ACE2, CALM3 and TNNI3K polymorphisms as potential disease modifiers in hypertrophic and dilated cardiomyopathies

Abstract

The marked clinical and genetic heterogeneity seen in hypertrophic (HCM) and dilated cardiomyopathies (DCM) suggests involvement of disease modifiers and environmental factors in the pathophysiology of these diseases. In the current study, we examined association of single nucleotide polymorphisms (SNPs) of three candidate genes, ACE2 (rs6632677), TNNI3K (rs49812611) and CALM3 (rs13477425) with clinical phenotypes of HCM and DCM patients of North Indian ethnicity. Prevalence of ACE2 (7160726 C>G) variant genotypes (CG and GG) was significantly higher in DCM subjects as compared to controls. Prevalence of TNNI3K (3784 C>T) and CALM3 (-34T>A) variant homozygous genotype were significantly higher in HCM and DCM subjects as compared to controls. DCM patients with CT genotype showed significant decrease in LVEF as compared to CC genotype (p < 0.03). There was significant gene-gene interaction between these SNPs and three-way SNP combination of ACE2 C>G, TNN13K C>T, CALM3 A>T gene variants and was associated with high risk of HCM and DCM. Presence of ACE2 (7160726 C>G) and CALM3 (-34T>A) variant genotypes in HCM Patients with mutations (sarcomeric or non sarcomeric genes) was associated with increased mean septal thickness, further suggesting a role of these gene variants in modifying disease phenotype. Our results suggest that ACE2, TNNI3K and CALM3 polymorphisms are associated with increased risk of HCM and DCM and may act as disease modifiers of these diseases.

Association of ACE2 genetic polymorphisms with hypertension-related target organ damages in south Xinjiang

“…In the Framingham Heart Study [41], every 5-mm increase in LAD increased the development of AF by 39%. A recent study correlated rs6632677 with left ventricular remodeling [42], and it has been associated with AF risk in the Chinese population [43]. In contrast, we found that rs6632677 was not associated with risk of AF (see Supplementary Table 7), and the genotypes of the 3 ACE2 SNPs associated with LAE were also associated with increased AF risk (OR = 2.20–2.62).…”

Association of ACE2 polymorphisms with susceptibility to essential hypertension and dyslipidemia in Xinjiang, China

“…Meanwhile, we found that rs2074192 and rs879922 were not only non-correlated with IS but also had nothing to do with the recurrence risk of stroke [ 38 ]. Although rs6632677 was not associated with hypertension, dyslipidemia and stroke, it was found to be related to left ventricular remodeling [ 39 ] and possible atrial fibrillation risk in Chinese population [ 40 ]. However, association of SNP rs2048683 with hypertension, dyslipidemia and stroke had been pretty “silent”, suggesting that the loci were not protective factors but they are at least not a harmful factor on EH and EH related cardiovascular events.…”

Overlapping Phenotypes and Degree of Ventricular Dilatation Are Associated with Severity of Systolic Impairment and Late Gadolinium Enhancement in Non-Ischemic Cardiomyopathies

“…Although this report found no connections of coexisting trabeculations that fit within NC/C ratio criteria in DCM with clinical points, it only could be partially compared to the present study and our previous study due to using triple criteria of thinning of the compact myocardium, NC/C ratio, and sufficient share of non-compact myocardium in total mass of the left ventricle [ 27 ]. The second most common combination, DCM/HCM, was found in nearly one-third of our overlapping patients, but this combination could be even more powerfully connected with undesirable prognosis due to partially shared gene basics [ 28 , 29 ]. The least frequent combination in our settings was the DCM/HCM/LVNC, with only a single case in the monitored period, which was also previously described in a large registry with clinical endpoints, which reported a greater incidence of cardiovascular adverse events [ 30 ].…”