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

Am J Kidney Dis. 2003 Jul;42(1):133-42. doi: 10.1016/s0272-6386(03)00416-5.


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, 1 3' 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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 3' Untranslated Regions / genetics
  • African Continental Ancestry Group / genetics
  • Alleles
  • Amino Acid Substitution
  • Case-Control Studies
  • Diabetes Mellitus, Type 2 / enzymology
  • Diabetes Mellitus, Type 2 / genetics*
  • Diabetic Nephropathies / enzymology
  • Diabetic Nephropathies / genetics*
  • European Continental Ancestry Group / genetics
  • Exons / genetics
  • Genetic Predisposition to Disease
  • Genetic Variation*
  • Genotype
  • Haplotypes / genetics
  • Humans
  • Kidney Failure, Chronic / enzymology
  • Kidney Failure, Chronic / genetics*
  • Kidney Failure, Chronic / therapy
  • Linkage Disequilibrium
  • Matrix Metalloproteinase 9 / genetics*
  • Matrix Metalloproteinase 9 / physiology
  • Minisatellite Repeats
  • Polymorphism, Genetic
  • Polymorphism, Single Nucleotide
  • Promoter Regions, Genetic / genetics
  • Renal Dialysis


  • 3' Untranslated Regions
  • Matrix Metalloproteinase 9