Dataset Information

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.

SUBMITTER: Yaghootkar H

PROVIDER: S-EPMC7027759 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Publications

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.

Yaghootkar H H Abbasi F F Ghaemi N N Rabbani A A Wakeling M N MN Eshraghi P P Enayati S S Vakili S S Heidari S S Patel K K Sayarifard F F Borhan-Dayani S S McDonald T J TJ Ellard S S Hattersley A T AT Amoli M M MM Vakili R R Colclough K K

Diabetic medicine : a journal of the British Diabetic Association 20190725 12

<h4>Aim</h4>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.<h4>Methods</h4>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 decarb ...[more]

PMID: 31276222

Similar Datasets

Project description:Aims/hypothesisIdentifying individuals suitable for monogenic autoimmunity testing and gene discovery studies is challenging: early-onset type 1 diabetes mellitus can cluster with additional autoimmune diseases due to shared polygenic risk and islet- and other organ-specific autoantibodies are present in both monogenic and polygenic aetiologies. We aimed to assess whether a type 1 diabetes genetic risk score (GRS) could identify monogenic autoimmune diabetes and be useful to prioritise individuals for gene discovery studies.MethodsWe studied 79 individuals with diabetes and at least one additional autoimmune disease diagnosed before the age of 5 years. We screened all participants for the seven genes known to cause monogenic autoimmunity that can include diabetes (AIRE, IL2RA, FOXP3, LRBA, STAT1, STAT3, STAT5B). We genotyped the top ten risk alleles for type 1 diabetes, including HLA and non-HLA loci, to generate a type 1 diabetes GRS.ResultsOf the 79 individuals studied, 37 (47%) had mutations in the monogenic autoimmunity genes. The type 1 diabetes GRS was lower in these individuals than in those without mutations in these genes (median 9th vs 49th centile of type 1 diabetes controls, p < 0.0001). Age of diabetes diagnosis and type 1 diabetes GRS combined to be highly discriminatory of monogenic autoimmunity (receiver operating characteristic AUC: 0.88). Most individuals without a mutation in a known gene had a high type 1 diabetes GRS, suggesting that they have polygenic clustering of type 1 diabetes and additional autoimmunity and should not be included in gene discovery studies.Conclusions/interpretationWe have shown that the type 1 diabetes GRS can identify individuals likely to have monogenic autoimmunity, helping both diagnostic testing and novel monogenic autoimmunity gene discovery. Individuals with monogenic autoimmunity have a different clinical course to those with polygenic type 1 diabetes and can respond well to therapies targeting the underlying genetic defect.

Dataset Information

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.

Aim

Methods

Results

Conclusions

Publications

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.

Similar Datasets

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