P3‐124: HDL cholesterol levels mediate association of CETP genotype with mortality

Abstract

A single-nucleotide polymorphism (SNP) in the cholesteryl ester transfer protein (CETP) gene at codon 405 (isoleucine to valine V405; rs5882) has been associated with exceptional longevity in cross-sectional data and with a reduced risk of AD in some cohort studies. This SNP is associated with lower levels of circulating CETP protein and corresponding elevations in HDL levels. The goal of this study was to examine the association of this CETP SNP with all-cause mortality and to examine the mediating role of HDL cholesterol level. Analyses were based on follow-up data from the Einstein Aging Study, a longitudinal study of aging and cognition of 70+ year old initially community-dwelling residents of the Bronx, NY (USA). Mortality was ascertained through US National Death Index and informant reports. Linear mixed models were used to assess the stability of HDL levels across time in individuals and the association of CETP genotype with HDL over time. Cox models using age as the time scale estimated hazard ratios (HR) for all-cause mortality associated with CETP genotype and HDL cholesterol. In 1140 study participants, valine homozygosity was associated with lower mortality compared to II (HR 0.63, 95% CI [0.47, 0.85], P=0.002) and also compared to IV (HR 0.69 [0.51–0.92], P=0.01). 627 of these participants had HDL measurements at one or more clinic visits, of this group, 89 have died. In mixed linear models, VV genotype was associated with higher HDL cholesterol than II (difference 4.24[0.94, 7.54] mg/dl, P=0.01) but the difference in HDL levels between VV and heterozygous participants was non-significant (VV > IV, difference 1.00[-2.09, 4.08] mg/dl, P=0.53). Higher HDL was strongly associated with lower mortality (HR 0.963[0.946, 0.980]/mg/dl, P<.0001). Inclusion of mean HDL in survival models attenuated the association of CETP genotype with mortality (VV vs. II HR 0.69[0.37, 1.30], P=0.25, VV vs. IV HR 0.78[0.42, 1.43], P=0.42). Inclusion of race, education, and sex did not materially affect results in any model. CETP rs5882 is associated with reduced rates of all-cause mortality. Attenuation of this association by HDL levels suggests that the effect of genotype may be partially mediated through HDL, and suggest that additional mechanisms must be involved. Similar effects may pertain to AD.