NEW ORLEANS — Genetic research can confirm which risk factors cause CHD and which are merely associated with CHD, according to a speaker at the National Lipid Association Scientific Sessions.
Traditional risk factors including age, male sex, smoking, hypertension, diabetes, high LDL, low HDL and high levels of apoliprotein B only explain 60% to 70% of MI cases, Muredach P. Reilly, MBBCH, MSCE, Herbert and Florence Irving Professor of Medicine and director designate of the Irving Institute for Clinical and Translational Research at Columbia University, said during a presentation.
Researchers have learned that genetics plays a large role in CVD events that cannot be explained by traditional risk factors, as men with a parent with early-onset CVD have a 3.2-fold higher risk for CHD, while women with such a parent have a 2.9-fold higher risk, he said.
For example, he said, individuals with gain-of-function PCSK9 mutations have greatly increased risk for CHD, while those with loss-of-function PCSK9 mutations have dramatically lower risk for CHD.
Currently, there are more than 50 loci identified that confer a genome-wide increased risk for CHD, but only 12 loci are associated with lipid traits and five with BP traits, meaning many of the others are not associated with traditional CV risk factors, Reilly said.
Mendelian randomization studies — which, when well-designed, are almost as effective as randomized controlled trials because they are similar except for comparing a variant allele vs. a reference allele instead of an intervention vs. a control — have shed light on which factors have a causal relationship with various forms of CVD, he said.
He cited one example of researchers who showed that variants known to raise LDL are also associated with increased risk for MI, establishing that high LDL plays a role in MI risk.
Similar studies have determined that apolipoprotein C-III and LPL levels also appear to play a causal role in CVD, he said.
“We have made a treasure trove of discoveries,” he said. “We can make genetic inferences about the direction of causality. … We know now that all of the loci for LDL cholesterol seem to relate to heart disease. This seems to be true also for most loci for triglycerides, but not so for HDL cholesterol itself.”
These findings have led to a wave of novel therapies targeting risk factors that appear to have a causative relationship with CHD, most notably elevated PCSK9, according to Reilly. – by Erik Swain
Reilly M. Human Genetics Impact on Clinical Practice in Lipidology. Presented at: National Lipid Association Scientific Sessions; May 19-22, 2016; New Orleans.
Disclosure: Reilly reports no relevant financial disclosures.