Genetic Predisposition Of Dilated Cardiomyopathy And The Involvement Of Cardiac Magnetic Resonance Phenotype And Prognosis-a Genome-wide Association Study

Objective:Dilated cardiomyopathy is a kind of disease which is involved in complex genetic factors.However,the current molecular genetics studies have not sufficiently explained the involvement of genetic factors in this disease.There has not been any study aimed at discovering the potential relevance between single nucleotide polymorphisms and DCM susceptibility as well as DCM clinical phenotypes in Han population.This study aims at unveiling the relationship between genetic polymorphisms and susceptibility as well as clinical imaging phenotypes of DCM by genome-wide association study(GWAS).Materials and Methods:463 DCM patients underwent cardiac magnetic resonance imaging(CMRI)are included,their clinical and imaging information was recorded and peripheral venous whole blood sample was taken.Chip box CPT-PMRA from Affymetrix was used for genotyping.The SNPs maps were compared between 463 DCM patients and 1521 unrelated people in order to discover SNPs of susceptibility.The imaging data involved structural parameters like LVEDV,LVEF and cardiac fibrosis parameters like LGE,ECV.Those parameters are used for deep phenotyping of DCM patients,and further association study in genome.In this cohort,450 patients were followed-up by telephone,and 110 patients underwent second CMRI after one-year standardized therapy.According to the recovery level of cardiac structure and function,the 110 patients were divided in three groups: reverse remodeling,no significant change and remodeling-progressed.The groups were compared in genome-wide level.Results:After quality control and gene imputation,the SNPs capable for analysis are5,471,654 in all.In genome-wide level,no susceptibility SNP was found in DCM patients.Besides,seven susceptibility SNPs from past researches was found significant(P<0.05)in our study.Among 464 DCM patients who underwent CMRI,rs958914 in gene KIF21 A,rs5763302,rs4540055 in TLR1 were found with significant relevance to imaging parameters.For rs958914,the Native T1 of patients with TT genotype is 4.2% higher than CC genotype(1318.02±77.23 ms vs1264.27±75.81ms).For rs4540055,the LVEDV of patients with AC genotype is 23.9%larger than AA genotype(368.48±146.25 ml vs 297.18±98.53ml).Among 450 patients followed-up,73 patients have reached primary clinical endpoints,116 patients have reached secondary endpoints.In Cox analysis,BMI,LVEF,diabetes and inotropic medicine usage were independent prognostic factors in both single-factor analysis and multiple-factor analysis.No significant relevance was found between prognosis and SNPs in genome-wide level.Among 110 patients underwent second CMRI,41 patients reached LVRR(LVEDV reduction > 10%),47 patients did not show significant change(LVEDV reduction:-5%～10%),22 patients have remodeling progressed.In genome-wide level,rs757263 between gene TRIM31 and TRIM40 was significantly relevant to LVRR level,the chance of getting remodeling progressed is much higher in genotype TT comparing to genotype CC(87.5% vs 5.8%).Conclusion:By genome-wide association study,we found significant SNP relevant to left ventricular structural parameters and fibrosis level parameters in dilated cardiomyopathy patients.This study confirmed the involvement of genetic polymorphism and its relationship between clinical imaging phenotypes,which may further guide the risk stratification and prognosis evaluation of DCM.