1. Genetic variation in the matrix metalloproteinase genes and diabetic nephropathy in type 1 diabetes
- Author
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Masahiko Kure, Jonathon Dunn, G. David Poznik, James H. Warram, Jan Skupien, Marcus G. Pezzolesi, Andrzej S. Krolewski, Josyf C. Mychaleckyj, and Pisut Katavetin
- Subjects
Adult ,Adolescent ,Genotype ,Endocrinology, Diabetes and Metabolism ,Population ,Single-nucleotide polymorphism ,Genome-wide association study ,Locus (genetics) ,Biology ,Biochemistry ,Article ,End stage renal disease ,Young Adult ,Endocrinology ,Genetic variation ,Genetics ,Humans ,Diabetic Nephropathies ,Genetic Predisposition to Disease ,Allele ,Child ,education ,Molecular Biology ,Alleles ,Genetic association ,education.field_of_study ,Infant, Newborn ,Genetic Variation ,Infant ,Matrix Metalloproteinases ,Diabetes Mellitus, Type 1 ,Child, Preschool ,Genome-Wide Association Study - Abstract
Genetic data support the notion that polymorphisms in members of the matrix metalloproteinase (MMP) family of genes play an important role in extracellular matrix remodeling and contribute to the pathogenesis of vascular disease. To identify novel genetic markers for diabetic nephropathy (DN), we examined the relationship between MMP gene polymorphisms and DN in the Genetics of Kidneys in Diabetes (GoKinD) population. Genotypic data from the Genetic Association Information Network (GAIN) type 1 DN project were analyzed for associations across 21 MMP genes in 1,705 individual with type 1 diabetes, including 885 normoalbuminuric control subjects and 820 advanced DN case subjects. In total, we investigated the role of 1,283 SNPs (198 genotyped SNPs and 1,085 imputed SNPs) mapping to the MMP genes. We identified associations at several correlated SNPs across a 29.2 kb interval on chromosome 11q at the MMP-3/MMP-12 locus. The strongest associations occurred at 2 highly-correlated SNPs, rs610950 (OR = 0.50, P = 1.6×10−5) and rs1277718 (OR = 0.50, P = 2.1×10−5). Further examination of this locus identified 17 SNPs (2 genotyped SNPs and 15 imputed SNPs) in complete linkage disequilibrium associated with DN (P-values < 2.5×10−4), including a non-synonymous SNP (rs652438, Asn357Ser) located in exon 8 of MMP-12 that significantly reduced the risk of DN among carriers of the serine substitution relative to homozygous carriers of asparagine (OR = 0.51; 95% CI = 0.37–0.71, P = 6.2×10−5). Taken together, our study suggests that genetic variations within the MMP-3/MMP-12 locus influence susceptibility of DN in type 1 diabetes.
- Published
- 2011