macronutrient intake to influence hemoglobin A1c. Simulation-based power calculations accounting for measurement error suggested that substantially larger sample sizes may be necessary to discover further gene-macronutrient interactions., (© 2023 by the American Diabetes Association.)

Objective: Diabetes is the leading cause of nontraumatic lower-limb amputations in the U.S., but no research has prospectively examined associations between limb-specific measurements and amputation risk among patients without foot ulcer. We investigated amputation risk by limb in relation to the same limb- and person-level factors., Research Design and Methods: We conducted a 22-year prospective study among 1,461 male patients with diabetes without foot ulcer (mean age 62.4 years), with 2,893 lower limbs among subjects recruited between 1990 and 2002 from one Department of Veterans Affairs general internal medicine clinic. The following information was collected: demographic, lifestyle, and diabetes characteristics; visual acuity; kidney function (estimated glomerular filtration rate [eGFR]); and lower-limb measurements including presence of Charcot deformity, sensory neuropathy by 10-g monofilament, dorsal foot transcutaneous oximetry (TcPO 2 ) at 44°C, and ankle-brachial index (ABI)., Results: Over 25,735 limb-years, 136 amputations occurred. A multivariable Cox model identified multiple independent risk factors: sensory neuropathy (hazard ratio 3.09 [95% CI 2.02-4.74]), ABI ≤0.5 vs. >0.9 to <1.3 (3.98 [2.31-6.85]), ABI ≥1.3 vs. >0.9 to <1.3 (2.20 [1.18-4.09]), 1-SD decrease in eGFR (1.18 [1.00-1.38]), poor vision (1.70 [1.05-2.73]), body weight in 21.4-kg increments (0.78 [0.61-0.98]), and age >70 years vs. <57 years (0.13 [0.04-0.38]). Although TcPO 2 was not significantly associated with amputation overall, TcPO 2 <26 mmHg significantly predicted a higher risk in the ABI ≥1.3 category., Conclusions: Arterial disease and neuropathy emerged as the only limb-specific risk factors for amputation, but these and several person-level factors may be amenable to prevention or treatment interventions to potentially reduce diabetic amputation risk., (© 2018 by the American Diabetes Association.)