Association of MMP2 and TIMP2 genetic polymorphisms with COPD and circulating MMP-2 and TIMP-2 protein levels: a case–control study

Chronic obstructive pulmonary disease (COPD) is a heterogeneous and progressive respiratory disorder in which genetic susceptibility interacts with environmental exposures to influence disease development. Extracellular matrix (ECM) remodeling is an important component of COPD pathogenesis, and dysregulation of the matrix metalloproteinase-2 (MMP2)–tissue inhibitor of metalloproteinase-2 (TIMP2) axis may contribute to structural alterations in the lung. However, limited information is available regarding MMP2 and TIMP2 genetic variation and circulating protein concentrations among individuals from North India. This study investigated the association of selected MMP2 and TIMP2 polymorphisms and circulating MMP2 and TIMP2 concentrations with COPD. A hospital-based case–control study was conducted among 100 participants, comprising 65 patients with clinically stable COPD and 35 healthy controls. Participants were recruited using a consecutive sampling approach. COPD was confirmed by post-bronchodilator spirometry. Eight candidate single nucleotide polymorphisms (SNPs) in MMP2 and TIMP2 were initially screened by DNA sequencing, and polymorphic variants were subsequently evaluated for genotype and allele associations with COPD. Circulating MMP2 and TIMP2 concentrations were measured using enzyme-linked immunosorbent assays. Genotype–protein associations were further examined within the COPD group using multivariable linear regression adjusted for age, sex, body mass index (BMI), and smoking exposure expressed as pack-years. Of the eight candidate SNPs screened, three were polymorphic in the study cohort: MMP2 rs243865 (− 1306 C/T), TIMP2 rs2277698 (+ 853 G/A), and TIMP2 rs8179090 (− 418 G/C). MMP2 rs243865 was significantly associated with COPD at both the genotype level ( P = 0.0294; OR = 2.901, 95% CI: 1.148–7.752) and allele level ( P = 0.0421; OR = 2.467, 95% CI: 1.012–5.624). TIMP2 rs2277698 was also significantly associated with COPD at the genotype level ( P = 0.0155; OR = 3.273, 95% CI: 1.327–8.679) and allele level ( P = 0.0247; OR = 2.705, 95% CI: 1.153–6.064). Similarly, TIMP2 rs8179090 showed significant genotype-level ( P = 0.0218; OR = 3.246, 95% CI: 1.176–8.482) and allele-level ( P = 0.0305; OR = 2.782, 95% CI: 1.156–6.579) associations with COPD. The genotype distributions of the three polymorphisms did not significantly deviate from Hardy–Weinberg equilibrium in controls. Circulating MMP2 concentrations were significantly higher in patients with COPD than in controls (36.664 ± 13.73 vs. 21.479 ± 4.83 ng/mL; P < 0.0001), whereas TIMP2 concentrations were significantly lower (3.086 ± 0.734 vs. 4.599 ± 1.103 ng/mL; P < 0.0001). However, in multivariable analyses within the COPD group, none of the three polymorphisms was significantly associated with circulating MMP2 or TIMP2 concentrations after adjustment for age, sex, BMI, and pack-years. MMP2 rs243865, TIMP2 rs2277698, and TIMP2 rs8179090 were significantly associated with COPD in this North Indian cohort, while circulating MMP2 and TIMP2 concentrations were significantly altered in patients with COPD. Nevertheless, the absence of statistically significant adjusted genotype–protein associations indicates that the present findings do not demonstrate a direct genotype-dependent effect of these polymorphisms on circulating MMP2 or TIMP2 concentrations. The genetic associations and protein-level alterations should therefore be considered distinct but potentially complementary observations. Larger multicentre studies incorporating smoking-exposed controls, larger sample sizes, longitudinal phenotyping, and functional validation are warranted to clarify the biological significance of these variants in COPD. Not applicable.