Submitted to: Current Opinion in Lipidology
Publication Type: Review article
Publication Acceptance Date: 1/29/2005
Publication Date: 4/1/2005
Citation: Lai, C., Parnell, L.D., Ordovas, J.M. 2005. The apoa1/c3/a4/a5 gene cluster, lipid metabolism and cardiovascular disease risk. Current Opinion in Lipidology 2005, 16:153-166. Interpretive Summary: The four apolipoproteins APOA1/C3/A4/A5 are major components of cholesterol transport vehicles and, with essential roles in plasma fat metabolism, influence the development of atherosclerosis. Many genetic variants have been examined within the APOA1/C3/A4/A5 gene cluster. Certain variants have been shown to be more frequent in populations with certain characteristics related to cardiovascular disease (CVD). However, the close physical distance of these four genes and the interrelated molecular functions of these four apolipoproteins have encumbered attempts to determine the individual role of each of the many variants on fat metabolism and CVD risk. Recent investigations of genetic linkage and the particular combination of variations within this cluster shed light onto the complexity of relationships among these four genes, and their association with CVD. Examination of variants in regions regulating gene activity and their association with disease phenotypes provide a better overall understanding of gene function. A comparison of the DNA sequences of these genes from several related organisms will provide insight into gene control elements and the function of human genetic variations located in such regulatory regions. Although different populations exhibit different frequencies of variations within this gene cluster, certain combinations of variants recur. Importantly, it has been noted that a subset of variants can serve to represent a more complex combination of variants. Such sampling is known as haplotype tagging and employing haplotype analysis should increase the power and reduce the cost of future population studies. Despite consistent association of some genetic variants with certain CVD risk characteristics, controversy remains in terms of the associations with actual disease phenotypes. We propose that the degree to which the APOA1/C3/A4/A5 genes are turned on or off can be influenced by environmental factors, such as dietary intake and exercise, and genetic variations within the gene control regions differentially sense and respond to those environmental factors. This is supported by the observation that associations are not consistent in different populations. Future studies focusing on regulatory variants may be more fruitful to locate and define genetic variants within the cluster that have a definite role in CVD.
Technical Abstract: APOA1/C3/A4/A5 are key lipoprotein components determining their metabolic fate, and potentially, atherosclerosis risk. This review examines the most current evidence regarding linkage disequilibria and haplotype structure within the A1/C3/A4/A5 gene cluster, and assesses the information available regarding genetic variability at this cluster and its association with lipid metabolism and CVD risk. In addition, the availability of genomic information for several species is used to draw (attention to / inferences about the location of) regulatory regions and functional variants within this cluster. Multiple genetic variants have been examined within this cluster during the last 20 years. However, the close physical distance of these genes and the interrelated molecular functions of these four apolipoproteins have encumbered attempts to determine the individual role of each of the many variants on lipid metabolism and CVD risk. Recent investigations of linkage disequilibrium and haplotype structure within this cluster shed light into the complexity of relationships among these four genes, and their association with CVD. Examination of variants in gene regulatory regions and their association with lipid and disease phenotypes provide a better understanding of gene functions. Comparative genomics will provide insight into regulatory regions and functional variants conserved across species. Genetic variability at APOA1/C3/A4/A5 cluster has been extensively examined in relation to alterations in lipid metabolism and CVD risk. However, the findings are not consistent across populations. This is in part due to the classical approach of studying single, and mostly non functional, polymorphisms. Moreover, the expression of specific alleles may be depend upon the concurrent presence of environmental factors, such as diet, smoking and physical activity. Association studies using haplotype tag SNPs should increase the power to detect true associations and interactions. We hypothesize that phenotypes (plasma lipids or CVD risk) observed in association with transcriptional regulatory variants can be readily modified by environmental factors (dietary intake, lifestyle). This is supported by the observation that associations are not consistent in different studies/populations. Therefore, studies focusing on regulatory variants may be more fruitful to locate/define functional variants within the cluster.