|Lai, Chao Qiang|
|Cupples, L. Adrienne|
Submitted to: Journal of Lipid Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/2/2005
Publication Date: 7/1/2005
Citation: Yang, Q., Lai, C., Parnell, L.D., Cupples, L., Adiconis, X., Zhu, Y., Wilson, P.W., Housman, D.E., Sherman, A.M., D'Agostino, R.B., Ordovas, J.M. 2005. Genome-wide linkage analyses and candidate gene fine mapping for HDL3 cholesterol: the Framingham Study. Journal of Lipid Research. 46(7):1416-1425. Interpretive Summary: Lipoproteins are particles carrying cholesterol and fats in the bloodstream. Their levels in blood are used as predictors of heart disease risk, and these levels are controlled in part by genetic factors. One of the major lipid- related risk factors is determined by the levels of high-density lipoproteins (HDL). The levels of these macromolecules in plasma is determined by a host of environmental and genetic factors. Among the first, the most relevant are diet, smoking, alcohol and physical activity. Among the latter, several genes have been already identified associated with HDL levels, but all together still explain a very small percent of the total genetic contribution. Therefore, it is paramount to identify more gene targets that could help to understand the metabolism of HDL and define new therapeutic approaches to increase HDL and to decrease cardiovascular disease risk. In this research, we have searched for new genes for HDL in the whole human genome of participants in the Framingham Heart Study and narrowed down our search to a region of chromosome 6 that may hold additional clues to the metabolism of HDL. In addition, we have preliminary data suggesting that several genes within that region could be responsible for the observed variation in plasma HDL levels in the population. These findings could open new therapeutic avenues to our fight against cardiovascular disease. Moreover, it could be used to differentiate among individuals according to their genetic cardiovascular risk and to target those subjects at higher risk for more aggressive dietary therapy.
Technical Abstract: High Density Lipoprotein (HDL) cholesterol (C) has been found to be inversely associated with coronary heart disease and has a genetic component; however few studies have reported conclusive linkage evidence. It has been hypothesized that the subfractions of HDL such as HDL3-C may be better phenotypes for linkage studies. Using HDL3-C levels measured on 907 Framingham Heart Study subjects from 330 families around 1987, we conducted a genome-wide variance components linkage analysis with 401 microsatellite markers spaced about 10 cM apart. Traditional risk factors were adjusted in a sex-specific regression model prior to the linkage analysis. Nine candidate genes were identified and annotated using a bioinformatics approach in the region of the highest linkage peak. Twenty-eight single nucleotide polymorphisms (SNPs) were selected from the candidate gene, and linkage and family-based association fine mapping were conducted with these SNPs adding to the existing microsatellite marker map. The highest multipoint LOD score was 3.7 at 133 cM on chromosome 6 from the initial linkage analysis. Linkage analyses with additional SNPs yielded the highest LOD score of 4.0 at 129 cM on chromosome 6. Family-based association analysis revealed that rs2257104 in PLAGL1 at approximate 143 cM was associated with multivariable adjusted HDL3 (p-value=0.03). Further study of this variant and exploration of other variants in PLAGL1 are warranted to narrow down potential functional variants of HDL-C metabolism.