Functional SNPs in the lymphotoxin-alpha gene that are associated with susceptibility to myocardial infarction

Laboratory for Cardiovascular Diseases, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), 4-6-1, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
Nature Genetics (Impact Factor: 29.65). 01/2003; 32(4):650-4. DOI: 10.1038/ng1047
Source: PubMed

ABSTRACT By means of a large-scale, case-control association study using 92,788 gene-based single-nucleotide polymorphism (SNP) markers, we identified a candidate locus on chromosome 6p21 associated with susceptibility 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). Homozygosity with respect to each of the two SNPs in LTA was significantly associated with increased risk for myocardial infarction (odds ratio = 1.78, chi(2) = 21.6, P = 0.00000033; 1,133 affected individuals versus 1,006 controls). In vitro functional analyses indicated that one SNP in the coding region of LTA, which changed an amino-acid residue from threonine to asparagine (Thr26Asn), effected a twofold increase in induction of several cell-adhesion molecules, including VCAM1, in vascular smooth-muscle cells of human coronary artery. Moreover, the SNP, in intron 1 of LTA, enhanced the transcriptional level of LTA. These results indicate that variants in the LTA are risk factors for myocardial infraction and implicate LTA in the pathogenesis of the disorder.

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Available from: Kouichi Ozaki, May 17, 2014
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    • "A single nucleotide polymorphism (SNP) located at position +252 in the first intron of the TNF-β, named as NcoI polymorphism (A252G, rs909253) consists of a Guanine (G) in the allele TNFB1 (allele G) and of an Adenine (A) in the allele TNFB2 (allele A) (Messer et al. 1991). This polymorphism has been associated with an increase in the transcription of the TNF-α gene and the susceptibility to many diseases including myocardial infarction (Ozaki et al. 2002), sepsis (Delongui et al. 2011), and ischemic stroke (Wang et al. 2009b). Some studies demonstrated that TNF-β NcoI polymorphism was associated with susceptibility for stroke. "
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    ABSTRACT: Polymorphisms in genes coding for pro-inflammatory molecules represent important factors for the pathogenesis and outcome of stroke. The aim of this study was to evaluate the relationship between the tumor necrosis factor beta (TNF-β) NcoI (rs909253) polymorphism with inflammatory and metabolic markers in acute ischemic stroke. Ninety-three patients and 134 controls were included. The TNF-β polymorphism was determined using PCR-RFLP with NcoI restriction enzyme. Stroke subtypes and neurological deficit score were evaluated. White blood cell counts, erythrocyte sedimentation rate (ESR), plasma levels of IL-6 and TNF-α, serum high sensitivity C-reactive Protein (hsCRP), serum lipid profile, plasma levels of glucose and insulin, and homeostatic model assessment of insulin resistance (HOMA-IR) were determined. Stroke patients presented higher white blood cell counts, hsCRP, ESR, glucose, insulin, and HOMA-IR, and lower HDL cholesterol than controls (p < 0.01). There was no difference in genotypic and allelic frequency of TNF-β NcoI polymorphism among patients and controls (p > 0.05). However, stroke patients carrying the TNFB2/B2 genotype presented higher levels of TNF-α, white blood cell counts, total cholesterol, LDL cholesterol, glucose, insulin, and HOMA-IR than those with other genotypes (p < 0.05). White blood cells, IL-6, hsCRP, and ESR were positively correlated with the neurological deficit of the patients (p < 0.05). Taken together, TNF-β NcoI polymorphism, by itself, was not associated with increased susceptibility for stroke development. However, the homozygous genotype for the allele TNFB2 was associated with higher expression of classical inflammatory and metabolic markers of development and outcome of stroke than other genotypes. The identification of variant alleles might allow both better prediction of susceptibility for stroke as well the identification of novel stroke mechanisms that could be target to new therapeutic approaches. Stroke patients carrying the TNFB2 variant allele could have a beneficial effect with the anti-inflammatory therapies in the early inflammatory phase of stroke.
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    • "It has been demonstrated that the association of the LT-a ?249A/G variant with diabetes depends on the simultaneous carriage of specific HLA class II alleles (Noble et al. 2006). Specific LT-a polymorphisms have been reported to correlate with LT-a secretion (Koss et al. 2000), and the carriage of the ?249G allele was correlated with enhanced production of LT-a (Messer et al. 1991; Weissensteiner and Lanchbury 1997; Ozaki et al. 2002). In this study, the ?249G allele was underrepresented in diabetes cases, compared with earlier studies implicating increased LT-a production in enhanced inflammation (Belfer et al. 2004) and diabetes risk (Rabinovitch 1998). "
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    ABSTRACT: We investigated the association of the lymphotoxin (LT)-α gene polymorphism +249A/G with type 1 diabetes. The distribution of genotypes of the LT-α +249A/G single nucleotide polymorphism (SNP) was assessed in 115 diabetic patients and 123 normoglycemic control subjects, using PCR-restriction fragment length polymorphism analysis. Among unselected patients, the SNP was significantly associated with increased risk of diabetes (χ(2) = 8.44, p = 0.014) and was found to be more pronounced among female (χ(2) = 8.37, p = 0.02) than male (χ(2) = 6.11, p = 0.047) patients. A significant association was detected between LT-α +249A/G and increased risk of diabetes, in particular for young-onset patients (χ(2) = 6.92, p = 0.031). Moreover, we reported significant differences in levels of HbA1c, triglycerides, alanine transaminase, and anti-glutamic acid decarboxylase-65 among alleles. Additional studies with extended patient age groups and different ethnicities are needed to confirm our findings.
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    • "The importance of SNP polymorphism in genes is shown up through its association with biological functions, especially about gene-based SNP genetic association studies in human [34] [35]. But few about such study in other species. "
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