Genetic variation, gene-expression and circulating levels of matrix metalloproteinase-9 in patients with stable coronary artery disease

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• 作者：Trine B.  ; Opstad^a ;   ; ^b ;   ; ^{trineoa@medisin.uio.no} ; Alf-Aage R.  ; Pettersen^a ;   ; ^b ;   ; ^{alfaage@online.no} ; Thomas W.  ; Weiss^a ;   ; ^b ;   ; ^{thomas.weiss@meduniwien.ac.at} ; Sissel  ; Å ; kra^a ;   ; ^b ;   ; ^{sissel.akra@ulleval.no} ; Reidun  ; &Oslash ; vsteb&oslash ; ^c ;   ; ^{reidun.ovstebo@medisin.uio.no} ; Harald  ; Arnesen^a ;   ; ^b ;   ; ^d ;   ; ^{harald.arnesen@ulleval.no} ; Ingebj&oslash ; rg  ; Seljeflot^a ;   ; ^b ;   ; ^d ;   ; ^{ingebjorg.seljeflot@ulleval.no}
• 关键词：Matrix metalloproteinase-9 ; Single nucleotide polymorphism ; mRNA ; Coronary artery disease ; Zymography
• 刊名：Clinica Chimica Acta
• 出版年：2012
• 出版时间：18 January 2012
• 年：2012
• 卷：413
• 期：1-2
• 页码：113-120
• 全文大小：557 K

文摘

Background

Mediators involved in atherosclerosis and plaque rupture may have importance as risk markers for coronary artery disease (CAD). We have investigated the influence of matrix metalloproteinase (MMP)-9 genetic variations on gene- and protein expression in stable CAD patients.

Methods

The promoter ?562C/T and exon 6 R279Q A/G polymorphisms were determined in 1001 patients with angiographically verified stable CAD and in 204 healthy controls. Genotype and gene-expression were determined by real-time PCR. Serum levels of MMP-9 and its inhibitor TIMP-1were measured immunologically and by zymography (MMP-9 activity).

Results

None of the polymorphisms associated with the presence of CAD, myocardial infarction or type 2 diabetes, whereas the variant allele of the R279Q polymorphism associated with hypertension (adjusted p = 0.015). The T- and G alleles associated with lower and higher mRNA levels, respectively (p < 0.005 both), also shown in an experimental ex-vivo LPS stimulated model. T-allele carriers had higher concentrations of MMP-9 (adjusted p = 0.032) and the GG genotype induced lower MMP-9 gelatinolytic activity (p = 0.01). Higher MMP-9 gene-expression and TIMP-1 levels were observed in patients with previous myocardial infarction, the latter also was elevated in diabetics (< 0.05, all).

Conclusion

The investigated MMP-9 polymorphisms influenced gene- and protein expression differently and the R279Q polymorphism associated significantly with hypertension.