Type 1 Diabetes Genetic Risk Score: A Novel Tool to Discriminate Monogenic and Type 1 Diabetes
Article Figures & Tables
Figures
- Figure 1
T1D-GRS is higher in T1D patients than in confirmed MODY patients and control subjects without diabetes. A: Dot plot of T1D-GRS from 1,963 T1D patients, 805 MODY (subtype of monogenic diabetes) patients, and 2,938 control subjects without diabetes. The blue bar highlights the median T1D-GRS for each group. The upper red horizontal line shows a GRS equivalent to 50th centile for the T1D cohort, and the lower red horizontal line shows a GRS equivalent to 5th centile for the T1D cohort. The control subjects and T1D patients came from WTCCC (11). B: ROC curve (area under the curve 0.87) for T1D-GRS to discriminate MODY (n = 805) and T1D (n = 1,963).
- Figure 2
T1D-GRS identified proven and probable monogenic NDM. A: T1D-GRS identified proven monogenic NDM. A total of 242 white European patients with NDM (diagnosed before 6 months of age) who had comprehensive genetic testing for all 23 NDM genes were grouped by their T1D-GRS (12). The subgroups of T1D-GRS are based on centiles of the T1D cohort: low to high score groups (left to right). The bar chart shows the proportion of proven monogenic NDM (total n = 194, patients with positive genetic test, black bar) and NDM with unknown etiology (total n = 48, NDMX patients, white bar) for each score category. The total number of patients is also shown for each category. B: T1D-GRS identified probable monogenic NDM and probable T1D in NDMX patients. The T1D-GRS distribution of NDMX patients (n = 48) showed bimodal distribution with peaks at <5th T1D centile and >75th T1D centile with the nadir around 50th T1D centile. T1D-GRS 50th T1D centile categorized this group as probable T1D (T1D-GRS >50th T1D centile, n = 21) and probable monogenic diabetes due to mutations in as-yet undiscovered disease genes (T1D-GRS ≤50th T1D centile, n = 27).
Tables
- Table 1
T1D-GRS is discriminatory for T1D and MODY
Categories based on GRS centiles of T1D cohort (actual score value) T1D, n (%) Confirmed MODY, n (%) Total Odds ratio for T1D (95% CI) <5th centile (<0.234) 98 (5) 423 (53) 521 1 5–25th centile (0.234–0.262) 392 (20) 242 (30) 634 7 (5–9) 26–50th centile (0.263–0.280) 492 (25) 89 (11) 581 24 (16–36) 51–75th centile (0.281–0.299) 491 (25) 42 (5) 533 50 (29–89) >75th centile (>0.299) 490 (25) 9 (1) 499 235 (73–755) Total 1,963 (100) 805 (100) 2,768 The groups were categorized by GRS centiles of the T1D cohort. The odds ratios are relative to <5th centile of T1D-GRS category.
- Table 2
Clinical characteristics of patients with proven and probable monogenic NDM and probable T1D
Proven monogenic NDM <6 months, n = 194 Probable monogenic NDM <6 months (T1D-GRS ≤50th T1D centile), n = 27 Probable T1D <6 months (T1D-GRS >50th T1D centile), n = 21 P value (proven monogenic vs. probable monogenic) P value (proven monogenic vs. probable T1D) T1D-GRS, median (IQR) 0.231 (0.206–0.251) 0.237 (0.210–0.250) 0.299 (0.295–0.313) 0.86 <0.001 Age at diagnosis in weeks, median (IQR) 5 (1–12) 1 (0.6–6) 12 (3–20) 0.13 0.04 Male, n (%) 111 (57) 17 (63) 15 (71) 0.68 0.25 Presence of other autoimmune disorders, n (%) 1 (1) 1 (4) 3 (14) 0.23 0.003 Syndromic presentation, n (%) 77 (40) 9 (33) 2 (10) 0.67 0.007 Consanguineous parents, n (%) 3 (2) 0 0 1.00 1.00 NDMX patients were categorized into probable T1D and probable monogenic NDM by T1D-GRS equivalent to 50th centile of T1D cohort. Fisher exact test was used to compare proportions, and Mann-Whitney U test was used to compare continuous variables. IQR, interquartile range.
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