Atherosclerosis 152 2000 367 – 376
Association of TaqIB polymorphism in the cholesteryl ester transfer protein gene with plasma lipid levels in a healthy Spanish
population
Dolores Corella
a
, Carmen Sa´iz
a
, Marisa Guille´n
a
, Olga Portole´s
a
, Francisco Mulet
a
, Jose´ I. Gonza´lez
a
, Jose´ M. Ordova´s
b,
a
Genetic and Molecular Epidemiology Unit, Public Health Department, School of Medicine, Uni6ersitat de Vale`ncia, Valencia, Spain
b
JM-USDA Human Nutrition Research Center on Aging at Tufts Uni6ersity,
711
Washington St., Boston, MA
02111
, USA Received 14 June 1999; received in revised form 25 October 1999; accepted 5 November 1999
Abstract
Genetic variants at the cholesteryl ester transfer protein CETP locus have been associated with CETP activity and mass, as well as plasma high density lipoprotein cholesterol HDL-C and apolipoprotein A-I levels. We have examined allele frequencies
and lipid associations for the common CETP TaqIB polymorphism in a sample of 514 healthy subjects 231 men, mean age 37.4 years, and 283 women, mean age 35.7 years residing in Valencia Spain. The frequency of the less common TaqIB2 allele 0.351;
95 CI: 0.322 – 0.380 was significantly lower than those reported for Northern European populations. Consistent with previous studies, we found a significant association of the TaqIB polymorphism with HDL-C levels. Homozygotes for the B1 allele had
lower HDL-C levels than subjects carrying the B2 allele P trend B 0.001 and 0.002, for men and women, respectively. No statistically significant genotype effects were observed for any of the other lipid measures. Multivariate models including TaqIB
genotype, body mass index, smoking, alcohol, physical activity, marital status and education were fitted to predict HDL-C levels. The TaqIB polymorphism was consistently an independent predictor of HDL-C levels P B 0.001, and explained 5.8 of its
variance. To evaluate gene-environmental interactions, first order interaction terms were tested into the multivariate model. No statistically significant interactions between the TaqIB genotypes and smoking, alcohol, physical activity or education were
detected. In conclusion, we observed a significant association of the TaqIB polymorphism with HDL-C levels, which remained consistent across different levels of behavioral factors. Moreover, we found that the TaqIB2 allele frequency was lower in our
sample than in other European populations, which could be a contributing factor to the unexpectedly high prevalence of coronary heart disease observed in the region of Valencia. © 2000 Elsevier Science Ireland Ltd. All rights reserved.
Keywords
:
Cholesteryl ester transfer protein; Genetic polymorphisms; High density lipoproteins; Coronary heart disease www.elsevier.comlocateatherosclerosis
1. Introduction
The inverse association between high density lipo- protein – cholesterol HDL-C levels and coronary heart
disease CHD risk has been known for over 25 years [1,2]. However, the mechanisms underlying this rela-
tionship [3,4] and the factors responsible for the wide distribution of HDL-C concentrations observed in the
general population are not yet fully understood. Plasma HDL-C levels are determined by a variety of
environmental and genetic factors. Epidemiological studies have demonstrated positive associations be-
tween HDL-C concentrations and alcohol consump- tion, estrogens, and exercise, whereas a negative
association has been observed with tobacco smoking [5,6]. Our understanding of the genetic factors deter-
mining HDL-C levels in the general population is more limited. Preliminary twin and family studies indicated
that 40 – 60 of the variation of HDL-C between indi- viduals was determined by genetic factors [7].
CETP is a glycoprotein that plays an important role in the transport of excess cholesterol from peripheral
Corresponding author. Tel.: + 1-617-5563102; fax: + 1-617- 5563103.
E-mail address
:
ordovashnrc.tufts.edu J.M. Ordova´s. 0021-915000 - see front matter © 2000 Elsevier Science Ireland Ltd. All rights reserved.
PII: S 0 0 2 1 - 9 1 5 0 9 9 0 0 4 7 7 - 3
tissues to the liver. This glycoprotein mediates the transfer of cholesteryl esters from HDL or LDL into
triglyceride-rich lipoproteins, and thereby stimulates re- verse cholesterol transport [8]. The CETP mRNA en-
codes
a polypeptide
of Mr53000,
which is
N-glycosilated at four sites, giving rise to the mature form of CETP of Mr74000 [9]. The CETP gene encom-
passes 16 exons and it has been assigned to chromo- some 16 16q21 near the LCAT locus. Sib pair linkage
analyses have suggested that variation in HDL-C be- tween individuals was related to the inheritance of
alleles at or near the cholesteryl ester transfer protein CETP gene [10]. Several polymorphisms and rare
variants have been detected [11,12], and some of these have been shown to have a significant effect on plasma
lipid levels [12 – 14]. A common polymorphism detected using TaqI TaqIB has been shown to be a silent base
change affecting the 277th nucleotide in the first intron of the CETP gene [15]. The allele carrying the cutting
site for the TaqI enzyme is called B1, whereas the one in which the cutting site is missing is known as B2. This
polymorphism has been consistently associated with plasma levels of HDL-C, individuals carrying the B2
allele having the highest levels of HDL-C [16 – 18]. However, this association might be population specific
[14,19] and highly influenced by environmental factors such as alcohol consumption and tobacco smoking
[17,20,21]. Therefore, the aim of this study was to estimate allele frequencies of the TaqIB polymorphism,
and to investigate the relationship between this poly- morphism and plasma lipid levels taking into account
other biological and environmental factors in a healthy population from Valencia on the Mediterranean coast
of Spain. This region presents an unusually high rate of cardiovascular disease that, at the present time, is the
highest in the country [22]. The results of this research could contribute to our understanding of the genetic
and environmental factors associated with cardiovascu- lar risk.
2. Methods
