A Second Susceptibility Gene for Developing Rheumatoid Arthritis in the Human MHC Is Localized within a 70-kb Interval Telomeric of the TNF Genes in the HLA Class III Region

Ôta, Masao; Katsuyama, Yoshihiko; Kimura, Akinori; Tsuchiya, Kuniyoshi; Kondo, Masakazu; Naruse, Taeko K.; Mizuki, Nobuhisa; Itoh, Kyogo; Sasazuki, Takehiko; Inoko, Hidetoshi

doi:10.1006/geno.2000.6371

Cited by 98 publications

(78 citation statements)

References 46 publications

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“…Studies of the haplotype structure of the TNF locus have described many haplotypes in this genomic region 41 and suggested that the TNF region contains a gene that makes a contribution to susceptibility independently of the contribution of HLA-DRB1. 24,42 This gene was then identified as IkBL (NFKBIL1), 43 which has also been implicated in susceptibility to myocardial infarction. 44 Further studies are needed to show that the variants of IkBL or LTA are functional and directly contribute to the pathogenesis of RA and further fine mapping of the TNF region must rule out linkage to other disease loci.…”

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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Section: Autoimmune Disease Associationsmentioning

confidence: 99%

Is there a future for TNF promoter polymorphisms?

2004

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“…The TNFA gene is located within the class III region of the MHC. The strong linkage disequilibrium among the Ͼ200 genes of the MHC has made it challenging to delineate the specific contribution of individual MHC genes to the pathogenesis of RA (19)(20)(21). Increased production of TNF␣ has been demonstrated in DR3ϩ and DR4ϩ individuals as compared with DR2ϩ individuals, suggesting genetic variation in levels of TNF␣ production (22).…”

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confidence: 99%

Association of tumor necrosis factor α polymorphism, but not the shared epitope, with increased radiographic progression in a seropositive rheumatoid arthritis inception cohort

Khanna

Park

et al. 2006

Arthritis & Rheumatism

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Objective. To determine whether the tumor necrosis factor ␣ (TNFA) -308 guanine-to-adenosine polymorphism and/or the shared epitope (SE) is associated with radiographic damage in patients with early rheumatoid arthritis (RA).Methods. The cohort consisted of 189 patients with early seropositive RA (median 5.6 months since symptom onset) who had active disease, no previous disease-modifying antirheumatic drug treatment, and >2 sets of scored radiographs of the hands/wrists and forefeet. TNFA -308 polymorphism was analyzed by polymerase chain reaction pyrosequencing. The SE was defined as presence of any 1 of the following HLA-DRB1 alleles: *0101, *0102, *0401, *0404, *0405, *0408, *0410, *1001, *1402, or *1406. Radiographic progression was assessed by the total Sharp score.Results. Using a weighted least-squares regression analysis, patients with the -308 TNFA AA plus AG genotypes (n ‫؍‬ 49) had significantly higher rates of progression in erosion scores (median 0.84 versus 0.48 units/year), joint space narrowing (JSN) scores (0.42 versus 0.04), and total Sharp scores (1.70 versus 0.61) compared with patients with the TNFA GG genotype (n ‫؍‬ 140). Presence of the SE (n ‫؍‬ 137) was associated with significantly lower progression rates (per year) for total Sharp scores (median 0.9 versus 1.25 units/year) and JSN scores (0.04 versus 0.41), but not for erosion scores (0.50 versus 0.61) compared with patients without the SE (n ‫؍‬ 52). In a least-squares multiple linear regression model, the presence of the AA plus AG genotypes was associated with a significantly higher progression rate after adjusting for the presence of the SE, interaction between the SE and the AA plus AG genotypes, baseline log C-reactive protein level, Health Assessment Questionnaire Disability Index, total Sharp score, swollen joint count, and presence of osteophytes (osteoarthritis). There was a strong linkage disequili-

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“…We first used microsatellite markers to investigate the HLA-linked susceptibility loci. These microsatellite markers were used in earlier studies to discover the susceptibility loci of various diseases, including chronic rheumatoid arthritis, 24,30,31 Takayasu arteritis, 28,32 and autoimmune pancreatitis, 26 which suggested that these markers might capture specific haplotypes of HLA or non-HLA genes. However, because we investigated only 15 microsatellite markers, these markers might not be enough to capture all the susceptibility genes for DVTnegative CTEPH.…”

Section: Discussionmentioning

confidence: 99%

HLA-DPB1 and NFKBIL1 may confer the susceptibility to chronic thromboembolic pulmonary hypertension in the absence of deep vein thrombosis

et al. 2009

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Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by pulmonary hypertension caused by thromboembolism of the pulmonary artery. Etiology of CTEPH may be heterogeneous and is largely unknown, but genetic factors are considered to be involved in the etiology. It has been reported that deep vein thrombosis (DVT) and/or coagulation factor variants are predisposing factors to CTEPH. However, more than half of the CTEPH patients, especially the Japanese, do not have prior DVT or coagulation abnormality, suggesting that there should be other risk factors for CTEPH. Moreover, there are several reports on the association between CTEPH and human leukocyte antigen (HLA). To further clarify the HLA-linked gene(s) controlling the susceptibility to CTEPH, 160 patients (99 without DVT and 61 with DVT) and 380 healthy controls were analyzed for polymorphisms in 15 microsatellite markers and 5 genes in the HLA region. We found a strong association of HLA markers with the DVT-negative CTEPH, DPB1*0202 (odds ratio (OR)¼5.07, 95% confidence interval (CI)¼2.52-10.19, P¼0.00000075, corrected P-value (Pc)¼0.00014), IKBL-p*03 (OR¼2.33, 95% CI¼1.49-3.66, P¼0.00017, Pc¼0.033) and B*5201 (OR¼2.47, 95% CI¼1.56-3.90, P¼0.000086, Pc¼0.016), whereas no significant association was observed for the DVT-positive CTEPH. The comparison of clinical characteristics of patients stratified by the presence of susceptibility genes implied that the DPB1 gene controlled the severity of the vascular lesion, whereas the IKBL gene (NFKBIL1) was associated with a relatively mild phenotype.

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A Second Susceptibility Gene for Developing Rheumatoid Arthritis in the Human MHC Is Localized within a 70-kb Interval Telomeric of the TNF Genes in the HLA Class III Region

Cited by 98 publications

References 46 publications

Is there a future for TNF promoter polymorphisms?

Is there a future for TNF promoter polymorphisms?

Association of tumor necrosis factor α polymorphism, but not the shared epitope, with increased radiographic progression in a seropositive rheumatoid arthritis inception cohort

HLA-DPB1 and NFKBIL1 may confer the susceptibility to chronic thromboembolic pulmonary hypertension in the absence of deep vein thrombosis

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