In the JournalsPerspective

Genetic predisposition to CHD alters risk associated with smoking

Elevated incidence of CHD attributable to smoking was less prominent in those with a genetic predisposition to CHD than in those without it, according to a study published in Circulation: Genomic and Precision Medicine.

George Hindy, MD, PhD, postdoctoral research fellow at the Broad Institute of Massachusetts Institute of Technology and Harvard University, and colleagues analyzed data from 24,443 participants (mean age, 58 years; 62% women) from the Malmö Diet and Cancer Study. Patients completed questionnaires on their physical activity, smoking habits, medication history, education and diet history. Nurses also measured BP and took blood samples. Participants were excluded if they had prevalent CHD.

CHD was defined as CABG, fatal or nonfatal MI, PCI or death caused by ischemic heart disease.

Participants were categorized based on their smoking status: never smokers, former smokers and current smokers. Genotyping was performed, and each participant was given a polygenic risk score based on presence or absence of 50 single nucleotide polymorphisms known to be associated with CHD. Follow-up was conducted for a median of 19.4 years.

During follow-up, 13.2% of participants developed CHD. The polygenic risk score modified the increased risk for CHD associated with smoking (P for interaction = .005).

Participants in the lowest tertile for polygenic risk score had the highest magnitude of increased incidence of CHD caused by smoking (OR per smoking risk category = 1.42; 95% CI, 1.29-1.56) compared with those in the highest tertile (OR per smoking risk category = 1.2; 95% CI, 1.11-1.3). Men had a stronger interaction (P for interaction = .001) compared with women (P for interaction = .44). Family history did not affect CHD associated with smoking.

The polygenic risk score improved net reclassification and discrimination when added to traditional risk factors in participants who never smoked, but such improvements were not seen in current smokers (P < .001).

“Our results show that smoking status may provide a valuable stratification tool for prioritization of individuals who would benefit from using a [polygenic risk score] to improve prediction of future CHD,” Hindy and colleagues wrote. “The [polygenic risk score] provided better discrimination on the top of a traditional risk factor model among never smokers compared with smokers.”

In a related editorial, Roberto Elosua, MD, PhD, of the cardiovascular epidemiology and genetics group at Institut Hospital del Mar d’Investigacions Mediques in Barcelona, Spain, wrote: “Hindy et al use an alternative method, defining a genetic risk score and analyzing the interaction between this genetic risk load and smoking on CAD. This approach is becoming more popular and could contribute to the identification of subgroups of the population that would obtain higher benefits from modifying their exposure to the environmental factor under study.” – by Darlene Dobkowski

Disclosures: The authors and Elosua report no relevant financial disclosures.

Elevated incidence of CHD attributable to smoking was less prominent in those with a genetic predisposition to CHD than in those without it, according to a study published in Circulation: Genomic and Precision Medicine.

George Hindy, MD, PhD, postdoctoral research fellow at the Broad Institute of Massachusetts Institute of Technology and Harvard University, and colleagues analyzed data from 24,443 participants (mean age, 58 years; 62% women) from the Malmö Diet and Cancer Study. Patients completed questionnaires on their physical activity, smoking habits, medication history, education and diet history. Nurses also measured BP and took blood samples. Participants were excluded if they had prevalent CHD.

CHD was defined as CABG, fatal or nonfatal MI, PCI or death caused by ischemic heart disease.

Participants were categorized based on their smoking status: never smokers, former smokers and current smokers. Genotyping was performed, and each participant was given a polygenic risk score based on presence or absence of 50 single nucleotide polymorphisms known to be associated with CHD. Follow-up was conducted for a median of 19.4 years.

During follow-up, 13.2% of participants developed CHD. The polygenic risk score modified the increased risk for CHD associated with smoking (P for interaction = .005).

Participants in the lowest tertile for polygenic risk score had the highest magnitude of increased incidence of CHD caused by smoking (OR per smoking risk category = 1.42; 95% CI, 1.29-1.56) compared with those in the highest tertile (OR per smoking risk category = 1.2; 95% CI, 1.11-1.3). Men had a stronger interaction (P for interaction = .001) compared with women (P for interaction = .44). Family history did not affect CHD associated with smoking.

The polygenic risk score improved net reclassification and discrimination when added to traditional risk factors in participants who never smoked, but such improvements were not seen in current smokers (P < .001).

“Our results show that smoking status may provide a valuable stratification tool for prioritization of individuals who would benefit from using a [polygenic risk score] to improve prediction of future CHD,” Hindy and colleagues wrote. “The [polygenic risk score] provided better discrimination on the top of a traditional risk factor model among never smokers compared with smokers.”

In a related editorial, Roberto Elosua, MD, PhD, of the cardiovascular epidemiology and genetics group at Institut Hospital del Mar d’Investigacions Mediques in Barcelona, Spain, wrote: “Hindy et al use an alternative method, defining a genetic risk score and analyzing the interaction between this genetic risk load and smoking on CAD. This approach is becoming more popular and could contribute to the identification of subgroups of the population that would obtain higher benefits from modifying their exposure to the environmental factor under study.” – by Darlene Dobkowski

Disclosures: The authors and Elosua report no relevant financial disclosures.

    Perspective
    Amit V. Khera

    Amit V. Khera

    We have known since the 1950s that risk for MI runs in families. However, only recently have we had the tools to look at the exact drivers in various populations’ DNA of this inborn increase in risk. One recently developed approach to quantify genetic susceptibility involves the use of a polygenic risk score. The idea is that a given genetic variant may have small effect, but adding up the effects of 50 different variants may be more impactful.

    For a given person coming into my clinic with an MI, the question is often, why did this happen? If an individual has a strong history of smoking cigarettes, this might explain that case. In people who never smoke, perhaps it was related to having been born with unfavorable genetics.

    The authors of the present study confirm that the effects of genetics are stronger among patients who never smoked compared with those that do. This is consistent with what we long suspected, but now confirmed using a polygenic risk score that quantifies a person’s genetic susceptibility.

    Moving forward, we are working to make these scores even better, including not just 50 variants, but several million scattered across a person’s genome. Ultimately, this is likely to explain a significant fraction of MIs that occur in people without traditional risk factors such as smoking, diabetes or hypertension.

    In the future, individuals’ polygenic score for MI is likely to be available to individuals and their health care providers. We are working to figure out how best to use this knowledge to help prevent MIs. We have already demonstrated that individuals with a strong genetic predisposition can overcome this increased risk by following a healthy lifestyle or taking cholesterol-lowering medications such as statins.

    • Amit V. Khera, MD
    • Cardiology Today Next Gen Innovator Cardiologist Genetics Researcher Massachusetts General Hospital

    Disclosures: Khera reports no relevant financial disclosures.