Selection on Alleles Affecting Human Longevity and Late-Life Disease: The Example of Apolipoprotein E

It is often claimed that genes affecting health in old age, such as cardiovascular and Alzheimer diseases, are beyond the reach of natural selection. We show in a simulation study based on known genetic (apolipoprotein E) and non-genetic risk factors (gender, diet, smoking, alcohol, exercise) that, because there is a statistical distribution of ages at which these genes exert their influence on morbidity and mortality, the effects of selection are in fact non-negligible. A gradual increase with each generation of the ε2 and ε3 alleles of the gene at the expense of the ε4 allele was predicted from the model. The ε2 allele frequency was found to increase slightly more rapidly than that for ε3, although there was no statistically significant difference between the two. Our result may explain the recent evolutionary history of the epsilon 2, 3 and 4 alleles of the apolipoprotein E gene and has wider relevance for genes affecting human longevity

Cholesteryl ester transfer protein TaqIB variant, high-density lipoprotein cholesterol levels, cardiovascular risk, and efficacy of pravastatin treatment - Individual patient meta-analysis of 13,677 subjects

Background - Several studies have reported that the cholesteryl ester transfer protein (CETP) TaqIB gene polymorphism is associated with HDL cholesterol (HDL-C) levels and the risk of coronary artery disease ( CAD), but the results are inconsistent. In addition, an interaction has been implicated between this genetic variant and pravastatin treatment, but this has not been confirmed. Methods and Results - A meta-analysis was performed on individual patient data from 7 large, population-based studies ( each > 500 individuals) and 3 randomized, placebo-controlled, pravastatin trials. Linear and logistic regression models were used to assess the relation between TaqIB genotype and HDL-C levels and CAD risk. After adjustment for study, age, sex, smoking, body mass index (BMI), diabetes, LDL-C, use of alcohol, and prevalence of CAD, TaqIB genotype exhibited a highly significant association with HDL-C levels, such that B2B2 individuals had 0.11 mmol/L (0.10 to 0.12, P <0.0001) higher HDL-C levels than did B1B1 individuals. Second, after adjustment for study, sex, age, smoking, BMI, diabetes, systolic blood pressure, LDL-C, and use of alcohol, TaqIB genotype was significantly associated with the risk of CAD ( odds ratio = 0.78 [0.66 to 0.93]) in B2B2 individuals compared with B1B1 individuals ( P for linearity = 0.008). Additional adjustment for HDL-C levels rendered a loss of statistical significance ( P = 0.4). Last, no pharmacogenetic interaction between TaqIB genotype and pravastatin treatment could be demonstrated. Conclusions - The CETP TaqIB variant is firmly associated with HDL-C plasma levels and as a result, with the risk of CAD. Importantly, this CETP variant does not influence the response to pravastatin therap

Association between TaqIB polymorphism of cholesteryl ester transfer protein and coronary artery disease in the Chinese population*

Objective: To assess whether the TaqIB polymorphism of cholesteryl ester transfer protein (CETP) is associated with coronary artery disease (CAD) in Chinese population, we performed a meta-analysis in this paper. Methods: We searched PubMed, Embase, the Science Citation Index (SCI), the China Biological Medicine database (CBM), the China National Knowledge Infrastructure (CNKI), and the Wanfang database for relevant articles. Data were extracted, and pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Results: The literature search yielded 448 studies, in which 10 case-control studies including 1 694 cases and 1 456 controls matched the selection criteria. The combined B1 and B2 allele frequencies were 0.587 and 0.413, respectively. The pooled OR was 1.10 (95% CI, 0.89–1.34) for comparing the B1B1 or B1B2 carriers with B2B2 carriers, and was 1.27 (95% CI, 1.09–1.49) in the B1B1 carriers versus B2B2 or B1B2 carriers. Conclusions: In the present study, the TaqIB polymorphism of CETP was found to be associated with CAD in the Chinese population