Genetic association of single nucleotide polymorphisms in endonuclease G-like 1 gene with type 2 diabetes in a Japanese population

Abstract

Aims/hypothesis In order to identify type 2 diabetes disease susceptibility gene(s) in a Japanese population, we applied a region-wide case-control association test to the 20.4 Mb region between D3S1293 and D3S2319 on chromosome 3p24.3-22.1, supported by linkage to type 2 diabetes and its related traits in Japanese and multiple populations. Materials and methods We performed a two-stage association test using 1,762 Japanese persons with 485 gene-centric, evenly spaced, common single nucleotide polymorphism (SNP) markers with minor allele frequency >0.1. For mouse studies, total RNA was extracted from various organs of BKS.Cg-+Lepr db /+Lepr db and control mice, and from MIN6, NIH3T3 and C2C12 cell lines. Results We detected a landmark SNP375 (A/G) (rs2051211, p=0.000046, odds ratio=1.33, 95% CI 1.16-1.53) in intron 5 of the endonuclease G-like 1 (ENDOGL1) gene. Systematic dense SNPs approach identified a susceptibility linkage disequilibrium (LD) block of 116.5 kb by |D′|, an LD units map and a critical region of 2.1 kb by r 2 in ENDOGL1. A haplotype-based association test showed that an at-risk haplotype is associated with disease status (p= 0.00001). The expression of ENDOGL1 was rather ubiquitous with relatively abundant expression in the brain and Diabetologia

The role of DNA exonucleases in protecting genome stability and their impact on ageing

“…EndoG has been reported to lie in the mitochondrial inter-membrane space away from the DNA (Ohsato et al 2002), whilst EXOG is located in the inner membrane where the mitochondrial DNA attaches (Cymerman et al 2008), suggesting a functional as well as a physical split, with EndoG responsible for the cell death function performed by Nuc1p in yeast and EXOG involved in cellular proliferation. Both exonic (Cymerman et al 2008) and intronic SNPs have been reported in the ExoG gene; the latter is associated with type 2 diabetes (Moritani et al 2007), a disease linked with age.…”

<i>Bhlhe40</i>, a potential diabetic modifier gene on <i>Dbm1</i> locus, negatively controls myocyte fatty acid oxidation

“…It was suggested that the alteration in Bhlhe40 expression was possibly dependent on some of these SNPs through structural modification of transcription factor binding or transcriptional cofactor recruitment. Intron SNPs are also candidate causative polymorphisms which affect gene expression levels, as reported in diabetic populations (Grant et al, 2006;Horikawa et al, 2000;Moritani et al, 2007;Tsukada et al, 2006). Due to the muscle-specific difference of Bhlhe40 expression in congenic mice, we assumed that the causative SNP is associated with a tissue-specific transcriptional regulator.…”

Identification of Association of Common AGGF1 Variants with Susceptibility for Klippel‐Trenaunay Syndrome Using the Structure Association Program

“…Although the polymorphisms in exon 7 and intron 11 did not result in amino acid changes in the AGGF1 protein (I405I), it is still possible that these genetic alterations may function in the regulation of AGGF1 transcription. Many reports suggest that synonymous or intronic SNPs are significantly associated with different diseases such as diabetes, Alzheimer's disease, and schizophrenia by regulating the transcription of the some relevant genes (Law et al 2007;Moritani et al 2007;Tokuhiro et al 2003;Wiener et al 2007). Recently, a synonymous SNP in exon 26 of the MDR1 gene was shown to exert its functional effect through a novel mechanism of altered timing of co-translational folding and trafficking of P-glycoprotein Sauna et al 2007).…”