However, suppression of LTα activity might be relevant in the context of RA-related comorbidities, as patients with RA have an increased risk of myocardial infarction (MI) compared with the general population, and specific polymorphisms of the LTα gene have been linked to increased MI risk.
Lymphotoxin alpha (LTα) is expressed in human atherosclerotic lesions and genetic variations in the LTα pathway have been linked to myocardial infarction.
For LTAA252G, a borderline significant overall association was found, indicating that GG genotype may confer an increased susceptibility to MI compared to AA and AG genotypes.
On 6p21, an HLA allele, DQB1(*)0604, could show one of the most prominent association signals in an ∼8-Mb interval that encompasses the LTA gene, where an association with myocardial infarction had been reported in another Japanese study.
Our findings indicate that the LTA and LGALS2 polymorphisms affect the subclinical phenotype of the coronary artery, which predisposes to the incidence of MI.
Previous case-control studies suggested the single nucleotide polymorphisms of lymphotoxin-alpha (LTA) gene and galectin-2 (LGASL2) gene are associated with coronary artery disease and myocardial infarction.
Single-nucleotide polymorphisms within the BAT1-NFKBIL1-LTA genomic region (6p21.3) and the LGALS2 gene (22q13.1), encoding a regulator for lymphotoxin-alpha, the product of the LTA gene, have been reported to be linked with the risk of myocardial infarction in Japanese.
These observations showed that, while the LTA 252GG genotype might modify the development of coronary atherosclerosis, the relation of LTA and LGALS2 to MI itself remained much less certain.
Single-nucleotide polymorphisms within the BAT1-NFKBIL1-LTA genomic region (6p21.3) and the LGALS2 gene (22q13.1), encoding a regulator for lymphotoxin-alpha, the product of the LTA gene, have been reported to be linked with the risk of myocardial infarction in Japanese.
Clinical, genetic, and epidemiological studies have linked lymphotoxin-alpha (LTA), a proinflammatory cytokine, to coronary artery disease and myocardial infarction.
In two MI populations of European descent with markedly different ascertainment strategies, we were not able to identify a significant association of SNPs in the LTA genomic region or the LGALS2 gene with MI.
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.
Genome-wide association studies have also been undertaken, and the pro-inflammatory cytokine lymphotoxin-alpha (LTA), and its key ligand galectin-2 (LGALS2) have been identified as genes implicated in predisposition for heart attack.
To further understand the roles of LTA protein in the pathogenesis of MI, we searched for proteins that interact directly with LTA protein and identified galectin-2 protein as a binding partner of LTA protein.
Associations between variations in the lymphotoxin-alpha gene (LTA) and myocardial infarction, cerebral infarction and type 1 diabetes have previously been reported.
Four new susceptibility genes have been identified using genome-wide association studies or genome-wide linkage studies: LTA (encoding cytokine lymphotoxin-alpha) on 6p21.3 for MI; LGALS2 (encoding galectin-2, an LTA-interacting protein) on 22q12-q13 for MI; ALOX5AP (encoding 5-lipoxygenase activating protein involved in synthesizing potent pro-inflammatory leukotrienes) on 13q12-13 for MI and stroke; and PDE4D (encoding phosphodiesterase 4D) on 5q12 for ischemic stroke.
The emerging data are quite conflicting and do not provide definitive evidence for a role of these gene variants in the pathogenesis of IHD; a possible exception is the G252A and polymorphism in the TNF-beta gene (also known as lymphotoxin-alpha) which, in a comprehensive genome-scan linkage analysis of unrelated Japanese, but not in a smaller German population, was linked to myocardial infarction.
We have identified functional SNPs within the lymphotoxin-alpha gene (LTA) located on chromosome 6p21 that conferred susceptibility to myocardial infarction.
A recent large-scale, genome-wide association study of single nucleotide polymorphisms showed a strong association between susceptibility to myocardial infarction and the Thr26Asn polymorphism in the lymphotoxin-alpha (LTA) gene.
The homozygous variant of LTA characterized by the intron 1 252A-->G (252G) transition, which naturally coexists with an exon 3 804C-->A (804A) single-nucleotide polymorphism (SNP), has been reported as a susceptibility gene for myocardial infarction.
In 2002, LTA was identified as a major risk factor for myocardial infarction (MI) in Japanese individuals, in a large-scale case-control study using 92,788 gene-based single-nucleotide polymorphism (SNP) markers in the whole human genome.