Lymphotoxin-α Gene and Risk of Myocardial Infarction in 6,928 Cases and 2,712 Controls in the ISIS Case-Control Study

Lymphotoxin-α (LTA) is a pro-inflammatory cytokine that plays an important role in the immune system and local inflammatory response. LTA is expressed in atherosclerotic plaques and has been implicated in the pathogenesis of atherosclerosis and coronary heart disease (CHD). Polymorphisms in the gene encoding lymphotoxin-α (LTA) on Chromosome 6p21 have been associated with susceptibility to CHD, but results in different studies appear to be conflicting. We examined the association of seven single nucleotide polymorphisms (SNPs) across the LTA gene, and their related haplotypes, with risk of myocardial infarction (MI) in the International Study of Infarct Survival (ISIS) case-control study involving 6,928 non-fatal MI cases and 2,712 unrelated controls. The seven SNPs (including the rs909253 and rs1041981 SNPs previously implicated in the risk of CHD) were in strong linkage disequilibrium with each other and contributed to six common haplotypes. Some of the haplotypes for LTA were associated with higher plasma concentrations of C-reactive protein (p = 0.004) and lower concentrations of albumin (p = 0.023). However, none of the SNPs or related haplotypes were significantly associated with risk of MI. The results of the ISIS study were considered in the context of six previously published studies that had assessed this association, and this meta-analysis found no significant association with CHD risk using a recessive model and only a modest association using a dominant model (with narrow confidence intervals around these risk estimates). Overall, these studies provide reliable evidence that these common polymorphisms for the LTA gene are not strongly associated with susceptibility to coronary disease.Synopsis: Lymphotoxin-α gene (LTA) encodes a cytokine involved in the immune system that has been linked with risk of coronary heart disease (CHD). In one of the first genome-wide association studies, a Japanese group reported that polymorphisms for the LTA gene were associated with a 1.8-fold higher risk of CHD. The authors of this current paper examined associations of several polymorphisms for the LTA gene with risk of CHD in a case-control study of 6,928 heart attack survivors and 2,712 unrelated controls in the United Kingdom. None of the polymorphisms for LTA (including those examined in the original Japanese study) were associated with CHD risk. Moreover, a meta-analysis of all published studies found no significant association of LTA with CHD risk. These findings emphasize the need for large-scale studies to have sufficient power to detect associations of genetic variants with CHD risk and the need for replication of any such associations in independent studies of even larger size.