Endocrine Abstracts

Aims: Genetic variations mediating matrix metalloproteinase-2 (MMP-2) expression may result in individual differences in susceptibility to particular diseases. Our aim was to investigate the possible association of certain MMP-2 gene variants with type 2 diabetes mellitus (T2DM) in a Tunisian population.

Subjects and Methods: A case-control study involving 310 normoglycemic control subjects and 791 T2D patients was performed. A total of four MMP-2 SNPs (-1306 C/T; -1575 G/A; -735 C/T and rs9923304 C/T were selected for this study, based on their established minor allele frequency (MAF) >5% in Caucasians and association with T2DM comorbidities. Genotyping of MMP-2 variants was performed by real time PCR. Replicated blinded quality control samples were included to evaluate reproducibility of the genotyping procedure; concordance was > 99%.

Results: The MAF of the -1306C/T and the -1575G/A MMP-2, were significantly different between T2DM cases and controls. Setting homozygous wild-type genotype carrier as reference, a reduced risk of T2DM was seen with the -1306C/T and the -1575G/A genotypes. The inheritance hypothesis for this polymorphism was tested according to three genetic models: codominant, dominant, and recessive. According to the dominant model, individuals with GT + TT genotypes of the -1575G/A MMP-2 SNP had a 0.68-fold reduced risk of developing the disease (P=0.012). Moreover, a significant association was shown under the dominant model of the -1306C/T polymorphism with P=0.007 and OR (95% CI) = 0.66 (0.49–0.89), which revealed a 0.66-fold reduced risk within individuals with CT + TT vs individuals with a double homozygote CC genotype. This association persists after controlling for the BMI, total cholesterol and triglyceride covariates as three adjustments models. Haploview analysis revealed limited linkage disequilibrium between the tested MMP-2 and variants, with most haplotypes (99.5%) captured by 7 MMP-2 haplotypes. Taking the GCCC haplotype as reference for MMP-2 (OR=1.00), a reduced frequency of TTCC haplotypes (P=0.04) and the GTCC haplotype (P=3.5x 10⁻⁵) was noted in T2D which indicates a protective nature of these two haplotypes for T2D development. Conclusions: To the best of our knowledge, our study is the first to demonstrate the potential of -1306 C/T and -1575 G/A MMP-2 SNPs to reduce the risk of developing type 2 diabetes mellitus.