European Heart Journal ( 2016 ) 37 ( Abstract Supplement ), 368 ... heart rate turbulence (HRT), microvolt Twave alternans (mTWA), age, gender, NYHA, 6MWT, ...
Abstract: P1792 Cumulative effect of LMNA gene single nucleotide polymorphisms on the phenotype of dilated cardiomyopathy Authors: T. Vaikhanskaya 1, T.V. Kurushka 1, L.N. Sivitskaya 2, N.G. Danilenko 2, O.G. Davidenko 2, 1Republican Scientific and Practical Center “;Cardiology”; Minsk Belarus, 2Institute of Genetics and Cytology, National Academy of Science Minsk Belarus, Topic(s): Cardiomyopathies Citation: European Heart Journal ( 2016 ) 37 ( Abstract Supplement ), 368 The purpose of this study was to assess genotypephenotype correlations in patient with dilated cardiomyopathy (DCM) due to Lamine A/C (LMNA) gene single nucleotide polymorphisms (SNPs). Methods: We enrolled 160 patients with DCM who had a primary manifestation of conduction or arrhythmic disturbances before dilated phenotype (aged 45,8±12,1; 67,5% male, NYHA 2,5±0,9; LVEF 26,9±9,76%). Exons in the functional regions and the adjacent part of introns of the LMNA gene were sequenced. Genetic testing, echocardiographic and electrocardiographic (ECG)/24hHolter ECG data including QTc dispersion, heart rate turbulence (HRT), microvolt Twave alternans (mTWA), age, gender, NYHA, 6MWT, serum BNP and CPK levels were analyzed. Results: Diseasecausing (according to SNPs&GO predictor) missense mutations in LMNA gene were found in 3 DCM patients: Arg190Pro (novel), Thp520Arg, Thr528Arg. The largest three SNPs were identified. The first SNP is c.1908C>T (H566H, rs4641) which was located at exon 10 of LMNA gene. It (TT and TC genotype) was found in 25 (15,6%) DCM pts. This SNP does not alter the primary sequence of the protein lamin A/C as it determines synonymous codon for histidine at position 566. However positive correlation was revealed between c.1908C>T and nonsustained/sustained ventricular tachycardia (Spearman k=0,57; p=0.009) also mTWA (k=0,61; p=0.0007). The second SNP is c.1489–41C>T (rs553016) which was located intron between 8 and 9 exons of LMNA gene. It was found in 18 (11,3%) DCM pts. The third SNP is c.861C>T (A287A, rs538089) which was located at exon 5 of LMNA gene. It was found in 16 (10%) DCM pts. No correlation between LMNA gene SNPs (rs553016, rs538089) singly with phenotype was determined in DCM pts. At the same time carriage of three or more SNPs (16/10% pts) was associated with biventricular dysfunction and heart transplantation (HT). So two combinations of several variants: rs553016 or rs4641 + rs53808 + rs11264443 (c.639+73C>T located intron between 3 and 4exons) were associated with HT (n=0,41; p=0.033). But if SNP c.1908C>T is very important as it is located adjacent to a splice site at exon 10; alternative splicing at this site leads to the production of altered lamin A/C transcripts or protein; while a mechanism of c.861C>T, c.1489–41C>T and c.639+73C>T in DCM are still unclear. Conclusions: We conclude that SNPs in LMNA gene are one of many genetic risk factors for the pathogenesis of DCM other than mutation in LMNA. Therefore, detailed genetic analysis of the LMNA gene in the affected patients at the early stage might help in better management and timely therapeutic intervention.
