Tumor necrosis factor locus polymorphisms in rheumatoid arthritis

Field, Max; Gallagher, Grant; Eskdale, Joyce; McGarry, F; Richards, Sandra; Munro, Robin; Oh, H.-H.; Campbell, Christopher

doi:10.1111/j.1399-0039.1997.tb02874.x

Cited by 25 publications

(13 citation statements)

References 15 publications

(4 reference statements)

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“…There have been many association studies of TNF polymorphisms and susceptibility to RA, and there have been similar studies of other diseases characterized by chronic inflammation (18,19,25,(28)(29)(30)(31). No previous study in RA has controlled for LD with specific DRB1 alleles, although many have matched cases and controls for carriage of DRB1*04, for the carriage of SEcontaining DRB1 alleles, or for carriage of specific DRB1 alleles, but not with specific assignment to haplotypes.…”

Section: Discussionmentioning

confidence: 99%

The effect of HLA–DR on susceptibility to rheumatoid arthritis is influenced by the associated lymphotoxin α–tumor necrosis factor haplotype

Newton

Brown

Milicic

et al. 2003

Arthritis & Rheumatism

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Objective. HLA-DRB1, a major genetic determinant of susceptibility to rheumatoid arthritis (RA), is located within 1,000 kb of the gene encoding tumor necrosis factor (TNF). Because certain HLA-DRB1*04 subtypes increase susceptibility to RA, investigation of the role of the TNF gene is complicated by linkage disequilibrium (LD) between TNF and DRB1 alleles. By adequately controlling for this LD, we aimed to investigate the presence of additional major histocompatibility complex (MHC) susceptibility genes.Methods. We identified 274 HLA-DRB1*04-positive cases of RA and 271 HLA-DRB1*04-positive population controls. Each subject was typed for 6 singlenucleotide polymorphisms within a 4.5-kb region encompassing TNF and lymphotoxin ␣ (LTA). LTA-TNF haplotypes in these unrelated individuals were determined using a combination of family data and the PHASE software program.Results. Significant differences in LTA-TNF haplotype frequencies were observed between different subtypes of HLA-DRB1*04. The LTA-TNF haplotypes observed were very restricted, with only 4 haplotypes constituting 81% of all haplotypes present. Among individuals carrying DRB1*0401, the LTA-TNF 2 haplotype was significantly underrepresented in cases compared with controls (odds ratio 0.5 [95% confidence interval 0.3-0.8], P ‫؍‬ 0.007), while in those with DRB1*0404, the opposite effect was observed (P ‫؍‬ 0.007).Conclusion. These findings suggest that the MHC contains genetic elements outside the LTA-TNF region that modify the effect of HLA-DRB1 on susceptibility to RA.

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Section: Discussionmentioning

confidence: 99%

The effect of HLA–DR on susceptibility to rheumatoid arthritis is influenced by the associated lymphotoxin α–tumor necrosis factor haplotype

Newton

Brown

Milicic

et al. 2003

Arthritis & Rheumatism

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“…Other studies have used microsatellites to analyse the TNF region 26,[35][36][37] and found that several of these markers were associated with incidence or severity of RA, although another study 38 found that this association was not independent of the known extended haplotype associations. Recent studies have found positive associations, including for the TNF À863A, 39 and a þ 851 intronic SNP, 40 and these authors state that they are now engaged in fine mapping of a larger interval, in an attempt to identify the causative locus.…”

Section: Autoimmune Disease Associationsmentioning

confidence: 99%

Is there a future for TNF promoter polymorphisms?

2004

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The in vitro study of TNF promoter polymorphism (SNP) function was stimulated by the numerous case-control (association) studies of the polymorphisms in relation to human disease and the appearance of several studies claiming to show a functional role for these SNPs provided a further impetus to researchers interested in the role of TNF in their disease of interest. In this review we consider case-control studies, concentrating on the autoimmune and inflammatory diseases rheumatoid arthritis, multiple sclerosis, ankylosing spondylitis, and asthma, and on infectious diseases including malaria, hepatitis B and C infection, leprosy and sepsis/septic shock. We also review the available evidence on the functional role of the various TNF promoter polymorphisms. In general, case-control studies have produced mixed results, with little consensus in most cases on whether any TNF polymorphisms are actually associated with disease, although results have been more consistent in the case of infectious diseases, particularly malaria. Functional studies have also produced mixed results but recent work suggests that the much studied À308G/A polymorphism is not functional, while the function of other TNF polymorphisms remains controversial. Studies of the TNF region are increasingly using extended haplotypes that can better capture the variation of the MHC region.

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“…Among the multiple genes believed to be involved, the HLA-DRB locus is one of the well-studied gene loci reported to be associated with this disease (Suzuki et al 2003;Weyand and Goronzy 2000). Our group recently found an association of tumor necrosis factor-a microsatellite with susceptibility and progression of RA in an Indian population (Agrawal et al 2005) that is distinct from other populations (Agrawal et al 2005;Field et al 1997). The precise etiology of this disease is unknown, but immune dysfunction is clearly one of its central features.…”

Section: Introductionmentioning

confidence: 99%

Association of mannose-binding lectin gene (MBL2) polymorphisms with rheumatoid arthritis in an Indian cohort of case-control samples

et al. 2005

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Single nucleotide polymorphisms in the mannose-binding lectin (MBL2) gene, as well as the serum MBL2 level, have been associated with various autoimmune diseases. We investigated whether such polymorphisms and/or the serum MBL2 level were associated with rheumatoid arthritis (RA) in an Indian population. The frequency of the B variant (codon 54) of the MBL2 gene was quite frequent in the healthy Indian population and was significantly (P=6.35·10 À6 ) lower in RA patients. We replicated this association (P=1.78·10 À5 ) in an independent cohort of control individuals. Promoter polymorphism at À550 nt showed a significant overrepresentation (P=0.003) of the minor allele G in severe RA patients compared with the less severe group. Haplotype LYA frequency was significantly (P=0.03) high in the less severe group, while the frequency of the HYA haplotype was significantly (P=0.04) increased in the severe RA patients. No statistically significant difference in serum MBL2 was observed as a whole, but the individuals homozygous for the LYA haplotype had significantly lower (P=0.017) serum MBL2 levels compared with individuals homozygous for the HYA haplotype. Therefore, the B variant of the MBL2 gene may be associated with protection from RA in our study population, and the promoter polymorphism (À550 nt) seems to have some role in disease progression.

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Tumor necrosis factor locus polymorphisms in rheumatoid arthritis

Cited by 25 publications

References 15 publications

The effect of HLA–DR on susceptibility to rheumatoid arthritis is influenced by the associated lymphotoxin α–tumor necrosis factor haplotype

The effect of HLA–DR on susceptibility to rheumatoid arthritis is influenced by the associated lymphotoxin α–tumor necrosis factor haplotype

Is there a future for TNF promoter polymorphisms?

Association of mannose-binding lectin gene (MBL2) polymorphisms with rheumatoid arthritis in an Indian cohort of case-control samples

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