Role of the OX40 ligand/receptor pair in coronary artery disease

Abstract

Atherosclerosis is the pathological basis for coronary artery disease (CAD), the leading cause of morbidity and mortality in developed countries. CAD and atherosclerosis have long been known to have a familial component and result from the interaction of several genes with a wide range of environmental and lifestyle factors. Because of this complexity, applying the positional cloning approaches to find new CAD susceptibility genes has resulted disappointing and most of them are still unknown. Evidence from epidemiological studies implies a possibility for CAD susceptibility genes independent of classical risk factors. Identification of such genes might reveal novel intriguing biological pathways, making quests for new susceptibility genes in a hypothesis-independent manner worthwhile. Mapping of quantitative traits in mouse is showing to be particularly useful for such purposes. Despite there is no convincing animal model of CAD in a genetically tractable species, manipulated mouse models and inbred strains have been proved informative for aspects of atherosclerosis, the underlying cause of CAD.

Based on these considerations we investigated the genetic susceptibility to atherosclerosis with the aim to find new possible genetic risk factors implicated in development of its clinical complications, like myocardial infarction and CAD. We applied a combined approach based on identification of loci that have quantitative effects (QTLs) in mouse, and evaluation of the homologous candidate genes in a human context. This strategy applied to strains susceptible to diet-induced atherosclerosis (C57BL/6) identified 0x401 as the gene underlying the atherosclerosis-susceptibility locus Ath1 on chromosome 1. 0x401 was shown to control lesion formation in female mice and a specific genetic variation in the human counterpart was shown to be associated with MI in women. Our efforts finalised to dissect the mechanism behind the observed association between OX40L and MI revealed a novel promoter polymorphism (-921C>T) indicated by haploChIP analysis to regulate OX40L transcriptional activity in vivo. This together with EMSA studies suggests that -921C>T is the functional polymorphism responsible for lower gene expression and the observed increased risk of MI in women.

To further evaluate the role of OX40L in relation to CAD we performed transmission-based tests in trio families and observed that a "mirror" of the haplotype previously found was more frequently transmitted to affected offspring, results being statistically significant only in the British subsample. However, in Swedish females the minor rs38506416 G-allele appeared to increase the risk of CAD and MI, in line with our previous findings. Overall, results support the view that genetic variation in OX40L contributes to the development of CAD reinforcing the hypothesis that interactions between the OX40L gene and gender might influence genetic susceptibility. Other evidences from our studies suggested that genetic variation in OX40, encoding the receptor of OX40L, also plays a role in the pathogenesis of MI, thus indicating the OX40L/OX40 pathway as a novel important factor contributing to atherosclerosis and CAD.

In conclusion, we reported that specific genetic variation in the OX40L/OX40 couple appears to promote a proinflammatory state destabilizing the atherosclerotic plaque and making it particularly prone to rupture. Since activated immune cells are proposed to initiate plaque rupture, OX40L and OX40, being involved in the recruitment and activation of T cells, might presumptively play an important role in atherogenesis. In addition, due to its characteristics the OX40 ligand/receptor pair may be an excellent target for therapy.