title: Genetic variation in the matrix metalloproteinase genes and diabetic nephropathy in type 1 diabetes.
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 1705 individual with type 1 diabetes, including 885 normoalbuminuric control subjects and 820 advanced DN case subjects. In total, we investigated the role of 1283 SNPs (198 genotyped SNPs and 1085 imputed SNPs) mapping to the MMP genes. We identified associations at several correlated SNPs across a 29.2kb 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.
authors.affiliation: Research Division, Joslin Diabetes Center, and Department of Medicine, Harvard Medical School, Boston, MA, USA.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Kure
authors.forename: Marcus G
authors.initials: MG
authors.lastname: Pezzolesi
authors.forename: G David
authors.initials: GD
authors.lastname: Poznik
authors.forename: Pisut
authors.initials: P
authors.lastname: Katavetin
authors.forename: Jan
authors.initials: J
authors.lastname: Skupien
authors.forename: Jonathon S
authors.initials: JS
authors.lastname: Dunn
authors.forename: Josyf C
authors.initials: JC
authors.lastname: Mychaleckyj
authors.forename: James H
authors.initials: JH
authors.lastname: Warram
authors.forename: Andrzej S
authors.initials: AS
authors.lastname: Krolewski
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000150:complications* / Q000235:genetics*; D003928:Diabetic Nephropathies / Q000209:etiology* / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D020782:Matrix Metalloproteinases / Q000235:genetics*; D055815:Young Adult
chemical_list: D020782:Matrix Metalloproteinases