Matrix metalloproteinase-9 promoter polymorphisms in Korean patients with systemic lupus erythematosus.

To investigate the association between functional promoter polymorphisms of matrix metalloproteinase-9 (MMP-9) and systemic lupus erythematosus (SLE), we analyzed MMP-9 promoter -1562 C>T and MMP-9 -90 (CA)(n) repeat polymorphisms in 135 Korean SLE patients (mean age, 34.7 years; 124 female and 11 male) and in 135 gender- and age-matched healthy controls (mean age, 35.4 years). Clinical and laboratory findings were collected during the follow-up period (mean, 63.5 months; range, 3-252 months), and Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) Damage Indexes were calculated. The levels of total MMP-9 were measured in sera of SLE patients and controls by enzyme-linked immunoabsorbent assay. The serum levels of MMP-9 in SLE patients were significantly lower than those of controls (mean +/- standard error of the mean, 1421.6+/-177.4 vs 3731.4+/-441.4 ng/ml, p=1.2 x 10(-5) by t test). Both functional polymorphisms were under the Hardy-Weinberg equilibrium state except (CA)(n) repeat polymorphisms in SLE patients (p=2.6 x 10(-5) by chi(2) goodness-of-fit test). The distribution of the MMP-9 promoter polymorphisms or haplotypes was not significantly different in SLE patients and controls. However the frequency of alleles with low numbers of CA repeats (n<21, 11.9% vs 7.0%, p=0.06 by the chi(2) test; odds ratio=1.78, 95% confidence interval=0.99-3.20) and the prevalence of low CA repeats homozygote tended to be higher in patients than in controls (5.2% vs 0.7%, p=0.07 by logistic regression, odds ratio=7.29, 95% confidence interval=0.88-60.10) in the recessive model. No relationship was found between MMP-9 polymorphisms and clinical features or damage as indicated by SLICC/ACR Damage Index in the study subjects. These results suggest that genetic polymorphisms of the MMP-9 promoter regions are not associated with the development of SLE in Korea.

Start codon polymorphisms in the vitamin D receptor and colorectal cancer risk.

The expression of the nuclear vitamin D receptor (VDR), which is involved in regulating cell growth and proliferation, may contribute to the development of colorectal cancer. Polymorphisms in the VDR gene (OMIM 601769) may influence the expression or function of the VDR protein. A population-based, case-control study of VDR start codon, intron, and exon polymorphisms, haplotypes for these polymorphisms, and the relationships between these polymorphisms and clinicopathological parameters in 190 colorectal cancer patients and 318 controls was conducted. The start codon variant VDR 27823*C/*C genotype was associated with an increased risk for colorectal cancer, while the 27823*T/*T genotype was associated with a decreased risk. In addition, the VDR 61888*G/*G genotype was associated with reduced colorectal cancer risk. The intron 8 60880G>A and exon 9 61968T>C polymorphisms were not associated with colorectal cancer risk. The VDR 27823*C-60890*G-61888*T-61968*T haplotype was associated with an increased risk of colorectal cancer, whereas the VDR 27823*T-60890*G-61888*G-61968*T haplotype was associated with a decreased risk of colorectal cancer. Moreover, the 27823*C/*C genotype was more frequently identified in patients with preoperative serum carcinoembryonic antigen (CEA) levels over 6ng/mL. These results suggest that the VDR start codon 27823*C allele may be linked to high risk for colorectal cancer, especially in a subset of colorectal cancers showing specific biological behaviors.

Clinical implications of matrix metalloproteinase-1, -3, -7, -9, -12, and plasminogen activator inhibitor-1 gene polymorphisms in colorectal cancer.

BACKGROUND AND AIM: Overexpression of matrix metalloproteinase (MMP)-1, -3, -7, -9, and plasminogen activator inhibitor-1 (PAI-1) are implicated in the invasion and metastasis of colorectal cancer, while MMP-12 provides a protective role against colorectal cancer. The promoter and exon polymorphisms of their genes, which are known to affect the transcription of these genes, were assessed to correlate with colorectal cancer susceptibility. METHODS: MMP1, 3, 7, 9, 12 and PAI1 were assayed in 185 colorectal cancer patients and 304 healthy controls using polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) analysis. Respective genotypes and haplotypes were compared between the population groups and also between clinicopathological characteristics in the colorectal cancer patients. RESULTS: The homozygous MMP1-1,607 dupG genotype was significantly more frequent in colorectal cancer patients than in healthy controls. The frequency of MMP1-1,607 dupG homozygotes was also greater in patients of less than or equal to 50 years of age, and in patients with 10 or more metastatic lymph nodes, compared with those of older age or with fewer lymph nodes. The frequency of MMP9-1,562 C homozygotes was significantly greater in colorectal cancer patients than in healthy controls. However, the genotype and allele frequencies of MMP3-1,171dupA, MMP7-181A > G, MMP12-82A > G, MMP9-90(CA)(14-27), and R279Q did not differ between the population groups or clinicopathological parameters. The MMP7-181A-MMP1-1,607dupG-MMP3-1,171A-MMP12-82A and MMP9-1,562C-90(CA)(20)+ 279Q haplotypes were significantly more frequent in colorectal cancer patients than in healthy controls. The genotype and allele frequencies of PAI1-675 G were similar between patients and healthy controls, but the frequency of PAI1-675 G homozygotes was significantly greater in patents over 50 years of age. CONCLUSIONS: MMP1-1,607 dupG and MMP9-1,562 C homozygotes demonstrated an increased risk of colorectal cancer regardless of ethnic differences, whereas other MMP and PAI1 polymorphisms did not. Nevertheless, specific MMP haplotypes on 11q22.1-23.3 and 20q12-13 seem to be implicated in susceptibility to colorectal cancer.