Association of polygenic risk scores with low-density lipoprotein cholesterol levels and control: findings from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL)

Abstract

BackgroundHypercholesterolemia is a prevalent cardiovascular (CVD) risk factor among Hispanics/Latinos; however, rates of cholesterol awareness and treatment are low in this population. Using a polygenic risk score (PRS) associated with low-density lipoprotein cholesterol (LDL) levels may help identify those who would benefit most from statin therapy. Previous LDL-PRS have been developed but they have not been properly evaluated for use in a highly diverse Hispanic/Latino population. MethodsThe Hispanic Community Health Study/Study of Latinos (HCHS/SOL) is a prospective study that enrolled 16,415 Hispanic/Latino adults aged 18-74 years from four U.S. communities in 2008-2011. We assessed the association of twenty PRS with baseline LDL levels and LDL control among 11,669 HCHS/SOL participants with complete data and consent to conduct genetic research. Weighted PRS were calculated using effect estimates obtained from the PGS Catalog. Multivariable linear regression analysis was used to derive effect estimates (betas ({beta}), 95% confidence intervals (CI)) for the association between each PRS, modeled continuously and by quintiles, with baseline LDL levels. Multivariable logistic regression was used to derive odds ratios and 95% CI for the association between each PRS and LDL control in statin users. Models were adjusted for predefined confounders and accounted for survey weights. ResultsA PRS developed with PolyFun-pred, using European GWAS summary statistics, provided the largest incremental improvement for predicting LDL levels for the full sample ({Delta}R2 0.114), Caribbean background ({Delta}R2 0.096), majority African ancestry ({Delta}R2 0.098), and majority Amerindian ancestry subgroups ({Delta}R2 0.123). PRSCSx-EUR, using multiple ancestry GWAS and weights, improved PRS performance most for the Mainland background ({Delta}R2 0.090) and majority European ancestry ({Delta}R2 0.061) subgroups. For every one standard deviation increase across the 20 PRS asssesed, LDL increase varied between 3 and 14mg/dL. Among 1,323 statin users, the odds of LDL control were greatly reduced with increasing PRS but differed between PRS and Hispanic/Latino background groups and genetic ancestry groups. ConclusionA polygenic risk score prioritizing functional annotations demonstrated superior performance for predicting LDL levels and LDL control across Hispanic/Latino subgroups. These results emphasize that further development of PRS is needed for improved risk prediction before clinical application in diverse populations. Clinical Perspective What is new?O_LITwenty previously validated polygenic risk scores associated with low-density lipoprotein (LDL) were found to be positively associated with LDL in a diverse population of Hispanics/Latinos living in the U.S. who have been historically underrepresented in genomic research. C_LIO_LIPRS developed using Hispanic/Latino GWAS summary statistics did not improve performance in all Hispanic/Latino subgroups. The PolyFun-pred PRS developed using European GWAS summary statistics and prioritizing functional annotations, improved performance most for subgroups historically underrepresented in genomic research. C_LIO_LIThe higher the PolyFun-pred PRS, the lower the likelihood participants had control of LDL levels while taking statins for both Caribbean and Mainland subgroups. C_LIO_LIWhat are the clinical implications? (<100 words) C_LIO_LIThe PolyFun-pred PRS shows promise to identify those at higher risk for increased LDL levels and may benefit from statin therapy; however, additional management may be necessary for those with high PolyFun-pred PRS because statin therapy was less likely to bring LDL under control. C_LIO_LIThe Hispanic/Latino population is genetically heterogeneous and should not have a one- size-fits-all approach when it comes to precision medicine. C_LIO_LITo be clinically useful, further research is needed to identify a PRS that will provide a diverse population of Hispanics/Latinos with the same benefit from pharmacogenomics and precision medicine as European populations to prevent widening health disparities. C_LI