Elsevier

Atherosclerosis

Volume 146, Issue 1, September 1999, Pages 153-160
Atherosclerosis

Absence of association between genetic variation in the LIPC gene promoter and plasma lipoproteins in three Canadian populations

https://doi.org/10.1016/S0021-9150(99)00113-6Get rights and content

Abstract

The promoter sequence variant -480T in the hepatic lipase gene (LIPC) has been shown to be significantly associated with low post-heparin hepatic lipase activity. Some studies have also found that the -480T variant is associated with elevation in plasma HDL cholesterol. We tested for associations of LIPC -480T with plasma lipoprotein traits in samples taken from three distinct Canadian populations: 657 Alberta Hutterites, 328 Ontario Oji-Cree and 210 Keewatin Inuit. Plasma HL activity was not available for analyses. The LIPC -480T allele frequencies in these three groups, respectively, were 0.219, 0.527 and 0.383, and the prevalence of LIPC -480T/T homozygotes was, respectively, 0.042, 0.274 and 0.167. No significant association was found between LIPC -480T and plasma HDL cholesterol or apolipoprotein AI concentration, after adjusting for covariates including gender and body mass index. There was no consistent relationship between the population mean plasma HDL cholesterol concentration and the population LIPC -480T frequency. Our findings are consistent with the idea that the common promoter variation in LIPC, which has been reported to be associated with variation in post heparin HL activity and HDL triglyceride concentration, is not always associated with variation in plasma HDL cholesterol concentration, possibly due to yet unspecified environmental or genetic factors.

Introduction

Despite the large number of genetic association studies that have been published over the last decade, there has been a lack of consensus regarding the role of common genomic variation in the genetic susceptibility to atherosclerosis and its related intermediate phenotypes [1]. Almost no allele of any gene studied to date has been shown to be consistently associated with variation in intermediate phenotypes of atherosclerosis, such as plasma lipoproteins, across diverse populations [2], [3]. Part of the inconsistency may be due to the fact that many of the DNA markers studied do not have a functional impact on the structure or expression of the gene product. Thus, most positive associations have been attributed to linkage disequilibrium with putative functional changes elsewhere at the genetic locus. Since linkage disequilibrium may vary between populations, factors such as admixture can produce falsely positive genetic associations [3], [4]. One way to reduce such confounding effects would include selecting DNA markers that directly mark a functional change in the gene of interest. Also, consistent results from complementary experimental evidence, such as using independent statistical approaches, independent study samples, in vitro studies and/or animal studies may increase confidence in the biological validity of genetic associations.

Recently, several groups have reported an association between variation in plasma biochemical traits and variation in the promoter sequence of the LIPC gene, which encodes hepatic lipase (HL) [5], [6], [7], [8], [9]. The associations were found with a C->T nucleotide change at position -480, or -514, depending upon the nucleotide taken as the transcription start site [10]. The most striking finding from these studies was a significantly lowered post-heparin HL activity associated with the -480T allele, with -480C/C homozygotes having the highest post-heparin HL activity, C/T heterozygotes having reduced levels (by ∼25%) and -480T/T homozygotes having the lowest levels (by ∼50%) [7], [8]. In addition, some of these groups also reported associations with plasma lipoprotein traits. For example, among 270 Finnish subjects, 16 were -480T/T homozygotes: these -480T/T subjects had significantly higher (by ∼10%) plasma HDL cholesterol and apolipoprotein (apo) AI compared with subjects with other genotypes [5]. Among 612 Dutch males, 11 were -480T/T homozygotes: these -480T/T subjects had significantly higher (by ∼15%) plasma HDL cholesterol compared with subjects with other genotypes [7]. Among 133 males from Dallas, 30 -480C/T heterozygotes and 2 -480T/T homozygotes, respectively, had significantly higher (by ∼10% and ∼50%) HDL cholesterol and apo AI than 101 -480C/C homozygotes [6]. In contrast, among 395 Finnish males, 26 -480T/T homozygotes did not have significantly different plasma HDL cholesterol compared with subjects with other genotypes [8]. Finally, it was recently suggested that the higher plasma HDL cholesterol in African American males compared with white Americans was related to a higher frequency of the LIPC -480T allele and, in particular, a higher frequency of LIPC -480T/T homozygotes in this ethnic group [9]. We report an association analysis between the LIPC promoter variant and plasma lipoproteins in samples taken from three distinct and independent Canadian populations: Alberta Hutterites, Sandy Lake Oji-Cree and Keewatin Inuit.

Section snippets

Hutterites

846 individuals from 21 colonies of Alberta Hutterites aged from 18 to 80 years participated in the Canadian Heart Health Survey for CHD risk assessment [11], [12], [13], [14], [15], [16], [17]. These individuals came from two sects, called Lehrerleut and Dariusleut [11], [12], [13], [14], [15], [16], [17]. Almost every one of the study subjects could be placed into a defined sibship representing one of 187 nuclear families. The average inbreeding coefficient for members of the study sample was

Baseline clinical and biochemical characteristics

A summary of the clinical and biochemical characteristics of the three study samples is shown in Table 1. While the mean ages of male and female Hutterites and Inuit were not different, both were significantly higher than those in male and female Oji-Cree (P<0.01). While the mean BMI of male and female Oji-Cree and Inuit were not different, both were significantly lower than those in male and female Hutterites (P<0.01). There were differences between the three study samples with respect to

Discussion

In this study of independent samples taken from three distinct Canadian populations, with a wide range of allele frequencies of the LIPC promoter polymorphism, we found no association between variation in the LIPC promoter and lipoprotein phenotypes between or within populations. Specifically, there was no association of the LIPC -480T allele, or of homozygosity for the LIPC -480T allele, and elevated plasma HDL cholesterol concentration in either men or women from any of the three study

Acknowledgements

We acknowledge the cooperation and assistance from: the Hutterite communities and the sample collectors from the Canadian Heart Health Surveys; the chief and council of the community of Sandy Lake; the Sandy Lake community surveyors; the Sandy Lake nurses and the staff of the University of Toronto Sioux Lookout program; and the members of the Health Canada research team. This work was supported by grants from the National Institutes of Health (1-R21-DK44597-01), the Ontario Ministry of Health

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