Type 1 diabetes genetic risk score discriminates between monogenic and Type 1 diabetes in children diagnosed at the age of <5 years in the Iranian population

Abstract

Aim To examine the extent to which discriminatory testing using antibodies and Type 1 diabetes genetic risk score, validated in European populations, is applicable in a non‐European population. Methods We recruited 127 unrelated children with diabetes diagnosed between 9 months and 5 years from two centres in Iran. All children underwent targeted next‐generation sequencing of 35 monogenic diabetes genes. We measured three islet autoantibodies (islet antigen 2, glutamic acid decarboxylase and zinc transporter 8) and generated a Type 1 diabetes genetic risk score in all children. Results We identified six children with monogenic diabetes, including four novel mutations: homozygous mutations in WFS1 (n=3), SLC19A2 and SLC29A3, and a heterozygous mutation in GCK. All clinical features were similar in children with monogenic diabetes (n=6) and in the rest of the cohort (n=121). The Type 1 diabetes genetic risk score discriminated children with monogenic from Type 1 diabetes [area under the receiver‐operating characteristic curve 0.90 (95% CI 0.83–0.97)]. All children with monogenic diabetes were autoantibody‐negative. In children with no mutation, 59 were positive to glutamic acid decarboxylase, 39 to islet antigen 2 and 31 to zinc transporter 8. Measuring zinc transporter 8 increased the number of autoantibody‐positive individuals by eight. Conclusions The present study provides the first evidence that Type 1 diabetes genetic risk score can be used to distinguish monogenic from Type 1 diabetes in an Iranian population with a large number of consanguineous unions. This test can be used to identify children with a higher probability of having monogenic diabetes who could then undergo genetic testing. Identification of these individuals would reduce the cost of treatment and improve the management of their clinical course.

Genetically defined favourable adiposity is not associated with a clinically meaningful difference in clinical course in people with type 2 diabetes but does associate with a favourable metabolic profile

“…Our study is unique as it is among few studies using genetic scores within people with diabetes. Previous studies consist of those which used genetic scores of type 1 diabetes to discriminate type 1 from type 2 or monogenic forms of disease 24,25 or to predict progression to insulin therapy in clinically diagnosed people with type 2 diabetes 26 or to delineate risk genotypes for type 2 diabetes 27,28 . Type 2 diabetes is a complex and common condition.…”

Different interaction of onset age and duration of type 1 diabetes on the dynamics of autoantibodies to insulinoma‐associated antigen‐2 and zinc transporter 8

“…The data we have presented suggest IA-2A, ZnT8A and GADA's rate of disappearance is faster in patients with an age of onset ≤10 years and relates to the disease duration. Therefore, to effectively discriminate between type 1 diabetes and other monogenic diabetes, such as Wolfram syndrome and maturity-onset diabetes of the young [17][18][19] , cystic fibrosis 20 or ketosis-prone diabetes 21 , we assert the importance of early examination of the anti-islet autoantibodies in this patient group. The diagnostic sensitivity of the anti-islet autoantibody tests we investigated tended to vary according to age at diabetes onset, with IA-2A and ZnT8A being higher in children, and GADA being higher in adults, as reported in previous studies [6][7][8] .…”

“…The data we have presented suggest IA‐2A, ZnT8A and GADA’s rate of disappearance is faster in patients with an age of onset ≤10 years and relates to the disease duration. Therefore, to effectively discriminate between type 1 diabetes and other monogenic diabetes, such as Wolfram syndrome and maturity‐onset diabetes of the young 17–19 , cystic fibrosis 20 or ketosis‐prone diabetes 21 , we assert the importance of early examination of the anti‐islet autoantibodies in this patient group.…”

Systematic Review of Polygenic Risk Scores for Type 1 and Type 2 Diabetes

“…The databases from where the articles were retrieved are shown in Table 1. There were six studies eligible for the systematic review, which developed PRSs for T1D [38,39,[42][43][44][45], and there were nine that studied PRSs for T2D [19,36,[46][47][48][49][50][51]54] (Table 1). The majority of the studies were conducted in Caucasian populations, while some of them conducted the studies in Hispanic, African-American, Asian-American, South African and Iranian populations.…”

“…The use of PRSs could become useful to identify a group of patients at risk; this will offer substantial clinical benefits while preventing growing morbidity and mortality associated with diabetes [38][39][40][41]. Several research groups have developed diabetes PRSs, fitting the scoring models to their study area [19,36,38,39,[42][43][44][45][46][47][48][49][50][51]. All of them have used AUC as a predictive parameter to identify the sensitivity and specificity of the outcome of interest.…”