Significance of common genetic variants associated with non-ischaemic cardiomyopathy in the general population.

AIMS: Common genetic variants have been linked to an increased risk of non-ischaemic cardiomyopathy (NICM). The primary objective of this study was to evaluate the significance of these variants in a general population.

METHODS AND

RESULTS

Thirteen NICM risk alleles, previously validated by meta-analyses of case-control genetic association studies, were used to determine genetic risk (GR) in a large, unselected cohort (n = 1897) of Olmsted County residents aged >45 years. Clinical and echocardiographic data, with biomarkers, were correlated with this NICM-GR over a median of 16 years of follow-up (interquartile range [IQR] 15-17). There were no significant differences between the study population quartiles, based on NICM-GR, in terms of age (median 61.6 [IQR 53.6-70.4]), sex (48% male), and cardiovascular risk factors. A significant correlation was detected by specific linear-regression models between NICM-GR and left ventricular (LV) ejection-fraction (beta [standard error]: -2.68 [0.68], p < 0.001), LV end-systolic-diameter (0.22 [0.06], p < 0.001), and LV end-diastolic-diameter (0.14 [0.06], p = 0.01). During follow-up, 46 subjects developed NICM. Using a 3:1 matched-cohort of non-NICM versus NICM patients, linear-regression analysis found a significant correlation between NICM-GR and NICM development (odds ratio 2.27, 95% confidence interval 1.06-4.85, p = 0.03). There was no significant association between these variants and heart failure biomarkers (aldosterone, natriuretic peptides, ST2, galectin-3).

CONCLUSIONS

The NICM-GR correlates with LV function and dimension, and subsequent development of NICM in the general population. The lack of correlation of these variants with cardiovascular risk factors and the renin-angiotensin-aldosterone axis or natriuretic peptides suggest different biological mechanisms involved. These findings support the need to explore newer pathophysiologic pathways in the development of NICM.