Abstract 2996: Association Between Gene Polymorphisms of Matrix Metalloproteinase and Left Ventricular Diastolic Function in Essential Hypertension
Background: Some studies have shown that disturbances in the matrix metalloproteinase (MMP) pathway are involved in the impairment of left ventricular (LV) diastolic function. To assess the hypothesis that MMP gene polymorphisms may specifically influence LV diastolic properties, this study investigated the relation of single nucleotide polymorphisms (SNPs) of MMP genes, particularly MMP-2 and its activator membrane type 1 MMP (MT1-MMP) genes, to LV diastolic dysfunction in hypertensives.
Methods: Genotyping in 17 SNPs identified by direct sequencing was performed with TaqMan PCR method in 748 Japanese patients with essential hypertension (405 men and 343 women, age 65 ± 11 years). In echocardiographic examinations, LV mass index (LVMI), the peak velocity ratio of atrial filling to early diastolic filling (A/E), and the deceleration time of the E wave (DcT) were determined.
Results: Among 11 SNPs in the MMP-2 gene and 6 SNPs in the MT1-MMP gene, G-724A genotypes in the promoter region of MT1-MMP gene had a significant association with LV diastolic dysfunction (A/E> = 1.5). In allele frequencies, A allele of G-724A was related to diastolic dysfunction (OR: 1.71, P= 0.002). In fact, both A/E and DcT significantly increased in subjects with GA + AA (A/E, 1.33 ± 0.40 vs 1.24 ± 0.35 in GG, P = 0.006; DcT, 224 ± 55 vs 215 ± 45 msec in GG, P = 0.037). Logistic regression analyses revealed that the presence of A allele was a significant predictor for diastolic dysfunction, independent of age, sex, blood pressure, and LVMI (P = 0.003). We previously found that TC + CC types of T54202C in the endothelin A (ET-A) receptor gene and AA type of A1166C in the angiotensin II type-1 (AT1) receptor gene were related to LV diastolic dysfunction. Interestingly, subjects with A allele of MT1-MMP G-724A in addition to these two SNP genotypes had a markedly higher prevalence of diastolic dysfunction, compared to those without either genotype (OR: 6.60, P = 0.0001).
Conclusions: Our findings show that a newly identified SNP in the MT1-MMP gene has a significant influence, independent of other determinants, on LV diastolic function in essential hypertension. Moreover, the combination of this SNP and ET-A and AT1 gene polymorphisms may be a powerful predictor for the development of diastolic dysfunction.