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Title: Coronary heart disease genetic risk score predicts cardiovascular disease risk in men, not women: The Multi-Ethnic Study of Atherosclerosis

Author
item HAJEK, CATHERINE - SANFORD HEALTH
item GUO, XIUQING - LOS ANGELES BIOMEDICAL RESEARCH INSTITUTE
item YAO, JIE - LOS ANGELES BIOMEDICAL RESEARCH INSTITUTE
item HAI, YANG - LOS ANGELES BIOMEDICAL RESEARCH INSTITUTE
item JOHNSON, W - UNIVERSITY OF WASHINGTON
item FRAZIER-WOOD, ALEXIS - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC)
item POST, WENDY - JOHNS HOPKINS UNIVERSITY
item PSATY, BRUCE - KAISER PERMANENTE
item TAYLOR, KENT - LOS ANGELES BIOMEDICAL RESEARCH INSTITUTE
item ROTTER, JEROME - LOS ANGELES BIOMEDICAL RESEARCH INSTITUTE

Submitted to: Circulation: Genomic and Precision Medicine
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/10/2018
Publication Date: 10/15/2018
Citation: Hajek, C., Guo, X., Yao, J., Hai, Y., Johnson, W.C., Frazier-Wood, A.C., Post, W.S., Psaty, B.M., Taylor, K.D., Rotter, J.I. 2018. Coronary heart disease genetic risk score predicts cardiovascular disease risk in men, not women: The Multi-Ethnic Study of Atherosclerosis. Circulation: Genomic and Precision Medicine. 11:e002324. https://doi.org/10.1161/CIRCGEN.118.002324.
DOI: https://doi.org/10.1161/CIRCGEN.118.002324

Interpretive Summary: Scientists use genetic risk scores to measure the risk that an individual has to develop a specific condition, such as coronary heart disease, arising from their genetic makeup. Genetic risk scores for cardiovascular diseases also have an important clinical role in predicting disease risk. Early studies developed genetic risk scores related to increased risk for cardiovascular problems and events. It is suggested in the literature that sex-specific differences exist in which genes predict cardiovascular problems; however, few studies have looked at potential differences in these genetic risk scores in men versus women. In this study, we developed a genetic risk score using variants found in published articles to be associated with coronary heart disease. We also used blood samples collected from 2,526 Caucasian participants from the Multi-Ethnic Study of Atherosclerosis (MESA) that did not have coronary heart disease at the beginning of the study. We found that many of the known variants of coronary heart disease may only be relevant in Caucasian men and not in Caucasian women. These results suggest that although coronary heart disease genetic risk scores are a meaningful screening mechanism, caution should be used when applying these in a broader population. Large-scale studies are needed to identify risk variants specific to women and individuals of other ethnicities before using coronary heart disease genetic risk scores in a clinical setting, however, this study may contribute information to future research which is of interest to clinicians and members of the public who wish to assess coronary heart disease risk.

Technical Abstract: Earlier studies have demonstrated that high genetic risk scores (GRSs) are associated with increased risk for cardiovascular events. However, none of the published coronary heart disease (CHD) GRS studies directly compare the performance of the risk score between men and women. This study is an analysis of the existing genotypic data from the MESA (Multi-Ethnic Study of Atherosclerosis) in the form of a literature-derived CHD GRS calculated for the white subpopulation of this cohort to evaluate whether a high CHD GRS was associated with an increased cardiovascular disease risk in the MESA cohort of white men and women. MESA participants were genotyped using the Affymetrix Genome-Wide Human Single Nucleotide Polymorphism (SNP) array 6.0. The CHD GRS was calculated using a literature-derived list of 46 SNPs and the Beta-coefficient or the odds ratio from the most recently published genome-wide association studies that included the SNP. Our findings revealed no apparent sex differences for age or mean GRS (all P>0.1). However, the rate of incident CHD in males was almost twice the rate in females. Mean GRS did not differ between males and females. The observation that in MESA whites, the association between GRS and cardiovascular events differed significantly between men and women supports the concept that at a genome level, CHD in women may have a different set of risk SNPs. Discovery studies in women alone or analyses stratified on sex are necessary to identify female-specific risk variants to better understand the pathophysiology of heart disease in women.