PCSK9 loss-of-function variants associate with lower LDL-C
PCSK9 Loss-of-Function Variants, Low-Density Lipoprotein Cholesterol, and Risk of Coronary Heart Disease and Stroke. Data From 9 Studies of Blacks and WhitesKent ST, Rosenson RS, Avery CL, et al. - Circ Cardiovasc Genet. 2017 Aug;10(4):e001632
PCSK9 gene gain-of-function variants lead to high LDL-C levels, whereas loss-of-function (LOF) variants are associated with lower LDL-C levels . Black individuals more commonly manifest Y142X and C679X nonsense PCSK9 LOF variants, which are associated with larger reductions in LDL-C than the missense R46L variant that is more common in white individuals [2,3]. Although there is some evidence that PCSK9 LOF variants are associated with a lower coronary heart (CHD) incidence, there are few data on the association between PCSK9 LOF variants and stroke risk .
In this meta-analysis, the associations between PCSK9 LOF variants with LDL-C, incident CHD and stroke events were evaluated in black individuals and white individuals enrolled in nine studies (AGES, ARIC Study, CHS, FHS, Health ABC, JHS, MESA, PROSPER Study and REGARDS Study)[5,6].
The baseline for the assessment of the LDL-C levels as well as to initiate follow-up for CHD and stroke outcomes, was the first available visit after January 1, 1995. The analyses included stratification by statin use. PCSK9 LOF variants Y142X (rs67608943) and C679X (rs28362286) were genotyped for 17 459 black individuals in six studies, whereas the PCSK9 LOF variant R46L (rs11591147) was genotyped for 31 306 white individuals in eight studies. Participants were considered to have a PCSK9 LOF variant if they carried at least 1 minor allele at Y142X or C679X (in black individuals) or at least 1 minor allele at R46L (in white individuals).
- 2.3% black individuals had a Y142X or C679X PCSK9 LOF variant and 3.1% white individuals had an R46L PCSK9 LOF variant.
- In a pooled analysis of six studies with black individuals, after adjustment for age, gender and statin use, PCSK9 LOF variants were associated with 35 mg/dL (95% CI 32–39) lower LDL-C levels.
- In a similar pooled analysis of eight studies with white individuals, the PCSK9 LOF variant was associated with 13 mg/dL (95% CI 11–16) lower LDL-C levels.
- In pooled analyses of six studies with black individuals, PCSK9 LOF variants were associated with an OR for CHD of 0.51 (95% CI 0.28–0.92).
- In white individuals, a lower CHD risk with the PCSK9 LOF variant was statistically significant in the REGARDS study only (OR 0.20, 95% CI 0.05–0.85). After pooling all eight studies, the OR for CHD was 0.82 (95% CI 0.63–1.06).
- The OR for stroke was 0.84 (95% CI 0.48–1.47) for all black individuals of six studies.
- The OR for stroke was 1.06 (95% CI 0.80–1.41) for all white individuals of eight studies.
- The associations of PCSK9 LOF variants with LDL-C, CHD and stroke among participants not taking statins were similar to the associations in the overall population.
- In pooled analyses of participants taking statins, PCSK9 LOF variants were associated with lower LDL-C levels in black individuals but were not associated with LDL-C levels in white individuals.
- When taking statins, the OR for CHD that associated with having a PCSK9 LOF variant was 1.46 (95% CI 0.77–2.79) among white individuals. None of the black individuals with a PCSK9 LOF variant experienced a CHD event.
- For stroke and taking statins, OR was 4.53 (95% CI 1.35–15.24) for black individuals and 0.91 (95% CI 0.39–2.11) for white individuals.
In a meta-analysis of 17 459 black individuals and 31 306 white participants from nine studies, PCSK9 LOF variants were associated with lower LDL-C levels and CHD risk, which was more prominent among black compared to white individuals. On the other hand, PCSK9 LOF variants were not associated with stroke risk. These results suggest that lifetime lower LDL-C levels are associated with lower CHD risk and support a dose-response association between LDL-C and CHD.