Abstract
Genetic factors play very important roles in the onset and progression of type 2 diabetes mellitus (T2DM). However, the genetic factors correlating with T2DM onset have not as yet been fully clarified. We previously found that copy number losses in the subtelomeric region on chromosome 4p16.3 were detected in early-onset Japanese T2DM patients (onset age <35 years) at a high frequency. Herein, we additionally found two novel copy number losses within the subtelomeric regions on chromosomes 16q24.2-3 and 22q13.31-33, which have significant associations with early-onset Japanese T2DM. The associations were statistically significant by Fisher's exact tests with P values of 5.19×10−3 and 1.81×10−3 and odds ratios of 5.7 and 4.4 for 16q24.2-3 and 22q13.31-33, respectively. Furthermore, copy number variation (CNV) analysis of the whole genome using the CNV BeadChip system verified simultaneous copy number losses in all three subtelomeric regions in 11 of our 100 T2DM subjects, while none of 100 non-diabetic controls showed the copy number losses in all three regions. Our results suggest that the mechanism underlying induction of CNVs is involved in the pathogenesis of early-onset T2DM. Thus, copy number losses within multiple subtelomeric regions are strongly associated with early-onset T2DM and examination of simultaneous CNVs in these three regions may lead to the development of an accurate and selective procedure for detecting genetic susceptibility to T2DM.
Highlights
Numbers of patients with type 2 diabetes mellitus (T2DM) have been increasing annually worldwide
The copy number variation (CNV) portion of the platform consists of probes covering CNV rich regions of the genome, such as megasatellites, duplicons, unSNPable regions (.15 kb gaps in HapMap single nucleotide polymorphism (SNP) map, and 5– 15 kb gaps with .2SNPs with Hardy-Weinberg failure), and CNVs registered in the Database of Genomic Variants
In searching for other CNVs associated with early-onset T2DM, we screened the whole genome for CNVs using the deCODEIllumina CNV370K BeadChip system in the same 100 early-onset Japanese T2DM subjects and 100 non-diabetic controls that we reported previously [32]
Summary
Numbers of patients with type 2 diabetes mellitus (T2DM) have been increasing annually worldwide. Environmental factors, such as aging, westernized high-fat diets, lack of exercise and everyday stress affect the onset and progression of T2DM. Concordance rates and heritability for T2DM are higher in identical than in fraternal twins [2]. When both parents have T2DM, the risk of this disease in their children is three to four times higher than that of the offspring of non-diabetics [3]. Many investigators worldwide have been intensively searching for genetic factors associated with susceptibility to T2DM
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