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Monogenic, polygenic risk for CVD may be lowered by lifestyle changes, statin therapy
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Spelling changes in DNA sequence can increase risk for CVD, but such genetic risk can be offset by lifestyle changes or medical therapies, two experts said during presentations at the National Lipid Association Scientific Sessions.
Monogenic risk for CVD
Nathan Stitziel, MD, PhD, assistant professor of medicine and genetics and director of the Center for Cardiovascular Genetics at Washington University School of Medicine in St. Louis, assistant director of McDonnell Genome Institute in St. Louis and a Cardiology Today Next Gen Innovator, discussed genetic factors that impact premature instances of CVD, including monogenic disorders, polygenic disorders and environmental factors.
Regarding single genes, carriers of rare low-density lipoprotein receptor (LDLR) mutations were associated with an increased risk for MI by 4.2-fold, and a 13-fold increased risk was found in those with null alleles at LDLR, according to a research letter in Nature by Stitziel and colleagues.
Stitziel added that in over 10,000 patients, of which 5,000 patients had early cases of MI and the other half were free of MI at an older age, the gene that was notably associated with the prevalence of MI was LDLR. In this patient population, the damaging mutations in LDLR were found in about one in 50 patients with MIs at an early age and in an estimated one in 200 patients in the control group.
In addition to mutations in LDLR, other disorders of cholesterol metabolism that can prevent with premature CVD include polygenic hypercholesterolemia and elevated lipoprotein(a), he said.
Beyond disorders of cholesterol metabolism, other monogenic forms of early-onset CAD may be associated with to peripheral artery disease, vasculidities, metabolic syndromes and inherited thrombophilias. For example, mutations in LRP6 appear to increase risk for both premature coronary atherosclerosis and metabolic syndrome as summarized in a review in Circulation: Cardiovascular Genetics from 2014.
The most common monogenic forms of early-onset CAD is environmental influences, Stitziel said. The other presentations including inherited thrombophilias, metabolic syndromes, PAD, vasculidities and other monogenic forms are less common.
Regarding therapies for CVD, Stitzel said that rare mutations in drug targets can provide insight as to whether those drugs are safe and effective. This is important because even though PCSK9 inhibitors have been previously shown to lower LDL, all patients with familial hypercholesterolemia (FH) may not benefit from PCSK9 inhibitors, according to an article from 2012 in Nature Reviews Drug Discovery. Rare human mutations in two genes now suggest two additional pathways to treating CVD.
Inhibiting NPC1L1 in patients with FH may reduce LDL. Stitziel referenced a 2008 study from The New England Journal of Medicine, where researchers wrote that patients treated with simvastatin and ezetimibe (Zetia, Merck) had an estimated 60% decrease in LDL vs. an estimated 42% of patients treated with simvastatin alone at 24 months.
Stitziel said that in his study from The New England Journal of Medicine from 2014, patients with loss-of-function mutations in NPC1L1, which is rare, had a lower LDL of 12 mg/dL (P = .04) and an OR for MI of 0.47 (P = .008). Researchers from another study in The New England Journal of Medicine in 2015 observed that lowering LDL with ezetimibe in addition to statin therapy also reduces the risk for MI.
According to a study in The New England Journal of Medicine in 2010, researchers wrote that the loss of ANGPTL3 can reduce triglycerides, LDL and HDL, although it was unclear at the time whether it protects a patient from CAD or whether it may lead to other issues. Stitziel added that studies since then have shown that loss-of-function mutations in ANGPTL3 may be atheroprotective. “These mutations can estimate the therapeutic efficacy of inhibitory drugs, and ANGPTL3 is now a genetically validated therapeutic target,” Stitziel said.
Polygenic risk for CVD
In a separate presentation, Sekar Kathiresan, MD, director of the Center for Genomic Medicine at Massachusetts General Hospital in Boston, director of the Cardiovascular Disease Initiative at the Broad Institute in Cambridge, Massachusetts, and associate professor of medicine at Harvard Medical School, discussed the polygenic risk for CVD.
In a study by Paul D. White, MD, and colleagues in JAMA in 1951, researchers found that in patients with MI, family history played a factor in 27% of cases vs. 14% in the control group.
Although the average age for U.S. patients with MI is 65 years for men and 72 years for women, there are patients whose onset for MI occurs earlier. In patients younger than 55 years, the cause of MI may be due to either monogenic factors, polygenic factors or high genetic risk. The question, Kathiresan said, is whether people with high genetic risk may have their risk reduced.
Patients with early-onset MI were more likely to have LDLR mutations (approximately 1 in 50 patients) vs. those without MI (approximately 1 in 200 patients). In a study in JAMA in 2017, Kathiresan and colleagues wrote that a one in 5,000 heterozygous deficiency of LPL was linked to a 4.3-fold increase in the clinical effect of MI. This increased to 4.5-fold in a one in 3,000 heterozygous deficiency of APOA5, according to a study in Nature.
Regarding the polygenic model, this can often vary by patient. Kathiresan’s research studies have “systematically searched for allele frequency differences between cases and controls at millions of polymorphisms across genome.”
Patients with high monogenic and/or polygenic risk are more likely to have a higher event rate. Monogenic risk can contribute to a fourfold increase in risk for MI, while polygenic risk is linked to a twofold increase in risk.
In The New England Journal of Medicine in 2016, Kathiresan and colleagues wrote that patients with high genetic risk who adhere to a favorable lifestyle decreased their risk by almost 50%. Genetic risk also decreased in those with less severe risk. Lifestyle changes including a BMI < 30 kg/m2, a healthy diet pattern, no smoking and regular physical activity can reduce a patient’s risk. The more factors a patient implements into their routine, the more favorable of an effect it will have on risk, he said.
Medications such as statin therapy can also reduce the effects of high genetic risk. There have been a number of randomized controlled studies that showed that statins including rosuvastatin, pravastatin and atorvastatin have an impact on polygenic risk scores and its effect on the risk for first MI.
Kathiresan discussed a study in Circulation in 2017 that compared the effects of statin therapy on patients with high genetic risk vs. other levels of risk. “Among those at high genetic risk, statins confer greater benefit,” Kathiresan said. Statins in patients with high genetic risk also led to a lower number needed to treat of 13 vs. 37 in the group with all other levels of risk.
Kathiresan concluded that MI risk may be monogenic (mutations in LDLR, LPL and APOA5) or polygenic (more than 50 common variants) and that patients with high genetic risk can offset risk through lifestyle changes and statin therapy. – by Darlene Dobkowski
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Disclosures: Kathiresan reports serving on scientific advisory boards for Celera, Eli Lilly, Genomics PLC, MedGenome, Merck, Novartis and Regeneron Genetics Center, and receiving research grants from Amarin and Bayer Healthcare. Stitziel reports no relevant financial disclosures.