Recent studies on the liver X receptor-alpha (LXR-alpha) have recognized its crucial protective role in the initiation of a cross-talk between lipid metabolism and inflammation regarded as a prerequisite for the development of atherosclerotic lesions. The present study was directed to explore the functional genomics of LXR-alpha gene within blood mononuclear cells of subjects suffering from coronary heart disease (CHD), revealed a paradoxical relationship between blood cellular LXR-alpha mRNA expression and the severity of coronary occlusion. In order to resolve this apparent paradox, the ligand binding domain of LXR-alpha gene was analyzed. The results of such a study revealed that three critical mutations in the domain comprising of amino acids Asp324, Pro327 and Arg328, were responsible for inability of this domain to interact with its natural ligands leading thereby to deregulation of its effector genes that are known to play crucial role in the cross-talk between lipid peroxidation and inflammation. This phenomenon was in conformity with functional assay of LXR-alpha dependent transcriptional activity within cells derived from normal and CHD subjects. Based upon these results we propose that the mutations in the LXR-alpha gene reported here for the first time not only may be exploited for the diagnosis of CHD in human subjects but also could be used as a marker for exploring the predisposition of human subjects towards CHD.