Role of inflammatory gene polymorphisms in left ventricular dysfunction (LVD) susceptibility in coronary artery disease (CAD) patients

Rationale: Inflammation exacerbates a number of deleterious effects on the heart, most notable being left ventricular dysfunction (LVD). A promoter polymorphism of the NFKB1 gene (encodes p50 subunit) results in lower protein levels of NFkB p50 subunits, which in its dimmer (p50)(2) form has anti-inflammatory effects. The active NFkB transcription factor promotes the expression of over 150 target genes including IL6 and TNF-alpha. Therefore, the aim of the present study was to assess the association of NFKB1,1L6 and TNF-alpha gene polymorphisms with LVD in coronary artery disease (CAD) patients. Methods and Results: The present study included a total of 830 subjects (600 CAD patients and 230 controls) and was carried out in two (primary and replication) cohorts. CAD patients with reduced left ventricle ejection fraction (LVEF <= 4.45%) were categorized having LVD. The NFKB1 -94 ATTG ins/del (rs28362491), IL6 -174 G/C (rs1800795) and TNF-alpha -308 G/A (r51800629) polymorphisms were genotyped by PCR/ARMS-PCR methods. The results of the primary cohort were validated in a replicative cohort and pooled by meta-analysis using Fisher's and Mantel-Haenszel test. The analysis showed that NFKB1 ATTG(1)/ATTG(1) genotype was significantly associated with LVD (Fisher's method p-value = 0.007, Mantel-Haenszel OR = 2.34), LV end diastole (p-value = 0.013), end systole (p-value = 0.011) dimensions, LV mass (p-value = 0.024), mean LVEF (p-value = 0.001) and myocardial infarction (p-value = 0.043). Conclusion: Our data suggests that NFKB1 -94 ATTG ins/del polymorphism plays significant role in conferring susceptibility of LVD and ATTG(1)/ATTG(1) genotype may modulate risk of heart failure by increasing ventricular remodeling and worsening LV function. (C) 2013 Elsevier Ltd. All rights reserved.