- This study evaluated whether adherence to a healthy lifestyle is associated with a lower risk of coronary artery disease (CAD) among carriers and noncarriers of pathogenic DNA variants in familial hypercholesterolemia (FH)–related genes
- Two independent analyses were conducted of participants in the UK Biobank: a case–control study of individuals with and without CAD (n=10,175), and a cohort study of participants with gene sequencing and lifestyle data available (n=39,930)
- In both studies, carriers of FH variants had an average three-fold increased risk of CAD compared with noncarriers, but a healthy lifestyle was associated with a lower risk of CAD in both groups, despite the minimal association with LDL cholesterol levels
- The probability of manifesting CAD by age 75 was 10% for individuals with no FH variant and a healthy lifestyle versus 66% for those with an FH variant and an unhealthy lifestyle
- Similar to the general population, individuals who carry FH variants are likely to benefit from lifestyle interventions to reduce their risk of CAD
Familial hypercholesterolemia (FH), caused by pathogenic DNA variants in any of three genes, is characterized by impaired clearance of low-density lipoprotein cholesterol (LDL-C) and an elevated risk of coronary artery disease (CAD).
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The risk of CAD is thought to be largely caused by the increase in LDL-C, but a team at Massachusetts General Hospital determined lifestyle factors also play an important role. Akl C. Fahed, MD, MPH, a researcher at the Cardiovascular Research Center, Amit V. Khera, MD, MSc, a researcher at the Center of Genomic Medicine, and colleagues report the details in JAMA Network Open.
The team derived two separate study populations from the UK Biobank:
- A case–control study of 10,175 unrelated participants (4,896 participants who received a diagnosis of CAD and 5,279 controls)
- A cohort study of 39,920 UK Biobank participants with gene sequencing and lifestyle data available
The researchers calculated a "healthy lifestyle score" by assigning one point to each of four favorable characteristics:
- Healthy diet pattern (at least three of the following: at least three pieces of fruit per day; ≥12 heaping tablespoons of vegetables per day; oily fish at least twice per week; processed meat once per week or less; red meat twice per week or less)
- Regular exercise (≥15 metabolic equivalents of task–hours per week)
- Not currently smoking
- Body mass index <30 kg/m2
Carrier Status, LDL-C, and Risk of CAD
In both studies, carrying a pathogenic or likely pathogenic FH variant was associated with an increased risk of CAD:
- Case–control study—On average, carriers of an FH variant had triple the odds of CAD compared with noncarriers (adjusted OR [aOR], 3.0; P<0.001)
- Cohort study—20% of carriers vs. 7% of noncarriers developed CAD (adjusted HR [aHR], 3.8; P<0.001)
Lifestyle, LDL-C and Risk of CAD
In both studies, healthy lifestyle was significantly associated with decreased CAD risk.
- In the case-control study, carriers with "unfavorable" lifestyle (score of 0 or 1) had aOR for CAD of 6.1 compared to noncarriers with an "intermediate" lifestyle (score of 2), but carriers with a "favorable" lifestyle (score of 3 or 4) had an aOR of only 1.4
- In the cohort study, carriers with "favorable" lifestyle had an aOR for CAD of 0.14 compared to carriers with "unfavorable" lifestyle
In both studies:
- Lifestyle score was only minimally associated with LDL-C concentrations
- There were no significant interactions between the FH carrier status and lifestyle score
Age-dependent Probability of CAD
The probability of manifesting CAD by age 75 was:
- 10% for individuals with no FH variant and a favorable lifestyle
- 24% for those with no FH variant and an unfavorable lifestyle
- 34% for those with an FH variant and a favorable lifestyle
- 66% for those with an FH variant and an unfavorable lifestyle
The estimated absolute risk reduction related to a favorable lifestyle versus an unfavorable lifestyle was more than double for FH variant carriers (32%) compared with noncarriers (14%).
The absolute risk estimates are likely to vary outside the UK Biobank context and need to be calibrated for more diverse populations.
Now that genomic information is increasingly available to inform individuals about their risk of CAD, they may feel anxious or resigned, believing CAD is inevitable. It's important to communicate that adherence to a healthy lifestyle may mitigate CAD risk.
Learn more about the Center for Genomic Medicine
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