Rare DNA Variants Protect Against Coronary Heart Disease, Provide More Evidence for Minimizing LDL-C
Key findings
- Rare naturally occurring DNA variants that inactivate APOB or PCSK9 have been associated with low levels of low-density lipoprotein cholesterol (LDL-C) and reduced risk of coronary heart disease (CHD)
- To build on previous studies, this analysis harmonized genetic and clinical data on 19,073 participants in five National Heart, Lung, and Blood Institute (NHLBI) study cohorts and separately studied 190,464 participants in the UK Biobank
- Protein-truncating variants in APOB or PCSK9 were identified in 801 individuals (0.4%) and were associated with 45–49 mg/dL lower estimated untreated LDL-C concentrations
- Over a median follow-up period of 21.5 years, the risk of an incident CHD event was 49% lower in carriers vs. noncarriers of the variants in both the NHLBI and UK Biobank cohorts
- There's growing recognition that lifetime cumulative exposure to LDL-C is a primary driver of risk for CHD, and these results support the recommendation that LDL-C should be maintained as low as possible and as early as possible
Rare protein-truncating DNA variants (PTVs) that inactivate either the apolipoprotein B gene (APOB) or the proprotein convertase subtilisin/kexin type 9 gene (PCSK9) are known to be associated with lower levels of low-density lipoprotein cholesterol (LDL-C).
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Furthermore, a report in NEJM on the Atherosclerosis Risk in Communities (ARIC) study linked PTVs in PCSK9 with up to 89% decreased risk of coronary heart disease (CHD) over 15 years. Similarly, a large case-control study published in Circulation: Genomic and Precision Medicine showed a 72% reduction in CHD risk among carriers of APOB PTVs.
By studying larger, multiethnic cohorts for up to 31 years, Massachusetts General Hospital researchers confirmed and extended those studies and other prior investigations. In JAMA Cardiology, they report PTVs in either APOB or PCSK9 are associated with significantly lower LDL-C concentrations and a 49% reduction in CHD risk.
The authors include Jacqueline S. Dron, PhD, a post-doctoral research fellow in the Center for Genomic Medicine, Pradeep Natarajan, MD, MMSc, director of the Cardiovascular Disease Prevention Center, and Amit V. Khera, MD, MSc, who led this work while on faculty at the Center for Genomic Medicine.
Methods
The team harmonized clinical data and whole-genome sequence data on 19,073 participants in five prospective studies sponsored by the National Heart, Lung, and Blood Institute (NHLBI): ARIC, CARDIA (Cardiovascular Risk Development in Young Adults), the Cardiovascular Health Study, the Framingham Offspring Study, and MESA (Multi-Ethnic Study of Atherosclerosis).
Participants in these studies were enrolled at multiple U.S. sites between 1971 and 2002 when they were 5 to 84 years old. Across the five studies, 3.3% self-reported as being Asian, 23.9% Black, 5.7% Hispanic, 67% white, and <0.1% of another race.
The researchers separately analyzed data on 190,464 participants in the UK Biobank, which enrolled individuals ages 40 to 69 years old between 2006 and 2010. These participants included 2.4% who self-reported as being Asian, 1.6% Black, 93.9% white, and 2.1% of mixed race, another race, or no reported race.
The researchers adjusted LDL-C measurements to reflect estimated untreated values for participants using lipid-lowering medications.
Prevalence of Variants
One hundred thirty-nine participants in the NHLBI studies carried a PTV in either APOB (0.2%) or PCSK9 (0.6%); all carriers were heterozygous. Consistent with prior reports, the prevalence of PCSK9 PTVs was significantly higher in Black participants (2.1%) than in those of other races/ethnicities (range, 0.4%–0.9%). There was no difference in the prevalence of APOB PTVs according to race/ethnicity.
662 UK Biobank participants carried a PTV in APOB only (0.1%), PCSK9 only (0.2%), or both genes (0.002%); all carriers were heterozygous. Again, the prevalence of PCSK9 PTVs was significantly higher in Black participants (2.7%) than in those of other races/ethnicities (range, 0.2%–0.5%). There was no difference in the prevalence of APOB PTVs according to race/ethnicity.
LDL-C Exposure
In both cohorts, carriers of an APOB or PCSK9 PTV had reduced mean estimated untreated LDL-C concentrations compared with noncarriers:
- NHLBI cohorts—80 vs. 128 mg/dL; adjusted difference, 49 mg/dL (P<0.001)
- UK Biobank cohort—100 vs. 146 mg/dL; adjusted difference, 45 mg/dL (P<0.001)
Incident CHD
Over a median follow-up period of 21.5 years, the risk of a CHD event was significantly lower in carriers than noncarriers:
- NHLBI cohorts—8.6% vs. 16.0%; adjusted HR, 0.51 (P=0.02)
- UK Biobank cohort—2.7% vs. 5.8%; adjusted HR, 0.51 (P=0.004)
Clinical Perspectives
These results about an inherited predisposition to lower LDL-C concentrations due to a rare inactivating DNA mutation in either of two genes provide additional support for the recommendation that LDL-C should be maintained as low as possible and as early as possible to prevent CHD, strengthening growing recognition that lifetime cumulative exposure to LDL-C is a primary driver of risk for CHD.
Early initiation of lipid-lowering therapies will benefit individuals with familial hypercholesterolemia.
The CHD risk reductions determined in this study for carriers of a PTV in APOB or PCSK9, based on approximately 50% reduction in gene activity due to a heterozygous mutation, may underestimate what could be achieved with potent pharmacologic therapy. Furthermore, a greater number of noncarriers in the study used lipid-lowering therapies, which probably mitigated the differences in observed CHD rates.
Furthermore, preclinical and early-phase clinical trials of investigational drugs targeting PCSK9 suggest up to 90% suppression may be achievable.
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