|Yin, Rui-Xing -|
|Li, Yi-Yang -|
|Lai, Chao Qiang|
Submitted to: Lipids in Health and Disease
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: August 19, 2011
Publication Date: August 19, 2011
Citation: Yin, R., Li, Y., Lai, C. 2011. Apolipoprotein A1/C3/A5 haplotypes and serum lipid levels. Lipids in Health and Disease. 10:140. DOI: 10.1186/1476-511X-10-140. Interpretive Summary: Composition of blood lipids are important risk factors for heart disease. It is well known that genetic variants in the apolipoprotein gene cluster (APOA1/C3/A4/A5, four genes) are associated with blood lipids. Past studies have generally looked at genetic variants individually, and the results have not been consistent. However, multiple genetic variants may work together and may have synergistic effects, i.e., combinations of multiple genetic variants can produce larger effects than the sum of the individual effects. In this study, we tested this idea by examining five genetic variants in this gene cluster in a Chinese population of 1030 subjects. Using five genetic variants, we constructed and identified 11 types of haplotypes (combination of five genetic variants) existing in the population. Overall, the haplotypes are strongly associated with all seven blood lipid traits. In particular, haplotype G-G-C-C-A and G-A-T-C-G showed consistent association with total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and other lipid traits. In addition, carriers of haplotype G-G-T-C-G had high concentrations of HDL-C in blood, whereas carriers of G-G-C-G-G had high concentrations of TC and triglyceride (TG) in blood. Importantly, we found haplotypes with five genetic variants explain much more blood lipid variation than any single variant alone. This suggests that the combination of multiple genetic variants in this gene cluster has a much stronger effect on blood lipids than individual variants alone. In conclusion, a combination of multiple genetic variants in the APOA1/C3/A4/A5 gene cluster shows stronger association with blood lipids composition in Chinese populations.
Technical Abstract: The association of single nucleotide polymorphisms (SNPs) in the apolipoprotein (Apo) A1/C3/A4/A5 gene cluster and serum lipid profiles is inconsistent. The present study was undertaken to detect the association between the ApoA1/C3/A5 gene polymorphisms and their haplotypes with serum lipid levels in the general Chinese population. A total of 1030 unrelated subjects (492 males and 538 females) aged 15-89 were randomly selected from our previous stratified randomized cluster samples. Genotyping of the ApoA1 -75 bp G>A, ApoC3 3238C>G, ApoA5 -1131T>C, ApoA5 c.553G>T and ApoA5 c.457G>A was performed by polymerase chain reaction and restriction fragment length polymorphism combined with gel electrophoresis, and then confirmed by direct sequencing. Pair-wise linkage disequilibria and haplotype analysis among the five SNPs were estimated. The levels of high-density lipoprotein cholesterol (HDL-C) and ApoA1 were lower in males than in females (P < 0.05 for each). The allelic and genotypic frequencies of the SNPs were no significant difference between males and females except ApoC3 3238C>G. There were 11 haplotypes with a frequency >1% identified in the cluster in our population. At the global level, the haplotypes comprised of all five SNPs were significantly associated with all seven lipid traits. In particular, haplotype G-G-C-C-A (6%; in the order of ApoA5 c.553G>T, ApoA5 c.457G>A, ApoA5 -1131T>C, ApoC3 3238C>G, and ApoA1 -75bp G>A) and G-A-T-C-G (4%) showed consistent association with total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), ApoA1, ApoB, and the ApoA1/ApoB ratio. In addition, carriers of haplotype G-G-T-C-G (26%) had increased serum concentration of HDL-C and ApoA1, whereas carriers of G-G-C-G-G (15%) had high concentrations of TC, triglyceride (TG) and ApoB. We also found that haplotypes with five SNPs explain much more serum lipid variation than any single SNP alone, especially for TG (4.4% for haplotype vs. 2.4% for -1131T>C max based on R-square) and HDL-C (5.1% for haplotype vs. 0.9% for c.553G>T based on R-square). Serum lipid parameters were also correlated with genotypes and several environment factors. Several common SNPs and their haplotypes in the ApoA1/C3/A5 gene cluster are closely associated with modifications of serum lipid parameters in the general Chinese population.