Application of a Genetic Risk Score to Racially Diverse Type 1 Diabetes Populations Demonstrates the Need for Diversity in Risk-Modeling

• Type of Material: Article
• Authors: Daniel J. Perry, College of Medicine; Clive H. Wasserfall, College of Medicine; Richard A. Oram, University of Exeter; MacKenzie D. Williams, College of Medicine; Amanda Posgai, College of Medicine; Andrew B. Muir, Emory University; Michael J. Haller, College of Medicine; Desmond A. Schatz, College of Medicine; Mark A. Wallet, College of Medicine; Clayton E. Mathews, College of Medicine; Mark A. Atkinson, College of Medicine; Todd M. Brusko, College of Medicine
• Language: English
• Date: 2018-03-14
• Publisher: NATURE PUBLISHING GROUP
• Publication Version: Final Published Version
• Copyright Statement: © 2018 The Author(s).
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41598-018-22574-5
• Title of Journal or Parent Work: Scientific Report- College of Agriculture Osaka Prefecture University
• ISSN: 1344-848X
• Volume: 8
• Issue: 1
• Start Page: 4529
• End Page: 4529
• Grant/Funding Information: These efforts were supported by grants from the National Institutes of Health P01 AI42288 (MAA), R01 DK106191 (TMB), UC4 DK104194 (CEM), and from the JDRF Career Development Award (2–2012–280 to TMB). RAO is supported by a Diabetes UK Harry Keen Fellowship.; DJP is supported by the JDRF Postdoctoral Fellowship Award (2-PDF-2016-207-A-N).
• Keywords: GENOME-WIDE ASSOCIATION; CLASS-I; HAPLOTYPES; Science & Technology - Other Topics; ONSET; CONSORTIUM; DISEASE; SUSCEPTIBILITY GENES; PREVALENCE; CHILDREN; Science & Technology; Multidisciplinary Sciences; PREDICTION
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, General

Abstract

Prior studies identified HLA class-II and 57 additional loci as contributors to genetic susceptibility for type 1 diabetes (T1D). We hypothesized that race and/or ethnicity would be contextually important for evaluating genetic risk markers previously identified from Caucasian/European cohorts. We determined the capacity for a combined genetic risk score (GRS) to discriminate disease-risk subgroups in a racially and ethnically diverse cohort from the southeastern U.S. including 637 T1D patients, 46 at-risk relatives having two or more T1D-related autoantibodies (≥2AAb + ), 790 first-degree relatives (≤1AAb + ), 68 second-degree relatives (≤1 AAb + ), and 405 controls. GRS was higher among Caucasian T1D and at-risk subjects versus ≤ 1AAb + relatives or controls (P < 0.001). GRS receiver operating characteristic AUC (AUROC) for T1D versus controls was 0.86 (P < 0.001, specificity = 73.9%, sensitivity = 83.3%) among all Caucasian subjects and 0.90 for Hispanic Caucasians (P < 0.001, specificity = 86.5%, sensitivity = 84.4%). Age-at-diagnosis negatively correlated with GRS (P < 0.001) and associated with HLA-DR3/DR4 diplotype. Conversely, GRS was less robust (AUROC = 0.75) and did not correlate with age-of-diagnosis for African Americans. Our findings confirm GRS should be further used in Caucasian populations to assign T1D risk for clinical trials designed for biomarker identification and development of personalized treatment strategies. We also highlight the need to develop a GRS model that accommodates racial diversity.