Genetic Variations in the Gene Encoding ELMO1 Are Associated With Susceptibility to Diabetic Nephropathy

Abstract

To search for a gene(s) conferring susceptibility to diabetic nephropathy (DN), we genotyped over 80,000 genebased single nucleotide polymorphisms (SNPs) in Japanese patients and identified that the engulfment and cell motility 1 gene (ELMO1) was a likely candidate for conferring susceptibility to DN, in view of the significant association of an SNP in this gene with the disease (intron 18؉9170, GG vs. GA؉AA, 2 ‫؍‬ 19.9, P ‫؍‬ 0.000008; odds ratio 2.67, 95% CI 1.71-4.16). In situ hybridization (ISH) using the kidney of normal and diabetic mice revealed that ELMO1 expression was weakly detectable mainly in tubular and glomerular epithelial cells in normal mouse kidney and was clearly elevated in the kidney of diabetic mice. Subsequent in vitro analysis revealed that ELMO1 expression was elevated in cells cultured under high glucose conditions (25 mmol/l) compared with cells cultured under normal glucose conditions (5.5 mmol/l). Furthermore, we identified that the expression of extracellular matrix protein genes, such as type 1 collagen and fibronectin, were increased in cells that overexpress ELMO1, whereas the expression of matrix metalloproteinases was decreased. These results indicate that ELMO1 is a novel candidate gene that both confers susceptibility to DN and plays an important role in the development and progression of this disease. Diabetes 54:1171-1178, 2005

Genetic Factors in Diabetic Nephropathy

“…Shimazaki et al (46) performed a gene-centric WGA in unrelated Japanese individuals who had type 2 DN and diabetes without nephropathy. A SNP in the 18th intron of engulfment and cell motility 1 (ELMO1) on chromosome 7p14 was strongly associated with DN, and the region of association extended 100 kb upstream and downstream from this SNP.…”

“…Because ELMO1 is a large gene, Shimazaki et al (46) genotyped an additional 516 polymorphisms in 640 Japanese DN case patients and 426 control subjects. Several of these additional markers were also associated, the strongest being the ϩ 9170 A/G SNP (GG versus AG ϩ AA; OR 2.67; P ϭ 0.000008).…”

Examination of Association with Candidate Genes for Diabetic Nephropathy in a Mexican American Population

“…Janssen et al (4) reported an association between DN and a microsatellite marker, D18S880, in CNDP1 among type 1 and type 2 diabetic patients from four different countries, and Freedman et al (2) reported its replication among type 2 diabetic Caucasian patients. Shimazaki et al (5) reported an association in the Japanese population between DN and ELMO1, which includes rs741301 as the most significant single nucleotide polymorphism (SNP).…”

The pursuit of genome-wide association studies: where are we now?

“…7,8 Subsequently, an additional candidate gene (that is, ELMO1) was also identified for diabetic nephropathy in 2005 using the same study design, and likewise, the identification of TNFSF15 for Crohn's disease (CD), and CALM1 for osteoarthritis where all the studies have genotyped around 80 000 SNPs. [9][10][11] The examples of these early days of GWAS were performed in Japanese populations by the same group of researchers. However, there are at least two major differences between these studies and the GWAS performed by Klein et al 1 In contrast to the GWAS of AMD, which used a commercial genotyping array; that is, Affymetrix Human Mapping 100K Set, the genotyping of all of the early versions of GWAS was not performed by microarray technologies, but instead by applying high-throughput multiplex PCR-Invader assay methods.…”