Abstract
Type 1 diabetes (T1D) tends to cluster in families, suggesting there may be a genetic component predisposing to disease. However, a recent large-scale genome-wide association study concluded that identified genetic factors, single nucleotide polymorphisms, do not account for overall familiality. Another class of genetic variation is the amplification or deletion of >1 kilobase segments of the genome, also termed copy number variations (CNVs). We performed genome-wide CNV analysis on a cohort of 20 unrelated adults with T1D and a control (Ctrl) cohort of 20 subjects using the Affymetrix SNP Array 6.0 in combination with the Birdsuite copy number calling software. We identified 39 CNVs as enriched or depleted in T1D versus Ctrl. Additionally, we performed CNV analysis in a group of 10 monozygotic twin pairs discordant for T1D. Eleven of these 39 CNVs were also respectively enriched or depleted in the Twin cohort, suggesting that these variants may be involved in the development of islet autoimmunity, as the presently unaffected twin is at high risk for developing islet autoimmunity and T1D in his or her lifetime. These CNVs include a deletion on chromosome 6p21, near an HLA-DQ allele. CNVs were found that were both enriched or depleted in patients with or at high risk for developing T1D. These regions may represent genetic variants contributing to development of islet autoimmunity in T1D.
Highlights
Type 1 diabetes (T1D) results from immune-mediated selective destruction of pancreatic islet cells resulting in insulin deficiency and hyperglycemia [1,2]
We sought to determine if copy number variations (CNVs) are associated with T1D by performing genome-wide CNV analysis on a cohort of 20 patients with T1D and 20 Ctrl patients using the Affymetrix Single nucleotide polymorphisms (SNPs) Array 6.0
Raw data from all 3 cohorts, 59 Affymetrix arrays in total, were inputted into the Birdsuite programs and copy numbers were called across the genome
Summary
Type 1 diabetes (T1D) results from immune-mediated selective destruction of pancreatic islet cells resulting in insulin deficiency and hyperglycemia [1,2]. With early diagnosis of disease or assessment of risk, immune therapy may impede islet destruction and preserve insulin production, delaying onset of clinical manifestations[2]. Another component of T1D that aids in our understanding of the disease and assessment of risk is genetic inheritance. 83 unaffected monozygotic twins were followed for nearly 44 years and incidence of autoimmunity or diagnosis of T1D was recorded. This study showed a 65% cumulative incidence of T1D by 60 years of age and more than 75% tested positive for an islet autoantibody during the course of the study. The risk of diabetes was 89% within 16 years of the first positive autoantibody test
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