Ozaki, K., Ohnishi, Y., Iida, A., Sekine, A., Yamada, R., Tsunoda, T. et al. Functional SNPs in the lymphotoxin- gene that are associated with susceptibility to myocardial infarction. Nat. Genet. 32, 650-654

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: 29.35). 01/2003; 32(4):650-4. DOI: 10.1038/ng1047
Source: PubMed


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 0.05). 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
    Full-text · Article · Jul 2014 · Metabolic Brain Disease
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    • "A total of 67 relevant papers were identified using the pre-specified search strategy. In accordance with the inclusion criteria, fifteen case-control studies [14], [16]–[23], [32]–[37] were included in this meta-analysis, with a total of 22,549 MI patients and 16,105 healthy controls. Of the included studies, twelve examined associations with A252G (one study reported data separately for Japanese and Korean), five examined associations with G10A, and nine examined associations with C804A. "
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    ABSTRACT: The lymphotoxin-α (LTA), as one of the mediators of inflammation, may play an important role in the pathogenesis of myocardial infarction (MI). Genetic association studies (GAS) that have investigated the association between three common polymorphisms (A252G, G10A and C804A) of the LTA gene and susceptibility to MI have produced contradictory and inconclusive results. The aim of this meta-analysis is to provide a relatively comprehensive account of the association of these polymorphisms with susceptibility to MI. A literature search for eligible GAS published before October 15, 2013 was conducted in the PubMed, Embase, Web of Science, Cochrane Library, and CNKI (China National Knowledge Infrastructure) databases. We performed a meta-analysis of fifteen case-control studies with a total of 22,549 MI patients and 16,105 healthy controls. For LTA A252G, a borderline significant overall association was found, indicating that GG genotype may confer an increased susceptibility to MI compared to AA and AG genotypes. Based on an ethnicity stratification analysis, a significant association was observed in Asians, but not in Caucasians. For LTA G10A, no significant overall association was found. However, subgroup analysis based on ethnicity suggested that the 10A allele may confer a significant increased susceptibility to MI only in Asian populations. For LTA C804A, the combined results revealed a significantly increased susceptibility to MI for carriers of the 804A allele in both overall analysis and stratified analyses. This meta-analysis shows that LTA C804A may be associated with an increased susceptibility to MI, whereas LTA A252G and G10A may confer a significant increased susceptibility to MI only in Asians. Thus, these polymorphisms of the LTA gene can probably be used with other genetic markers together to identify individuals at high susceptibility to MI especially in Asians.
    Full-text · Article · Mar 2014 · PLoS ONE
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    • "Previous studies have suggested that the functional polymorphism rs909253 is associated with gastric [15] and breast [17] cancers in Asians. Although the four SNPs (rs1041981, rs2239704, rs2229094 and rs746868) are present in high LD with rs909253 [27,28], inconsistent results of the four SNPs and cancer risk are observed for different cancers in Asian, North American and European populations [18-20,22-24,31-51]. In the current study, we perform a comprehensive meta-analysis to evaluate the effects of the four functional SNPs (rs1041981, rs2239704, rs2229094 and rs746868) on cancer risk. "
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    ABSTRACT: Lymphotoxin-alpha (LTA) is a pro-inflammatory cytokine that plays an important role in the inflammatory and immunologic response. Numerous studies have shown LTA polymorphisms as risk factors for cancers, but the results remain inconclusive. The goal of the present meta-analyses is to establish the associations between cancers and four LTA variants (rs1041981, rs2239704, rs2229094 and rs746868). A total of 30 case-control studies involving 58,649 participants were included in the current meta-analyses. Our results showed significant associations with increased cancer risk for rs1041981 (odd ratio (OR) = 1.15, 99% confidential interval (CI) = 1.07-1.25, P < 0.0001, I(2) = 12.2%), rs2239704 (OR = 1.08, 99% CI = 1.01-1.16, P = 0.021, I(2) = 0.0%) and rs2229094 (OR = 1.28, 99% CI = 1.09-1.50, P = 0.003, I(2) = 0.0%). No evidence was found for the association between rs746868 and cancer risk (OR = 1.01, 99% CI = 0.93-1.10, P = 0.771, I(2) = 0.0%). Subgroup meta-analysis suggested that rs2239704 was likely to increase the risk of hematological malignancy (OR = 1.10, 99% CI = 1.01-1.20, P = 0.023, I(2) = 0.0%), and rs2229094 was specific for the increased risk of adenocarcinoma (OR = 1.33, 99% CI = 1.11-1.59, P = 0.002, I(2) = 0.0%). In conclusion, our meta-analyses suggested that the LTA rs1041981, rs2239704 and rs2229094 polymorphisms contributed to the increased risk of cancers. Future functional studies were needed to clarify the mechanistic roles of the three variants in the cancer risk.
    Full-text · Article · Dec 2013 · PLoS ONE
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