Common genetic variants and modifiable risk factors underpin hypertrophic cardiomyopathy susceptibility and expressivity

Autor: Harper, A. R., Goel, A., Grace, C., Thomson, K. L., Petersen, S. E., Xu, X., Waring, A., Ormondroyd, E., Kramer, C. M., C. Y., Ho, Neubauer, S., Kolm, P., Kwong, R., Dolman, S. F., Desvigne-Nickens, P., Dimarco, J. P., Geller, N., Kim, D. -Y., Zhang, C., Weintraub, W., Abraham, T., Anderson, L., Appelbaum, E., Autore, C., Berry, C., Biagini, E., Bradlow, W., Bucciarelli-Ducci, C., Chiribiri, A., Choudhury, L., Crean, A., Dawson, D., Desai, M. Y., Elstein, E., Flett, A., Friedrich, M., Heitner, S., Helms, A., Jacoby, D. L., Kim, H., Kim, B., Larose, E., Mahmod, M., Mahrholdt, H., Maron, M., Mccann, G., Michels, M., Mohiddin, S., Nagueh, S., Newby, D., Olivotto, I., Owens, A., Pierre-Mongeon, F., Prasad, S., Rimoldi, O., Salerno, M., Schulz-Menger, J., Sherrid, M., Swoboda, P., van Rossum, A., Weinsaft, J., White, J., Williamson, E., Tadros, R., Ware, J. S., Bezzina, C. R., Farrall, M., Watkins, H.
Přispěvatelé: Cardiology, ACS - Heart failure & arrhythmias
Jazyk: angličtina
Rok vydání: 2021
Předmět:
LOCI
Genome-wide association study
Blood Pressure
Bioinformatics
DISEASE
SYSTOLIC HYPERTENSION
0302 clinical medicine
Adolescent
Adult
Aged
Cardiac Myosins
Cardiomyopathy
Hypertrophic
Carrier Proteins
Case-Control Studies
Formins
Genetic Predisposition to Disease
Genome-Wide Association Study
Heterozygote
Humans
Middle Aged
Myosin Heavy Chains
Risk Factors
Sarcomeres
Young Adult
Polymorphism
Single Nucleotide
11 Medical and Health Sciences
Genetics & Heredity
0303 health sciences
Hypertrophic cardiomyopathy
Single Nucleotide
3. Good health
GENOTYPE
cardiovascular system
Life Sciences & Biomedicine
Cardiomyopathy
macromolecular substances
Biology
AMERICAN-COLLEGE
03 medical and health sciences
Heart disorder
Mendelian randomization
Genetics
medicine
Expressivity (genetics)
cardiovascular diseases
Risk factor
GENOME-WIDE ASSOCIATION
Polymorphism
030304 developmental biology
HCMR Investigators
Science & Technology
Genetic heterogeneity
Case-control study
06 Biological Sciences
medicine.disease
Hypertrophic
DISCOVERY
030217 neurology & neurosurgery
Developmental Biology
Zdroj: Nature genetics, 53(2), 135-142. Nature Publishing Group
ISSN: 1546-1718
1061-4036
Popis: Hypertrophic cardiomyopathy (HCM) is a common, serious, genetic heart disorder. Rare pathogenic variants in sarcomere genes cause HCM, but with unexplained phenotypic heterogeneity. Moreover, most patients do not carry such variants. We report a genome-wide association study of 2,780 cases and 47,486 controls that identified 12 genome-wide-significant susceptibility loci for HCM. Single-nucleotide polymorphism heritability indicated a strong polygenic influence, especially for sarcomere-negative HCM (64% of cases; h2g = 0.34 ± 0.02). A genetic risk score showed substantial influence on the odds of HCM in a validation study, halving the odds in the lowest quintile and doubling them in the highest quintile, and also influenced phenotypic severity in sarcomere variant carriers. Mendelian randomization identified diastolic blood pressure (DBP) as a key modifiable risk factor for sarcomere-negative HCM, with a one standard deviation increase in DBP increasing the HCM risk fourfold. Common variants and modifiable risk factors have important roles in HCM that we suggest will be clinically actionable.
Databáze: OpenAIRE
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