Association of tumor necrosis factor receptor type II polymorphism 196R with systemic lupus erythematosus in the Japanese: Molecular and functional analysis

Objective

To investigate whether a polymorphism(s) or mutation(s) in the tumor necrosis factor receptor II (TNFRII) gene is involved in the pathogenesis of systemic lupus erythematosus (SLE).

Methods

All 10 exons of the TNFRII gene were analyzed by exon‐specific polymerase chain reaction–single‐strand conformation polymorphism, followed by nucleotide sequencing of exons that displayed aberrant bands. To analyze the function of the TNFRII polymorphisms, the full‐length TNFRII complementary DNA of each allele was transfected in HeLa cells and then studied for specific binding of ¹²⁵I‐TNFα, as well as interleukin‐6 (IL‐6) production and cytotoxic activity after treatment with recombinant human TNFα.

Results

We identified 4 polymorphisms, at codons 56, 181, 196, and 232. The latter 2 had amino acid substitutions M196R and E232K, respectively. Only the 196R allele was significantly associated with SLE in our 105 Japanese SLE patients, with an allele frequency of 20.5%, compared with 12.6% in 99 healthy controls (P = 0.0335). More importantly, using TNFRII‐transfected HeLa cells, we demonstrated significantly increased IL‐6 production by 196R TNFRII compared with 196M TNFRII. The cytotoxic activity induced by 196R TNFRII was also increased compared with that of 196M TNFRII. This increase was achieved without affecting the binding affinity of TNFα to TNFRII, as demonstrated by the finding that specific TNFα binding to the HeLa transfectants of 196R and 196M TNFRII was similar, with K_d values of 3.12 × 10⁻¹⁰M and 4.34 × 10⁻¹⁰M, respectively.

Conclusion

These results suggest that 196R TNFRII, which transduces the signals of TNFα more effectively than does 196M TNFRII, is involved in the pathogenesis of SLE.

     

Polymorphism of interleukin-10 promoter and tumor necrosis factor receptor II in Vietnamese patients with systemic lupus erythematosus

The polymorphism of the interleukin-10 (IL-10) promoter and tumor necrosis factor receptor II (TNFRII) in Vietnamese patients with systemic lupus erythematosus (SLE) was examined by using the polymerase chain reaction (PCR) method with genomic DNA and allele-specific primers. In the frequency of IL-10 promoter 1082 genotypes consisting of AA, A/G and GG, the allele frequency of G in the SLE patients was significantly higher than that in the healthy controls. On the other hand, there was no statistical difference in the frequency of TNF receptor (TNFR) II 196 genotypes between the SLE patients and healthy controls. It was therefore suggested that the polymorphism of the IL-10 promoter, but not TNFRII, might participate in the pathogenesis of SLE in Vietnamese.Abbreviations IL-10 Interleukin-10 - PCR Polymerase chain reaction - SLE Systemic lupus erythematosus - SNPs Single nucleotide polymorphisms - TNFR Tumor necrosis factor receptor     

Tumor necrosis factor receptor II gene polymorphism and severity of rheumatoid arthritis

OBJECTIVE: The gene encoding tumor necrosis factor receptor type II (TNFRII) is a strong candidate in the pathogenesis of rheumatoid arthritis (RA). An association between a single-nucleotide polymorphism (196M/R) in exon 6 of the TNFRII gene and familial RA was recently reported. The present study was undertaken to test the hypothesis that there is an association between this polymorphism and the severity of RA. METHODS: One hundred two white patients with early RA were included in this prospective study. The French version of the Health Assessment Questionnaire (F-HAQ) and a radiographic damage score (modified Sharp/van der Heijde method) were used to quantify the functional and structural severity of RA at baseline and after 4 years of followup. TNFRII 196M/R polymorphism genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism analysis. RESULTS: Among the 102 patients with RA, 63 (61.8%) were homozygous for the 196M allele, 36 (35.3%) were heterozygous for alleles 196M and 196R, and 3 (2.9%) were homozygous for the 196R allele. At baseline, the median radiographic and F-HAQ scores did not differ between RA patients who carried the 196R allele and those who did not. After 4 years of followup, the F-HAQ score was higher in RA patients carrying the 196R allele (median 1 [interquartile range (IQR) 0.125, 1.375]) than in noncarriers (0.375 [IQR 0, 1]) (P = 0.02), while the median radiographic score did not differ between RA patients who carried the 196R allele and those who did not. CONCLUSION: The results of the present study support the hypothesis that there is an association between the TNFRII 196 M/R gene polymorphism and the functional severity of early RA.     

A functional M196R polymorphism of tumour necrosis factor receptor type 2 is associated with systemic lupus erythematosus: a case-control study and a meta-analysis

OBJECTIVES: To perform a case-control study of a functional M196R polymorphism of tumour necrosis factor receptor type 2 (TNF-RII) in a Japanese population and a meta-analysis of all published reports on the polymorphism to investigate the association of the M196R polymorphism of TNF-RII with systemic lupus erythematosus (SLE). METHODS: The functional M196R polymorphism of TNF-RII was genotyped by using polymerase chain reaction combined with the subsequent single-strand conformation polymorphism (PCR-SSCP) analysis for screening, followed by nucleotide sequencing for confirmation. A total of 331 patients and 359 controls were subjected to a case-control study. A meta-analysis of the available case-control studies including all published data as well as our own data was performed to investigate the association of the functional M196R polymorphism of TNF-RII with SLE. RESULTS: Our case-control study did not show any significant association of a functional M196R polymorphism of TNF-RII with SLE, although there was a trend towards association. A meta-analysis of seven case-control studies in eight different ethnic populations including our own showed that 196M/R and 196R/R genotypes combined was significantly associated with an increased risk of SLE (odds ratio (OR) 1.29, 95% confidence interval (CI) 1.04 to 1.60; p = 0.02). Stratification by ethnicity showed a more significant association in Asians, including Japanese, Korean and Vietnamese (OR 1.40, 95% CI 1.10 to 1.78; p = 0.006). The effect of the 196R allele on SLE was not clear in Caucasians. CONCLUSIONS: The 196R allele of the functional M196R polymorphism of TNF-RII is a risk factor for SLE, especially in the Asian population.     

Missense polymorphisms within IL-10R1 exons are not associated with systemic lupus erythematosus in Chinese

Objective: Studies have suggested that interleukin-10 receptor1 (IL-10R1) is involved in genetic susceptibility to systemic lupus erythematosus (SLE) in animal models and Caucasians. Therefore, the current study was designed to determine whether the IL-10R1 gene plays a role in the pathogenesis of human SLE in the Chinese Han population. Methods: The seven exons of the IL-10R1 gene were amplified and sequenced using a BigDye Terminator v1.1 Cycle Sequencing kit and an ABI 3100 DNA Analyzer. A missense single nucleotide polymorphism (SNP) locus with a minor allele frequency of at least 0.1 was chosen to evaluate the correlation with the incidence of SLE. Results: Seven SNPs were found to reside in the exons of the IL-10R1 gene. Among the SNPs, A744G was evaluated for a correlation with the incidence of SLE because A744G was the only missense SNP with a minor allele frequency of at least 0.1. There was no significant difference in the distribution of the A and G alleles between the SLE patient group and the healthy control group (P?=?0.693). Furthermore, the genotype frequencies of A744A, A744G and G744G did not differ significantly between the two groups (P?=?0.906). Conclusion: In the Chinese Han population, missense SNPs within the exons of the IL-10R1 gene do not contribute to the development of SLE.     

Association between tumor necrosis factor receptor II and familial,but not sporadic,rheumatoid arthritis: evidence for genetic heterogeneity

OBJECTIVE: Tumor necrosis factor alpha (TNFalpha) binds the receptors TNFRI and TNFRII. Results of genome scans have suggested that TNFR2 is a candidate rheumatoid arthritis (RA) locus. A case-control study in a UK Caucasian population has shown an association between a TNFR2 genotype (196R/R in exon 6) and familial, but not sporadic, RA. The present study was undertaken to test this association in the French Caucasian population. METHODS: To test for an association in sporadic RA, 100 families were genotyped for the 196M/R polymorphism and analyzed using the transmission disequilibrium test and haplotype relative risk. To test for an association in familial RA, RA index cases from 100 affected sibpair (ASP) families were genotyped for 196M/R. Linkage analysis was performed with 3 TNFR2 microsatellite markers. RESULTS: The TNFR2 196R/R genotype was not associated with sporadic RA (odds ratio [OR] 0.59, P = 0.72), but was associated with familial RA (OR 4.0, P = 0.026). The association was most marked in the context of TNFR2 "twin-like" RA sibs (affected sibs sharing both TNFR2 haplotypes) (OR 9.2, P = 0.0017). Linkage analysis results were consistent with the association; most of the TNFR2 linkage evidence was found in the subgroup of families with 196R/R ASP index cases. CONCLUSION: This study is the first to replicate evidence of the involvement of TNFR2 in RA genetic heterogeneity. Our data refine the initial hypothesis, to suggest that a TNFR2 recessive factor, in linkage disequilibrium with the 196R allele, plays a major role in a subset of families with multiple cases of RA.     

A novel polymorphism of the human APRIL gene is associated with systemic lupus erythematosus

OBJECTIVE: We investigated the association of gene polymorphisms in APRIL, a new member of the TNF family, with systemic lupus erythematosus. METHODS: To detect polymorphisms of the human APRIL gene by exon-specific polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) analysis, we first determined the structure of the human APRIL gene. We designed exon-specific oligonucleotide primers according to the genomic DNA sequence of APRIL. All of the coding regions in exons of the APRIL gene were analysed by exon-specific PCR-SSCP in 148 SLE patients and 146 unaffected controls, then the nucleotide sequences of exons that displayed aberrant bands were determined. RESULTS: The human APRIL gene comprised at least six exons with five introns, spanning approximately 2.8 kilobases of the genomic DNA. By exon-specific PCR-SSCP, we identified two novel polymorphisms at codons 67 and 96. Both had amino acid substitutions: G67R and N96S respectively. Only the 67G allele was associated with SLE in 148 Japanese SLE patients, with allele frequency 0.662 compared with 0.575 for 146 unaffected controls (P=0.0302). The frequency of the individuals who possessed at least one 67G allele in SLE patients (91.9%) was significantly higher than that in the unaffected controls (80.1%) (P=0.0036). CONCLUSION: The 67G allele of APRIL may be a contributing factor in the pathogenesis of SLE.     

Association between paraoxonase-1 gene Q192R and L55M polymorphisms in systemic lupus erythematosus (SLE) and anti-phospholipid syndrome (APS) in a population from Cairo of Egypt

Paraoxonase-1 (PON1) is involved in the oxidative stress process that cause tissue damage observed in systemic lupus erythematosus (SLE) and anti-phospholipid syndrome (APS). The aim of the present study was to investigate the association of PON1 Q192R and L55M polymorphisms with risk of SLE and associated APS among Egyptian sample. The study included 120 SLE patients (45 without APS and 75 with APS) and 120 healthy subjects. PON1 Q192R and L55M polymorphisms were genotyped by real-time PCR. No significant differences in Q192R genotypes or allele frequencies were found between patients and controls (p = 0.5 and 0.1, respectively). The frequency of the 55M allele was significantly higher in SLE patients than in controls (66.6 vs. 43.3%), while the 55L allele was more frequent in controls (56.6%) than in patients (33.3%) (p = 0.03). The LL genotype was more frequent in controls (21.6%) than in patients (10%) while M allele carrier genotypes (LM + MM) were more frequent among patients (90%) than controls (78.3%), p = 0.04. Also, the 55M allele was more frequent in APS patients (73.3%) than in patients without APS (55.6%), p = 0.004. M allele carrier genotypes (LM + MM) was significantly higher among APS patients (95.4%) than in non-APS patients (80%), p = 0.008. Our results indicated that the PON1 L55M polymorphism associated with SLE and associated APS in a population from Cairo of Egypt, while the Q192R polymorphism plays no role in disease susceptibility. A large scale study to assess PON1 polymorphisms, PON1 activity, and markers of oxidative stress interaction is needed to clarify the role of PON-1 polymorphisms in the pathogenesis of SLE and associated APS.     

The PTPN22 C1858T polymorphism is associated with skewing of cytokine profiles toward high interferon-alpha activity and low tumor necrosis factor alpha levels in patients with lupus

OBJECTIVE: The C1858T polymorphism in PTPN22 has been associated with the risk of systemic lupus erythematosus (SLE) as well as multiple other autoimmune diseases. We have previously shown that high serum interferon-alpha (IFNalpha) activity is a heritable risk factor for SLE. The aim of this study was to determine whether the PTPN22 risk variant may shift serum cytokine profiles to higher IFNalpha activity, resulting in risk of disease. METHODS: IFNalpha was measured in 143 patients with SLE, using a functional reporter cell assay, and tumor necrosis factor alpha (TNFalpha) was measured by enzyme-linked immunosorbent assay. The rs2476601 single-nucleotide polymorphism in PTPN22 (C1858T) was genotyped in the same patients. Patients were grouped, using a clustering algorithm, into 4 cytokine groups (IFNalpha predominant, IFNalpha and TNFalpha correlated, TNFalpha predominant, and both IFNalpha and TNFalpha low). RESULTS: SLE patients carrying the risk allele of PTPN22 had higher serum IFNalpha activity than patients lacking the risk allele (P = 0.027). TNFalpha levels were lower in carriers of the risk allele (P = 0.030), and the risk allele was more common in patients in the IFNalpha-predominant and IFNalpha and TNFalpha-correlated groups as compared with patients in the TNFalpha-predominant and both IFNalpha and TNFalpha-low groups (P = 0.001). Twenty-five percent of male patients carried the risk allele, compared with 10% of female patients (P = 0.024); however, cytokine skewing was similar in both sexes. CONCLUSION: The autoimmune disease risk allele of PTPN22 is associated with skewing of serum cytokine profiles toward higher IFNalpha activity and lower TNFalpha levels in vivo in patients with SLE. This serum cytokine pattern may be relevant in other autoimmune diseases associated with the PTPN22 risk allele.     

Association of genotypes affecting the expression of interleukin-1beta or interleukin-1 receptor antagonist with osteoarthritis

OBJECTIVE: The majority of cytokines and growth factors known to be involved in cartilage metabolism are synthesized by the chondrocytes themselves. They are up-regulated in osteoarthritic (OA) cartilage, resulting in 2 opposite phenotypes, TNFalpha(high) and TNFalpha(low), that are characterized by an elevated number of tumor necrosis factor alpha (TNFalpha)-positive and interleukin-1beta (IL-1beta)-positive chondrocytes, respectively. To establish a hierarchy among the cytokines and growth factors expressed in articular chondrocytes, this study investigated cytokine genes for known polymorphisms that may contribute to the deregulated expression in OA cartilage. METHODS: Polymerase chain reaction techniques were performed either in a thermal cycler using standard methods or in a light cycler to analyze the frequencies of the TNFalpha (-308), IL-1 receptor antagonist (IL-1Ra) (intron 2), IL-1beta (exon 5), and IL-6 (-174) polymorphisms in 61 OA patients and 254 randomly chosen controls. RESULTS: For the TNFalpha(low) phenotype, a statistically significant association was found with the less frequent allele of IL-1beta, which carries a single-basepair substitution in exon 5 and may contribute to the characteristic increase in IL-beta-positive chondrocytes. In contrast, the TNFalpha(high) phenotype was significantly associated with the less frequent allele of IL-1Ra, which carries two 86-bp repeats in the second intron and is assumed to lead to an elevated expression of the antagonist. CONCLUSION: These results point to an association between the IL-1beta polymorphism and the TNFalpha(high) phenotype and between the IL-1Ra polymorphism and the TNFalpha(low) phenotype found in OA. Both associations suggest that IL-1beta may be more important than TNFalpha for the regulation of cytokine and growth factor expression in articular chondrocytes.     

The association between interleukin-6 polymorphisms and systemic lupus erythematosus: a meta-analysis

The aim of this study was to determine whether the functional interleukin-6 (IL-6) promoter -174 G/C and -572 G/C polymorphisms confer susceptibility to systemic lupus erythematosus (SLE) in ethnically different populations. Meta-analysis was conducted on the associations between the IL-6 polymorphisms and SLE using; 1) allele contrast, 2) the recessive model, 3) the dominant model, and 4) the additive model. A total of 11 studies were considered in this study, and ethnicity-specific meta-analysis was performed on European and Asian populations. Meta-analysis of the IL-6 -174 G/C polymorphism showed an association between SLE and the IL-6 -174 G allele in all study subjects (odds ratio (OR)?=?1.344, 95% confidence interval (CI)?=?1.052-1.718, p?=?0.018). Furthermore, stratification by ethnicity indicated an association between the IL-6 -174 G allele and SLE in Europeans (OR?=?1.264, 95% CI?=?1.037-1.541, p?=?0.020). Meta-analysis of the IL-6 -572 G/C polymorphism revealed that an association was found between SLE and the IL-6 -572 G/C polymorphism using the recessive model, but ethnicity-specific meta-analysis revealed no association between SLE and the IL-6 -572 G/C polymorphism in Asians. In conclusion, this meta-analysis demonstrates that the IL-6 -174 G/C polymorphism may confer susceptibility to SLE in Europeans, but that the IL-6 -572 G/C polymorphism is not associated with susceptibility to SLE in Asians.     

Neither IL-1beta, IL-1 receptor antagonist, nor TNF-alpha polymorphisms are associated with susceptibility to COPD

The cytokines that contribute to airway inflammation, including interleukin-1beta (IL-1beta) and tumour necrosis factor alpha (TNFalpha), might have key roles in the development of chronic obstructive pulmonary disease (COPD). Interleukin-1 receptor antagonist (IL-1RN), the physiological antagonist of IL-1beta, is also known to play a crucial role in several chronic inflammatory diseases. In this study, we investigated the association of the polymorphisms of IL-1beta, IL-1RN and TNFalpha with susceptibility to COPD. To elucidate the genotype of the IL-1beta polymorphisms at position -511 base and at the amino acid residue 105, the IL-1RN polymorphism in intron 2, and TNFalpha polymorphism at position -308, polymerase chain reaction (PCR) and restriction enzyme fragment length polymorphism (RFLP) were performed on blood samples from both patients with COPD (n = 53) and control subjects (n = 65). There were no differences on the allele and genotype frequency of IL-1beta, IL-1RN, and TNFalpha between the two groups. We could not find a significant link between the polymorphism of TNFalpha, which was previously reported to be associated with chronic bronchitis, and COPD. Furthermore, no association between genetic polymorphisms of IL-1beta and IL-1RN and individual susceptibility to COPD was found.     

Cytokine gene polymorphisms in Turkish patients with inflammatory bowel disease

OBJECTIVE: Crohn's disease (CD) and ulcerative colitis (UC) are chronic inflammatory diseases of the bowel, the causes of which are not fully known. Ethnic differences in disease prevalence, familial aggregation of the disease and studies of twins provide the most important evidence to suggest that genetic factors play a role in the pathogenesis of inflammatory bowel disease (IBD). The aim of this study was to examine the allelic polymorphisms that can determine the immune response levels in tumor necrosis factor alpha (TNFalpha), interleukin-1beta (IL-1B), interleukin-1 receptor antagonist ( IL-1RN) and interleukin-10 (IL-10) genes and to investigate their roles in the inflammatory pathway in IBD. MATERIAL AND METHODS: The study included 120 patients with UC and 70 patients with CD who were diagnosed either endoscopically or histopathologically. The control group comprised 105 healthy individuals who stated that they had never had any bowel disease during their life span. The polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method for polymorphisms in the TNFalpha gene at positions -308 and -238, the IL-10 gene at positions -1082 and -627, the IL-1B gene at -511 regions and the variable number of tandem repeat (VNTR) method for polymorphism in the intron 2 of the IL-1RN gene were performed. The results were analyzed on agarose gel electrophoresis. RESULTS: No significant differences were found in the allele and genotype frequencies of the polymorphisms in the IL-1B, IL10, TNFalpha and IL-1RN genes between the patients with UC and CD and controls. CONCLUSIONS: The results suggest that these polymorphisms were not important risk factors in the susceptibility to IBD in Turkish patients.     

Can tumor necrosis factor receptor II gene 676T>G polymorphism predict the response grading to anti-TNFα therapy in rheumatoid arthritis?

In this study we analyzed whether the polymorphisms 676T>G in the tumor necrosis factor receptor (TNFR) II gene and -308G>A in the TNFalpha promoter gene may influence the response grading to anti-TNFalpha therapy in rheumatoid arthritis. We enrolled and genotyped 105 RA patients treated with etanercept (n = 55), infliximab (n = 40) and adalimumab (n = 10) for 1 year. The clinical response was evaluated according to the ACR criteria every 3 months. Patients with TNFRII 676TG genotype was significantly associated with lower ACR response compared with 676TT genotype, at 3 (OR 3.78 95% CI 1.07-13.31) and 12 months (OR 4.30 95% CI 1.16-15.99) of treatment. No significant association between TNFalpha -308G>A polymorphism and the clinical response was found. TNFRII 676TG genotype is associated with a lower response to anti-TNFalpha therapy, independently from the specific agent used. This polymorphism could become a useful genetic marker for predicting the different response grading to anti-TNFalpha therapy.     

Interleukin-10 promoter microsatellite polymorphisms in systemic lupus erythematosus: association with the anti-Sm immune response

OBJECTIVES: Overproduction of interleukin-10 (IL-10) is a pivotal feature in the pathophysiology of systemic lupus erythematosus (SLE). In vitro IL-10 secretion has previously been related to haplotypes of the IL-10 promoter microsatellite polymorphisms IL10.R and IL10.G. Published data concerning the association of IL10.G alleles with susceptibility to SLE are inconsistent in different ethnic populations. We analysed the association of IL-10 promoter microsatellite polymorphisms with disease susceptibility and manifestations in German Caucasian patients with SLE. METHODS: Two hundred and ten (210) SLE patients fulfilling the 1997 revised ACR criteria and 158 ethnically, age- and sex-matched healthy controls were genotyped for the IL-10 promoter microsatellite polymorphisms by fragment length analysis. Haplotypes were reconstructed using a Bayesian coalescent theory-based method with PHASE software. Allele and haplotype distributions were compared between patients and controls and between subgroups of patients with different clinical and immunopathological findings. RESULTS: In the study population no significant associations of individual IL10.R and G alleles or their haplotypes with susceptibility to SLE or major clinical manifestations were observed. By contrast, alleles G14 and G15 and haplotypes R2-G14 and R2-G15 were significantly over-represented in anti-Sm antibody-positive patients. CONCLUSIONS: The IL-10 promoter microsatellite polymorphisms and their haplotypes do not constitute a major risk factor for SLE in German Caucasians. However, the identification of genetic markers such as the IL-10 high-response haplotype R2-G14 predisposing for the production of anti-Sm antibodies may help to elucidate the conditions that lead to the development of SLE.     

Association between rheumatoid arthritis and polymorphism of tumor necrosis factor receptor II, but not tumor necrosis factor receptor I, in Caucasians

OBJECTIVE: Tumor necrosis factor (TNF) is a powerful mediator of inflammation in rheumatoid arthritis (RA). In vivo, its acute effects are limited by binding to soluble receptors (TNFR), suggesting that TNFR genes could be important candidate risk factors. The present study was undertaken to investigate association of polymorphisms of TNFRI and TNFRII with RA in subjects in the UK. METHODS: Unrelated Caucasian RA patients (n = 291) and healthy Caucasian controls (n = 143) were genotyped for A/G polymorphism in exon 1 of TNFRI. From this sample, 240 of the patients and 137 controls were also typed for a single-nucleotide polymorphism (SNP) in exon 6 of the TNFRII gene. In followup studies, DNA samples from UK Caucasian RA patients with a positive family history (n = 149) and UK Caucasian patients with sporadic RA (n = 208) were also typed for the exon 6 TNFRII polymorphism. RESULTS: TNFRI polymorphism was not associated with RA (odds ratio [OR] for GG genotype 0.93, 95% confidence interval [95% CI] 0.54-1.60). For TNFRII, in the initial study group, patients with RA were significantly more likely to be positive for both the G allele and GG genotype than were controls (OR for GG genotype 2.55, 95% CI 1.11-5.86). The association appeared to be confined to those with a family history of RA. This finding was replicated in an independent cohort of patients with familial RA. CONCLUSION: The results of this study provide evidence of association between an SNP in the TNFRII gene and RA, the strongest association being observed in patients with a family history. No evidence of association between RA and TNFRI was demonstrated.     

Physical function and its response to exercise: associations with cytokine gene variation in older adults with knee osteoarthritis

BACKGROUND: We determined whether physical function and its response to exercise training are associated with polymorphisms in cytokine genes (interleukin-6 [IL-6] -174 G/C; tumor necrosis factor alpha [TNFalpha] -308 G/A and -238 G/A; and TNFalpha receptors [TNFR]1 +36 A/G, TNFR2 +676 T/G, and TNFR2 +1663 A/G), in 214 older (> or =60 years), overweight (body mass index > or =28 kg/m(2)) individuals with knee osteoarthritis. METHODS: Physical function (walking distance, stair-climb time, self-reported disability) was measured before and after an 18-month randomized, controlled exercise trial involving walking and weight lifting 3 days/week. RESULTS: In cross-sectional analyses, baseline walking distance was greater in individuals homozygous for the major G allele at IL-6 -174 compared to individuals with at least one C allele (p = .05). Both walking distance (p =.02) and stair-climb time (p = .003) were better in individuals homozygous for the major G allele of the TNFalpha -308 polymorphism compared to those with at least one A allele. Walking distance was better (p = .02), and stair-climb time tended to be better (p = .06), in individuals homozygous for the major T allele of the TNFR2 +676 polymorphism. No associations were seen with self-reported physical disability nor with the other polymorphisms. In response to exercise, there was a significant interaction between TNFalpha -308 genotype and exercise treatment on 6-month changes in stair-climb time (p = .007), and on 18-month changes in self-reported physical disability (p = .01), such that individuals with an A allele showed greater improvement in response to exercise. CONCLUSIONS: Walking distance and stair climbing speed are partly influenced by genetic variation in the IL-6 and TNFalpha genes in older individuals with knee osteoarthritis.