Associations between variations in the lymphotoxin-alpha gene (LTA) and myocardial infarction, cerebral infarction and type 1 diabetes have previously been reported.
Lymphotoxin alpha (LTα) is expressed in human atherosclerotic lesions and genetic variations in the LTα pathway have been linked to myocardial infarction.
Subsequent linkage-disequilibrium (LD) mapping and analyses of haplotype structure showed significant associations between myocardial infarction and a single 50 kb halpotype comprised of five SNPs in LTA (encoding lymphotoxin-alpha), NFKBIL1 (encoding nuclear factor of kappa light polypeptide gene enhancer in B cells, inhibitor-like 1) and BAT1 (encoding HLA-B associated transcript 1).
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.
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.
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.
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.
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.
Subsequent linkage-disequilibrium (LD) mapping and analyses of haplotype structure showed significant associations between myocardial infarction and a single 50 kb halpotype comprised of five SNPs in LTA (encoding lymphotoxin-alpha), NFKBIL1 (encoding nuclear factor of kappa light polypeptide gene enhancer in B cells, inhibitor-like 1) and BAT1 (encoding HLA-B associated transcript 1).
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.
Our findings indicate that the LTA and LGALS2 polymorphisms affect the subclinical phenotype of the coronary artery, which predisposes to the incidence of MI.
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.
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.
Subsequent linkage-disequilibrium (LD) mapping and analyses of haplotype structure showed significant associations between myocardial infarction and a single 50 kb halpotype comprised of five SNPs in LTA (encoding lymphotoxin-alpha), NFKBIL1 (encoding nuclear factor of kappa light polypeptide gene enhancer in B cells, inhibitor-like 1) and BAT1 (encoding HLA-B associated transcript 1).
Our findings suggest that six different and functionally relevant polymorphisms of the genes coding for IL-10, TNF-alpha, and TNF-beta are neither separately nor in cooperation associated with the risk of CAD or MI in angiographically examined patients.
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.
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.
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.