Lack of association of polymorphisms of the lymphotoxin ? gene with myocardial infarction in Japanese

Abstract

Vascular inflammation plays an important role in the development of myocardial infarction (MI). Lymphotoxin alpha (LTA) is a cytokine with multiple functions in regulation of the immune system and inflammatory reactions. The aim of this study was to examine whether polymorphisms of the LTA gene are associated with the risk of MI in Japanese men and women. A case-control association study was performed for the 252A-->G and 804C-->A polymorphisms of the LTA gene and the prevalence of MI. The study population comprised 3,689 unrelated Japanese individuals (2,486 men, 1,203 women), including 1891 patients with MI (1,493 men, 398 women) and 1798 control subjects (993 men, 805 women). Among the control subjects 257 individuals (108 men, 149 women) who had none of the conventional risk factors for coronary artery disease (CAD) were defined as low-risk controls. Genotypes for the two polymorphisms were determined with a fluorescence-based allele-specific DNA primer assay system. Among all study subjects the 252A-->G and 804C-->A polymorphisms exhibited linkage disequilibrium. No association of either polymorphism with MI was detected in men or in women in comparisons with total control or low-risk control subjects. However, each of the two polymorphisms was associated with the prevalence of type 2 diabetes mellitus both in men with MI and in those without MI in a recessive genetic model. No association was detected between the polymorphisms and other conventional risk factors for CAD. The LTA gene thus does not appear to be a susceptibility locus for MI in Japanese men or women, although it might affect susceptibility to type 2 diabetes in Japanese men.

Large-scale studies of the association between variation at the TNF/LTA locus and susceptibility to type 2 diabetes

“…Associations between a non-synonymous LTA variant (T60N) and type 2 diabetes have recently been reported in Danish and Japanese subjects [14,15]. In these studies, the rare homozygous T60N (AA) genotype was found to be associated with increased risk of disease.…”

“…If allowance is made, under realistic models [22,23], for the increase in susceptibility allele frequency to be expected when, as in the present study, cases have been selected for familiality and early onset, these power values rise to 91 and >99%, respectively. In the specific case of T60N, where previous evidence [14,15] supports a recessive effect (amino acids NN vs. T/−; genotypes AA vs. C/−), the present study has only 41% power to detect the effect size (OR 1.24) detected by Hamid and colleagues in unselected cases [14]. However, once again, allowance for the effects of case selection leads to power estimates of >99.9% for detection of the OR seen in the Danish early onset case subset (OR=1.99), or, more conservatively, 97% for an OR of 1.50.…”

“…In addition, a non-synonymous coding polymorphism in LTA (T60N, referred to as T26N in some studies) has been associated with myocardial infarction [13]. Recently, evidence implicating the T60N polymorphism with increased susceptibility to type 2 diabetes has emerged from two studies [14,15] conducted in Danish Caucasian and Japanese individuals.…”

Phenotype selection for detecting variable genes: a survey of cardiovascular quantitative traits and TNF locus polymorphism

“…There are, however, examples of well-powered studies implicating the TNF region, in particular in myocardial infarction, 3 but this too has been followed by non-replication. 11 A previous study examining TNF variation in a large coronary heart disease (CHD) sample provided only weak evidence of an effect upon TNF plasma levels (in contrast to the above cited examples of ACE etc). 12 Against this background, we have performed a systematic evaluation of quantitative traits typically examined in cardiovascular disease, providing a broader search for phenotypes that may be able to detect the presence of functional variation within the TNF region.…”

Genotype of galectin 2 (LGALS2) is associated with insulin-glucose profile in the British Women’s Heart and Health Study

“…The inflammatory cytokines lymphotoxin-α (LTA) and TNF-α play multiple roles in the development and function of the immune system and several studies have reported associations between these cytokines and insulin resistance [1]. In support of a role for LTA in the pathogenesis of metabolic traits, common genotypes of LTA have been shown to be associated with traits of the metabolic syndrome, type 2 diabetes and myocardial infarction [2][3][4][5] However, LTA and TNF-α are homologous, and their genes are in significant linkage disequilibrium (LD) [6]. LTA and TNF are also in LD with the extensive HLA cluster.…”