Hirakawa Shohei, Lange Ethan M, Colicigno Carla J, Freedman Barry I, Rich Stephen S, Bowden Donald W
Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
Am J Kidney Dis. 2003 Jul;42(1):133-42. doi: 10.1016/s0272-6386(03)00416-5.
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).
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.
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).
This comprehensive analysis of MMP9 and renal disease suggests a possible role for the (CA)n repeat in renal disease, consistent with previous reports.
基质金属蛋白酶是由许多细胞分泌的锌离子和钙离子依赖性内肽酶。基质金属蛋白酶9（MMP9）基因在多种肾脏疾病中表达增加。多项遗传学研究已将MMP9与终末期肾病（ESRD）联系起来。
在本研究中，对MMP9基因组DNA的2.2 kb启动子区域和所有13个外显子（3.3 kb）进行多态性扫描。评估MMP9多态性与肾脏疾病之间的遗传关联。
在白种人中鉴定出11个单核苷酸多态性（SNP；4个位于启动子区域，6个位于编码区，1个位于3'非翻译区[UTR]），在非裔美国人中鉴定出19个SNP（11个位于启动子区域，8个位于编码区，1个位于3'UTR）。还评估了先前在MMP9启动子区域鉴定出的高度多态性（CA）n重复序列。我们在白种人中发现了15个等位基因，在非裔美国人中发现了14个等位基因。比较了患者和对照人群之间的等位基因频率、基因型和三标记单倍型。单基因座分析未观察到差异。在患有2型糖尿病肾病（T2DM/ESRD）的非裔美国患者中，两种包含（CA）n重复等位基因的单倍型显示出临界显著差异。将（CA）n重复分布进行二分法分析表明，在白种人病例中，使用加性疾病易感性模型，较短的等位基因与ESRD相关（P = 0.05）。在扩大的受试者组中对（CA）n重复序列进行分析，有力地证明了较短等位基因与白种人ESRD相关（P = 0.00012），并提示在患有T2DM/ESRD的非裔美国人（P = 0.086）和未患有T2DM/ESRD的受试者（P = 0.047）中也有类似趋势。
对MMP9和肾脏疾病的这一综合分析表明，（CA）n重复序列在肾脏疾病中可能起作用，这与先前的报道一致。
