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Gene gene interaction between CETP and APOE polymorphisms confers higher risk for hypertriglyceridemia in oldest-old Chinese women

Liang Sun a, ,1, Caiyou Hu b,1, Chenguang Zheng c, Zezhi Huang d, Zeping Lv b, Jin Huang a, ⁎ Siying Liang a, Xiaohong Shi a, Xiaoquan Zhu a, Huiping Yuan a, Ze Yang a,

a The Key Laboratory of Geriatrics, Beijing Hospital and Beijing Institute of Geriatrics, Ministry of Health, Beijing, b Department of Neurology, Jiangbin Hospital, Nanning, Guangxi, China c Department of Cardiothoracic Surgery, Guangxi Maternal and Child Health Hospital, Nanning, Guangxi, China d Yongfu Committee of the ChinesePeople's Political Consultative Conference, Yongfu, Guangxi, China



The knowledge of dyslipidemiaand its genetic contributorsinoldest-old subjects islimited; inaddition, the ma- jority of oldest-old subjects are females. Evidence has accumulated that multiple genetic factors play important roles in determining susceptibility to dyslipidemia and extended life span. Cholesterol ester transfer protein (CETP) and apolipoprotein E (APOE) are two plausible candidate genes for human longevity owing to their func- tionally related modulation of circulating lipid homeostasis; however, few studies have considered their inter- play. In this study, we 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). In addition to replicating the associa- tion oflongevity,our maingoal wasto evaluatethe contribution of CETP*V,APOE*4andCETP*APOEinteraction to theriskofdyslipidemia.OnlyAPOE*4conferredariskagainstlongevityandwasassociatedwithhigh-cholesterol (hTC) and mixed dyslipidemia for oldest-old females. Moreover, CETP*V was found to be associated with hypertriglyceridemia (hTG) independently from APOE*4, age, BMI, alcohol drinking, TC, TG, HDL-c, and LDL-c. The stratification test, multivariable-adjusted logistic regression, and nonparametric MDR analysis all suggested a significant CETP*APOE interaction associated with hTG. The unadjusted odds for hTG were more than 4-fold in subjects with CETP*V and APOE*4 than those without either (OR = 4.36, P b 0.001). These results provide evi- dence of strong independent associations between hTG and CETP*V in oldest-old Chinese females, and APOE*4, as an independently non-significant variant, might interact with CETP*V resulting in an increased risk for hTG. © 2014 Elsevier Inc. All rights reserved.

1. Introduction

duetocomplexphysiologicalandsocialdiscrepancies betweengenders. Also, female oldest-old individuals outnumber males according to most demographic surveys, and these individuals are accompanied by better physical state and thus could survive from severe CAD. Many studies show that female oldest-old subjects remain free from diseases and dis- abilities until quite late in life. A better understandingof dyslipidemia in this population is thus of increasing global importance. Together these observations suggest the importanceof researchconcerningthe genetic risk factors for dyslipidemia, particularly for the female oldest-old population.

Dyslipidemia is characterized by elevation of serum triglycerides (TG), total cholesterol (TC), or both, or a low high-density lipoprotein (HDL) levels. It is one of the most common causes of atherosclerosis and coronary artery disease (CAD).Hypertriglyceridemia (hTG), a path- ological condition in whichTG levels areelevated,is an essentialform of dyslipidemia as a risk factor for CAD (Brunzell, 2007), particularly in the setting of low HDL cholesterol (HDL-c) levels and/or elevated LDL cho- lesterol (LDL-c) levels. The identification of risk factors of dyslipidemia would contribute to the prediction of CAD. Despite the rapid growth of the elderly population worldwide, most studies have only focused on middle-aged subjects.

Cholesterol metabolism is different in the oldest populations com- pared to younger subjects (Schatz et al., 2001). Cholesterol ester trans- fer protein (CETP) and apolipoprotein E (APOE) are two plausible candidate genes for human longevity due to their functionally related modulation of maintenance of circulating lipid homeostasis. CETP pro- motes the transfer of excess cholesterol ester (CE) from vessel wall to the liver through the reverse cholesterol transport (RCT) pathway (Lamarche et al., 1999). In this process, CETP increases the CE trans- ferred from HDL to apoB-containing lipoproteins in exchange for TG and phospholipids. APOE is involved in transport and redistribution of

Longevity in humans is linked to survival-associated genetic pat- terns rather than a dearth of disease-associated variants. Moreover, life expectancy is generally accepted as longer for women than men

Genotyping analysis of CETP I405V (Gudnason et al., 1999) andAPOE (Tagalakis et al., 2005) was performed as previously described. Genomic DNA was amplified by PCR in PTC-225 (MJ Research, USA) and after digestion overnight with Rsa I and Hha I, respectively (Takara, Shuzo), the products were separated by 12% polyacrylamide electrophoresis (Supplemental Fig. 1). The accuracy of genotyping has been further confirmed by Sanger's sequencing in 100 randomly selected cases.