| Atherosclerosis kills more Americans yearly, irrespective of sex or ethnic group, than any other disease. While considered a heterogeneous disorder, lipids and inflammatory mediators are integral to its etiology; in addition, a positive family history is an independent predictor of this disease. Therefore, investigating the genetics of atherosclerosis in large populations is an important area of research. The aim of this study is to identify genetic loci influencing lipid and inflammation biomarker levels so that the genetic architecture of atherosclerosis can be better understood. Linkage analysis was performed for total cholesterol, HDL, and triglycerides in a large sample of Asian, African American, Hispanic, and white families. Significant linkage was observed for total cholesterol in Hispanics on chromosome 2 (LOD = 3.1) and for HDL in Asians on chromosomes 3 (LOD = 3.5) and 12 (LOD = 3.3). There was no evidence in this study population of a genetic locus that jointly affects HDL and triglycerides levels. An investigation into the genetics of two inflammation markers, ICAM-1 and MCP-1, revealed heritabilities of 0.38 and 0.42, respectively in a sample of white families. The heritability for ICAM-1 was higher for normal weight individuals compared to obese, 0.77 vs. 0.44, respectively. Linkage analysis resulted in no LOD scores ≥2.0 for ICAM-1 using the whole sample, but suggestive linkage was observed in the normal weight individuals on chromosome 4 (LOD = 2.5 at 30 cM). A significant LOD score was observed for MCP-1 on chromosome 13 (LOD = 3.0) and suggestive linkage on chromosomes 14, 18, and 22. A likely candidate gene, DOCK9, resides under the peak on chromosome 13 and is known to up-regulate MCP-1. The identification of genetic loci influencing lipid phenotypes and the similarity with published linkage findings provides increased support that these regions contain genes that affect these traits. The discovery of linkage for ICAM-1 and MCP-1 suggest that genes control circulating levels of these biomarkers. Future research will seek to identify the functional mutations associated with variation in these phenotypes. Discovering these variations will be clinically important in the understanding, diagnosis, and/or treatment of atherosclerosis. |
