Evaluation of genetic variation and association in the matrix metalloproteinase 9 (MMP9) gene in ESRD patients

被引:34
作者
Hirakawa, S
Lange, EM
Colicigno, CJ
Freedman, BI
Rich, SS
Bowden, DW
机构
[1] Wake Forest Univ, Sch Med, Dept Biochem, Winston Salem, NC 27157 USA
[2] Wake Forest Univ, Sch Med, Dept Publ Hlth Sci, Winston Salem, NC 27157 USA
[3] Wake Forest Univ, Sch Med, Dept Internal Med, Winston Salem, NC 27157 USA
[4] Wake Forest Univ, Sch Med, Ctr Human Genom, Winston Salem, NC 27157 USA
关键词
Matrix metalloproteinase; renal disease; polymorphism; African Americans;
D O I
10.1016/S0272-6386(03)00416-5
中图分类号
R5 [内科学]; R69 [泌尿科学(泌尿生殖系疾病)];
学科分类号
1002 ; 100201 ;
摘要
Background: Matrix metalloproteinases are Zn2+- and Ca2+-dependent endopeptidases secreted by many cells. Expression of the matrix metalloproteinase 9 (MMP9) gene is increased in a variety of renal diseases. Several genetic studies have associated MMP9 with end-stage renal disease (ESRD). Methods: In this study, 2.2 kb of the promoter region and all 13 exons (3.3 kb) of MMP9 genomic DNA were scanned for polymorphisms. Genetic associations between MMP9 polymorphisms and renal disease were evaluated. Results: Eleven single-nucleotide polymorphisms (SNPs; 4 promoter, 6 coding region, and 1 3' untranslated region [UTR]) were identified in Caucasians and 19 SNPs (11 promoter, 8 coding region, 131 UTR) were identified in African Americans. A previously identified highly polymorphic (CA)n repeat in the promoter region of MMP9 also was evaluated. We found 15 alleles in Caucasians and 14 alleles in African Americans. Allele frequencies, genotypes, and 3-marker haplotypes were compared between patient and control populations. Differences were not observed using single-locus analyses. Two haplotypes that included the (CA)n repeat allele in African-American patients with type 2 diabetic nephropathy (T2DM/ESRD) showed borderline significant differences. Dichotomizing the (CA)n repeat distribution showed that shorter alleles in Caucasian cases were associated with ESRD using an additive disease-predisposing model (P = 0.05). Analysis of the (CA)n repeat in expanded sets of subjects showed strong evidence for an association of shorter alleles with ESRD in Caucasians (P = 0.00012) and suggested a similar trend in African Americans with T2DM/ESRD (P = 0.086) and subjects without T2DM/ESRD (P = 0.047). Conclusion: This comprehensive analysis of MMP9 and renal disease suggests a possible role for the (CA)n repeat in renal disease, consistent with previous reports. (C) 2003 by the National Kidney Foundation, Inc.
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页码:133 / 142
页数:10
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