Novel polymorphisms and the definition of promoter ‘alleles’ of the tumor necrosis factor and lymphotoxin α loci: inclusion in HLA haplotypes

Cruz, Ivana Beatrice Mânica da; Bradshaw, Daniel; Medhekar, B A

doi:10.1038/sj.gene.6364023

Cited by 30 publications

(31 citation statements)

References 70 publications

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“…Purified amplified DNA (300 ng) was sequenced with a set of 16 sequencing primers (5 pm; sequences available on request) utilizing the Big Dye Terminator sequencing kit (PE Applied Biosystems, Foster City, CA, USA) as described (Posch et al 2003). All sequences were confirmed from at least two separate amplifications.…”

Section: Dna Sequencing and Phylogenetic Analysismentioning

confidence: 99%

“…The nucleotides are numbered from the A in the ATG initiation translation codon of TGFB1desig-nated as +1, and therefore differ from nucleotide numbering of previous studies that used the major transcription start site as +1 (Awad et al 1998). Phylogenetic analysis of TGFB1 allelic sequences was performed as described (Posch et al 2003).…”

Section: Dna Sequencing and Phylogenetic Analysismentioning

confidence: 99%

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Allelic diversity in the TGFB1 regulatory region: characterization of novel functional single nucleotide polymorphisms

et al. 2005

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Altered TGF-beta1 expression due to polymorphisms affects a wide variety of normal cellular and disease processes such as T cell activation and proliferation, tumor progression, and asthma. In this study, a comprehensive examination of function and diversity was undertaken for the TGFB1 promoter region and exon 1 (-2,665 to +423). The known TGF-beta1 promoter was extended to encompass 463 bases by the identification of a strong enhancer activity for a distal segment (-2,665 to -2,204). Ten novel polymorphisms and 14 novel alleles were identified. Most single nucleotide polymorphisms (SNPs) appear to be randomly associated except c.-768_-769insC and c.+74G > C and a set of five novel polymorphisms present in a single allele in persons of African descent. The TGFB1 alleles clustered into three phylogenetic groups based on the common functional SNPs c.-1347C > T (commonly known as -509C-T) and c.+29T > C (commonly known as +869T-C) suggesting three phenotypic groups. Two SNPs unique to African-Americans affect the TGFB1 regulatory region. The c.-1287G > A SNP in the promoter alters the binding affinity of two unidentified transcription factor complexes which translates into a significant difference in reporter gene expression and the c.-387C > T SNP in the 5' UTR alters the binding of Stimulating protein 1 and 3. Thus, TGFB1 possesses a highly polymorphic, extensive regulatory region that likely impacts the pathogenesis of numerous TGF-beta1 related diseases.

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Section: Dna Sequencing and Phylogenetic Analysismentioning

confidence: 99%

Section: Dna Sequencing and Phylogenetic Analysismentioning

confidence: 99%

Allelic diversity in the TGFB1 regulatory region: characterization of novel functional single nucleotide polymorphisms

et al. 2005

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“…In our study, five significant SNPs in the original study were located in the LTA gene and two of them were part of the risk haplotype. One of them, rs1041981, is exonic with a threonine-to-asparagine change (36) causing increased expression of adhesion molecules, such as VCAM-1 and E-selectin (37). The other SNP (rs909253) has been associated with periodontal disease (34,35), as well as with myocardial infarction (37), rheumatoid arthritis (38), and asthma (39).…”

Section: Discussionmentioning

confidence: 99%

Genetic Variation on the BAT1-NFKBIL1-LTA Region of Major Histocompatibility Complex Class III Associates with Periodontitis

et al. 2014

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Periodontitis is a chronic inflammatory disease with a multifactorial etiology. We investigated whether human major histocompatibility complex (MHC) polymorphisms (6p21.3) are associated with periodontal parameters. Parogene 1 population samples (n ‫؍‬ 169) were analyzed with 13,245 single nucleotide polymorphisms (SNPs) of the MHC region. Eighteen selected SNPs (P < 0.001) were replicated in Parogene 2 population samples (n ‫؍‬ 339) and the Health 2000 Survey (n ‫؍‬ 1,420). All subjects had a detailed clinical and radiographic oral health examination. Serum lymphotoxin-␣ (LTA) concentrations were measured in the Parogene populations, and the protein was detected in inflamed periodontal tissue. In the Parogene 1 population, 10 SNPs were associated with periodontal parameters. The strongest associations emerged from the parameters bleeding on probing (BOP) and a probing pocket depth (PPD) of >6 mm with the genes BAT1, NFKBIL1, and LTA. Six SNPs, rs11796, rs3130059, rs2239527, rs2071591, rs909253, and rs1041981 (r 2 , >0.92), constituted a risk haplotype. In the Parogene 1 population, the haplotype had the strongest association with the parameter BOP, a PPD of >6 mm, and severe periodontitis with odds ratios (95% confidence intervals) of 2.63 (2.21 to 3.20), 2.90 (2.37 to 3.52), and 3.10 (1.63 to 5.98), respectively. These results were replicated in the other two populations. High serum LTA concentrations in the Parogene population were associated with the periodontitis risk alleles of the LTA SNPs (rs909253 and rs1041981) of the haplotype. In addition, the protein was expressed in inflamed gingival connective tissue. We identified a novel BAT1-NFKBIL1-LTA haplotype as a significant contributor to the risk of periodontitis. The genetic polymorphisms in the MHC class III region may be functionally important in periodontitis susceptibility.

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“…Furthermore, TNF-␣ and LTA loci are located in the MHC. A recent sequence analysis of 69 samples (27) found no association between TNF-␣ or LTA alleles and specific human leukocyte antigen (HLA) genes (HLA-B and HLA-DR) alleles. Although TNF-␣ alleles had some linkage with LTA alleles, it was not genotyped because no observed polymorphism in the former locus was significantly associated with MI in the Japanese genome-wide association study.…”

Section: Discussionmentioning

confidence: 99%

Functional Variants in the Lymphotoxin-α Gene Predict Cardiovascular Disease in Dialysis Patients

Liu¹,

Berthier-Schaad²,

Plantinga³

et al. 2006

Journal of the American Society of Nephrology

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TNF-␤ that is encoded by lymphotoxin-␣ gene (LTA) regulates adhesion molecules and IL-6. Previously, a genome-wide case-control study showed that LTA gene variants predisposed to cardiovascular disease (CVD). In a prospective study of 775 dialysis patients, LTA and IL-6 gene variants were tested as independent predictors of CVD risk. Four polymorphisms in the LTA gene and one in the IL-6 gene were genotyped. CVD events were ascertained from medical records. During a mean follow-up of 2.6 yr, 294 first-incident CVD events occurred. The LTA 26Asn variant predicted higher adjusted CVD risk (hazard ratio HR 1.33 for each additional copy of Asn allele; 95% confidence interval 1.14 to 1.55; P ‫؍‬ 0.0003). Two other nonsynonymous polymorphisms in the LTA, 13Agr and 51Pro, were associated with lower inflammatory activity and CVD risk. LTA haplotypes (based on all four single-nucleotide polymorphisms) were associated with inflammatory markers and predicted CVD risk (P ‫؍‬ 0.005) after adjustment. These LTA genotype associations were independent of the IL-6 ؊174G/C genotype association that was reported recently. LTA and IL-6 gene variants independently predicted risk for CVD among dialysis patients, suggesting that susceptibility in multiple inflammatory pathways contribute to the development of CVD.

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Novel polymorphisms and the definition of promoter ‘alleles’ of the tumor necrosis factor and lymphotoxin α loci: inclusion in HLA haplotypes

Cited by 30 publications

References 70 publications

Allelic diversity in the TGFB1 regulatory region: characterization of novel functional single nucleotide polymorphisms

Allelic diversity in the TGFB1 regulatory region: characterization of novel functional single nucleotide polymorphisms

Genetic Variation on the BAT1-NFKBIL1-LTA Region of Major Histocompatibility Complex Class III Associates with Periodontitis

Functional Variants in the Lymphotoxin-α Gene Predict Cardiovascular Disease in Dialysis Patients

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