Adherence to a healthy lifestyle decreases CAD risk even in familial hypercholesterolemia

Familial hypercholesterolemia (FH) is characterized by increased low-density lipoprotein (LDL) cholesterol concentrations and risk of coronary artery disease (CAD). Gene sequencing in large study populations have identified FH variants in 0.2% to 0.5% of the general population, with a prevalence among patients with early-onset CAD of up to 2%. Although the risk of CAD among carriers of a FH variant is thought to be largely caused by increased LDL cholesterol concentrations, lifestyle factors may also play an important role. Among those with increased genetic risk—as defined based on family history or an increased polygenic risk score—rates of CAD decreased by up to 50% among those who adhered to a healthy lifestyle, but it is not established if a similar gradient exists among FH variant carriers.

A new paper in JAMA Netw Open explores this topic using 2 independent data sets with gene sequencing and lifestyle data from the UK Biobank: a case-control study of 4896 cases and 5279 controls and a cohort study of 39 920 participants. Participants were recruited from 22 sites across the UK between March 21, 2006, and October 1, 2010. The case-control study included participants with CAD and controls at enrollment. The cohort study used a convenience sample of individuals with available gene sequencing data. The healthy lifestyle was defined based on a 4-point scoring system (1 point for each of the following: healthy diet, regular exercise, not smoking, and absence of obesity).

The case-control study included 10 175 participants (6828 men [67.1%]; mean [SD] age, 58.6 [7.2] years), and the cohort study included 39 920 participants (18 802 men [47.1%]; mean [SD] age at the end of follow-up, 66.4 [8.0] years). A variant was identified in 35 of 4896 cases (0.7%) and 12 of 5279 controls (0.2%), corresponding to an odds ratio of 3.0 (95% CI, 1.6-5.9), and a variant was identified in 108 individuals (0.3%) in the cohort study, in which the hazard ratio for CAD was 3.8 (95% CI, 2.5-5.8). However, this risk appeared to vary according to lifestyle categories in both carriers and noncarriers of familial hypercholesterolemia variants, without a significant interaction between carrier status and lifestyle (odds ratio, 1.2 [95% CI, 0.6-2.5]; P = .62). Among carriers, a favorable lifestyle conferred 86% lower risk of CAD compared with an unfavorable lifestyle (hazard ratio, 0.14 [95% CI, 0.04-0.41]). The estimated risk of CAD by the age of 75 years varied according to lifestyle, ranging from 10.2% among noncarriers with a favorable lifestyle to 24.0% among noncarriers with an unfavorable lifestyle and ranging from 34.5% among carriers with a favorable lifestyle to 66.2% among carriers with an unfavorable lifestyle.


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