Evidence for HDL-associated Variation in T-cell Receptor Gene Expression

High-density lipoprotein (HDL) levels, a common predictor of heart disease, are determined by genetic and environmental factors. Previous research on the genetic basis of this variation has had limited results. Examination of gene expression may bridge the gap and aid in identifying novel risk loci. Expression levels of 47,289 transcripts were characterized for lymphocytes in 1243 Mexican American participants in the San Antonio Family Heart Study. 117 transcripts from 99 genes show significant genetic correlation (p<5E-5) with HDL levels. Pathway analysis was used to identify biological domains enriched for these 99 genes. Enrichment was determined by an empirical p-value derived from comparing the test set to 100 randomly selected sets of 99 genes represented on the array. Of 723 pathways ascertained from Ariadne Pathway Studio, HDL-associated genes were overrepresented (p<0.05) in four. Three are signaling pathways for T-cell receptors which recognize MHC antigens and trigger transformation into cytotoxic or helper T-cells. The inhibitory natural killer cell receptor pathway, which produces immunoglobulin-like receptors responsible for the recognition of cell-surface MHC I antigens, also appears involved. While the anti-atherosclerotic role of HDL is well documented and focuses predominantly on inflammation, the genetic correlations between variation in expression of these genes and HDL levels suggest an additional role for HDL in immune cell function.