variants alone. The present study aimed to investigate the association between CETP and APOE polymorphisms and dyslipidemia risk in oldest-old Chinese women. Dyslipidemia is a common risk factor for atherosclerosis and CAD, and its genetic contributors in the oldest-old population, particularly females, remain poorly understood. CETP and APOE have been identified as plausible candidate genes for longevity due to their roles in circulating lipid homeostasis. However, the interplay between these genes has not been fully explored. Our study analyzed the distribution of CETP*V (rs5882) and APOE*4 (rs429358 and rs7412) in 372 oldest-old Chinese women (aged 80-109) and 340 controls (aged 20-58). We found that APOE*4 was associated with high cholesterol (hTC) and mixed dyslipidemia, whereas CETP*V was independently associated with hypertriglyceridemia (hTG). Furthermore, we found evidence of a significant CETP*APOE interaction associated with hTG. The odds for hTG were more than 4-fold in subjects with CETP*V and APOE*4 than those without either.

In conclusion, our study provides evidence of strong independent associations between hTG and CETP*V in oldest-old Chinese females. Additionally, APOE*4 might interact with CETP*V resulting in an increased risk for hTG. These findings highlight the importance of considering gene-gene interactions when investigating dyslipidemia risk in the oldest-old population.Analysis and/or revealed by the combinatory effect of loci in other pathways (Ndiaye et al., 2013). Thus, we hypothesized that the polymorphisms of CETP and APOE might interact in the signaling pathway, which could have greater effects on the dysregulation of serum lipids in oldest-old Chinese women. This study was conducted to assess potential CETP*APOE interaction and contribution to dyslipidemia in oldest-old Chinese women by the traditional parametric approach of logistic regression and the nonparametric method of multifactor dimensionality reduction.

2. Materials and methods 

2.1. Subjects 

The current study was based on the Longevity and Health of Aging Population in Guangxi China study conducted in 2008 and 2010. Yongfu County has been qualified as the longevity town by Geriatric Society of China in 2007.

3. Results 

We analyzed a total of 713 female Chinese subjects, including 372 oldest-old subjects and 340 controls in the present study. Subjects in oldest-old group had significantly lower TG and BMI; and higher FPG, LDL-c, HR, SBP, and DBP when compared with controls (Table 1). Seven hundred and thirteen female volunteers, from urban and rural areas of Yongfu County, South China, were enrolled after having been excluded from the subjects undertaking lipid-lowering drugs. The longevity group comprised 16 centenarians (aged 100-109), 322 nonagenarians (aged 90-99), and 34 octogenarians (aged 80-89). The geography and nationality matched control group consisted of 340 unrelated volunteers (aged 20-58, mean age 41.88 ± 12.20 years) without longevity history (no lineal family members aged above 80 for 3 generations). All subjects self-reported as belonging to Han nationality. The Ethics Committee of Beijing Hospital, Ministry of Health approved the study protocol. All participants were informed and provided with informed consent in writing.

Distributions of CETP and APOE polymorphisms in the oldest-old group and controls were in HWE (Table 2). Comparison between oldest-old and controls showed that, as expected, APOE*4 was less frequent in the oldest-old group (23.5% vs. 14.0% in controls vs. oldest-old, respectively; P = 0.001). No contribution of CETP I405V for longevity was found (P = 0.347). Stratified analysis in the oldest-old group according to the NCEP ATP III criteria suggested that APOE*4 also significantly associated with the risk for hTC (P = 0.001) and mixed dyslipidemia (P < 0.001). In addition, we also found that CETP genotype distributed differently between hTG and Control groups (P = 0.002), with hTG having a higher proportion of VV genotype in the hTG subgroup (30.5% vs.15.7% in hTG vs. controls, respectively).

As noted in Fig. 1, BMI, alcohol drinking, and TC increased the risk of hTG in our oldest-old subjects, and HDL-c significantly decreased the risk (P < 0.05). The odds of hTG for subjects with CETP*V allele were 1.88 times greater than subjects without the risk allele in the univariate polymorphism logistic regression model. After adjustment for APOE*4, age, BMI, alcohol drinking, TC, HDL-c, and LDL-c, the risk contribution was consistent (P < 0.05). When coupled with APOE genotypes containing at least one risk allele, the odds of being affected increased to 4.36 times greater for subjects with the CETP*V allele than those with neither risk allele. In addition, the interaction item estimated by logistic regression between CETP*V and APOE*4 significantly increased the risk of hTG (P = 0.002, OR = 3.25). There was no evidence for an increased risk for hTG due to the presence of APOE*4 itself (P = 0.079). In addition, we failed to repeat the findings that CETP conferred the risk of hTG and the interaction with APOE in our middle-aged controls (data not shown).