👤 Brian T Helfand

Low-density lipoprotein cholesterol (LDL-C) levels <100 mg/dL are generally considered normal. We tested the controversial hypothesis that a subset of individuals with 'normal' LDL-C levels may have a non-negligible risk of coronary artery disease (CAD) due to inherited factors, including monogenic variants and polygenic risk scores (PGS). A retrospective analysis of a prospective cohort from the Genomic Health Initiative at Endeavor Health, including 7880 participants without a prior diagnosis of CAD and not on statins at recruitment. Participants were stratified by baseline LDL-C levels and followed for incident CAD. The association of CAD risk with carrier status for pathogenic/likely pathogenic (P/LP) variants in Among participants, 31.2 % had LDL-C <100 mg/dL (normal), 39.5 % had LDL-C 100-129 mg/dL, and 29.3 % had LDL-C ≥130 mg/dL. Over a median follow-up of 8 years, CAD was diagnosed in 5.3 %, 6.9 %, and 7.6 % of participants in these LDL-C groups, respectively. Among those with normal LDL-C, CAD incidence rose to 9.5 % in individuals with high genetic risk (P/LP variants and/or high PGS). Genetic risk was significantly associated with CAD in multivariable models ( Individuals with 'normal' LDL-C levels can have substantial CAD risk if they carry high genetic risk. These findings underscore the importance of incorporating genetic information into CAD risk assessment, even among those with traditionally normal lipid profiles. Show less

Current genetic testing for coronary artery disease (CAD) primarily targets monogenic variants in individuals with severe hypercholesterolemia. Whether supplementing monogenic testing with polygenic risk scores for CAD and Lp(a; lipoprotein[a]) levels [PRS A genetic probability for CAD (GenProb In the UK Biobank development cohort, PVs, polygenic risk scores for CAD and PRS GenProb Show less

Men diagnosed with low-risk prostate cancer (PC) are increasingly electing active surveillance (AS) as their initial management strategy. While this may reduce the side effects of treatment for prostate cancer, many men on AS eventually convert to active treatment. PC is one of the most heritable cancers, and genetic factors that predispose to aggressive tumors may help distinguish men who are more likely to discontinue AS. To investigate this, we undertook a multi-institutional genome-wide association study (GWAS) of 5,222 PC patients and 1,139 other patients from replication cohorts, all of whom initially elected AS and were followed over time for the potential outcome of conversion from AS to active treatment. In the GWAS we detected 18 variants associated with conversion, 15 of which were not previously associated with PC risk. With a transcriptome-wide association study (TWAS), we found two genes associated with conversion ( Show less

Despite strong evidence of heritability, few studies have attempted to unveil the genetic underpinnings of testosterone levels. To identify testosterone-associated loci in a large study and assess their biological and clinical implications. The participants were men from the UK Biobank. A two-stage genome-wide association study (GWAS) was first used to identify/validate loci for low testosterone (LowT, <8 nmol/l) in 80% of men ( Associations of single nucleotide polymorphisms (SNPs) with LowT were tested using an additive model. Analyses of the expression quantitative trait loci (eQTLs) were performed to assess the associations between significant SNPs and expression of nearby genes (within 1 Mbp). A genetic risk score (GRS) was used to assess the cumulative effect of multiple independent SNPs on LowT risk. The two-stage GWAS found SNPs in 141 loci of 41 cytobands that were significantly associated with LowT ( Identification of the genetic variants associated with LowT may improve our understanding of its etiology and identify high-risk men for LowT screening. We identified 141 new genetic loci that can be incorporated into a genetic risk score that can potentially identify men with low testosterone. Show less