Journal
DIABETES
Volume 65, Issue 7, Pages 2094-2099Publisher
AMER DIABETES ASSOC
DOI: 10.2337/db15-1690
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Funding
- National Institute for Health Research (NIHR) Clinical Lectureship award
- Wellcome Trust [076113]
- Royal Society [105636/Z/14/Z]
- NIHR
- Wellcome Trust Institutional Strategic Support Fund [WT097835MF]
- Medical Research Council [MR/M005070/1]
- University of Exeter
- NIHR Exeter Clinical Research Facility
- MRC [MR/N01104X/1, MR/M005070/1, G1001799] Funding Source: UKRI
- Medical Research Council [MR/N01104X/1, MR/M005070/1, G1001799] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0611-10219, CL-2015-23-001, CL-2013-23-001] Funding Source: researchfish
- Wellcome Trust [110082/Z/15/Z] Funding Source: researchfish
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Distinguishing patients with monogenic diabetes from those with type 1 diabetes (T1D) is important for correct diagnosis, treatment, and selection of patients for gene discovery studies. We assessed whether a T1D genetic risk score (T1D-GRS) generated from T1D-associated common genetic variants provides a novel way to discriminate monogenic diabetes from T1D. The T1D-GRS was highly discriminative of proven maturity-onset diabetes of young (MODY) (n = 805) and T1D (n = 1,963) (receiver operating characteristic area under the curve 0.87). A T1D-GRS of >0.280 (>50th T1D centile) was indicative of T1D (94% specificity, 50% sensitivity). We then analyzed the T1D-GRS of 242 white European patients with neonatal diabetes (NDM) who had been tested for all known NDM genes. Monogenic NDM was confirmed in 90, 59, and 8% of patients with GRS <5th T1D centile, 50-75th T1D centile, and >75th T1D centile, respectively. Applying a GRS 50th T1D centile cutoff in 48 NDM patients with no known genetic cause identified those most likely to have a novel monogenic etiology by highlighting patients with probable early-onset T1D (GRS >50th T1D centile) who were diagnosed later and had less syndromic presentation but additional autoimmune features compared with those with proven mono genic NDM. The T1D-GRS is a novel tool to improve the use of biomarkers in the discrimination of monogenic diabetes from T1D.
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