TAP1 and TAP2 polymorphism in HLA-B27-positive subpopulations: no allelic differences in ankylosing spondylitis and reactive arthritis

The polymorphic TAP1 and TAP2 genes encode subunits of the transporter that delivers peptides to the HLA class I molecules. Because the polymorphism of the TAP genes has been shown to affect peptide transport, it has been suggested that TAP genes are potential regulators of the immune response. We studied TAP1 and TAP2 polymorphism in two multifactorial HLAB27-associated diseases, ankylosing spondylitis (N = 30) and reactive arthritis (N = 30), in order to establish whether TAP genes are involved in the different pathogenesis of these diseases. Healthy HLA-B27-positive individuals (N = 55) were chosen as the primary controls and 93 individuals represented the random Finnish population as secondary controls. We found differences between the random and HLAB27-positive populations, thus suggesting that certain TAP alleles are prevalent in HLA-B27 haplotypes. No differences were found between the AS and ReA groups nor between either of them and the healthy HLA-B27-positive controls. Thus it seems unlikely that TAP polymorphism, at the level studied, has a dominant role in the pathogenesis of these diseases. However, a family study is needed in order to determine whether the same TAP complexes are carried by the same haplotypes in these diseases. Human Immunology 44, 236–242 (1995)     

Genetic association between TAP1 and TAP2 polymorphisms and ankylosing spondylitis: a systematic review and meta-analysis

Objectives

Ankylosing spondylitis (AS) is a chronic inflammatory joint disease. The transporter associated with antigen processing (TAP) has been identified to play an important role in immune response as well as the HLA-associated diseases. The aim of our meta-analysis was to investigate the contribution of TAP (TAP1 and TAP2) polymorphisms to the risk of AS.

Methods

Meta-analyses were performed between 2 polymorphisms in TAP1 (TAP1-333, -637) and 3 polymorphisms in TAP2 (TAP2-379, -565, and -665) and AS.

Results

The meta-analyses were involved with 6 studies with 415 cases and 659 controls. Significant association was found between TAP1-333Val, TAP1-637Gly, and TAP2-565Thr and AS compared with combined control group (TAP1-333Val: p = 0.009, OR = 1.40, 95% CI 1.09–1.80; TAP1-637Gly: p = 0.002, OR = 1.48, 95% CI 1.15–1.91; p = 0.03, OR = 1.38, 95% CI 1.04–1.84). Subgroup analysis shown that significant association was only found in AS when compared with HLA-B27-negative controls (TAP1-333Val: p = 0.004, OR = 1.53, 95% CI 1.14–2.06; TAP1-637Gly: p = 0.004, OR = 1.52, 95% CI 1.15–2.02; p = 0.02, OR = 1.56, 95% CI 1.09–2.24), but not in AS when compared with HLA-B27-positive controls (p > 0.05). Moreover, no significant associations were found between haplotypes in TAP1 and TAP2 in both the combined and the subgroup analyses (p > 0.05).

Conclusions

TAP1-333Val, TAP1-637Gly, and TAP2-565Thr were likely to be associated with AS.

     

Analysis of TAP1 and TAP2 polymorphism of mother-infant in Chinese patients with pre-eclampsia

To analyze the polymorphism of TAP gene and the shared rates of alleles between mothers and their infants inChinese patients with pre-eclampsia,TAP1 and TAP2 genotyping was performed by the amplification refractorymutation system-polymerase chain reaction(ARMS-PCR)in 42 patients,106 normal pregnant women,and theirneonates.The allelic frequency of TAP and the alleles shared in maternal-fetus were compared and analyzed in thetwo groups.Our results showed that,with totally eight alleles of TAP1 and TAP2 examined in the samples,nosignificant difference was found in allelic frequencies between pre-eclampsia group and control group,as well asbetween mothers and their neonates.Similar finding was obtained in the comparison with shared alleles.Inconclusion,our results do not support a role for the polymorphisms of TAP in the etiology of pre-eclampsia.Cellular & Molecular Immunology.2005;2(2):141-144.     

TAP polymorphism is not associated with ankylosing spondylitis and complications with acute anterior uveitis in HLA-B27-positive Japanese

Abstract: HLA-B27 is associated with the etiology of ankylosing spondylitis (AS) and acute anterior uveitis (AAU). Transporter associated with antigen processing (TAP) 1 and TAP2 polymorphism influences the range of peptide presented by HLA class I molecules. In this report, contribution of TAP polymorphism to the susceptibility to AS and AAU was studied in HLA-B27-positive Japanese individuals. Patients were classified into three groups: 16 AS patients, 14 AAU patients and 22 patients with both AS and AAU. Twelve HLA-B27-positive healthy individuals were included as a control. TAP polymorphism was detected by PCR-RFLP methods. Significant differences in frequencies of TAP1 alleles were not found between patient groups. None of the TAP2 frequencies showed increased or decreased frequencies compared with HLA-B27-positive healthy controls. In comparison with a random Japanese control, TAP2D allele frequency was significantly increased in the AAU group, but failed to reach a significant level in a group consisting of the AAU-only patients and the patients with both AS and AAU. All of the patient groups were noted to have a significantly increased prevalence of the TAP2H allele as compared to random controls; however, the higher frequency of this allele was detected in HLA-B27 healthy controls as well. These observations suggest a linkage disequilibrium between TAP2D, TAP2H and HLA-B27 in Japanese.     

HLA-B27 polymorphism in patients with juvenile and adult-onset ankylosing spondylitis in Southern China

Abstract
Distribution of B27 subtypes in juvenile and adult-onset ankylosing spondylitis (JAS and AAS) in Southern China was studied. A total of 505 patients belonged to Han population were included (145 JAS and 360 AAS patients), and 1368 healthy individuals were included as controls. Human leukocyte antigen (HLA)-B27 typing was performed by Luminex liquid array combining polymerase chain reaction-sequence specific oligonucleotide probe (PCR-SSOP) and/or serological method. HLA-B27 subtyping was performed by polymerase chain reaction-sequence specific primer (PCR-SSP). The sequence-based typing was performed for the B*2715 samples to verify the PCR-SSP results. HLA-B27 was presented in 453 of 505 patients (89.7%), compared with 74 of 1368 controls (5.41%). B*2704 subtype in AS group was significantly higher than controls and B*2705 subtype significantly lower. B*2715 and B*2702 were found in 1.32% and 0.66% of the B27-positive patients but none in controls, and there was no significant difference between either of them and controls. B27-positive patients were 134 (92.4%) in JAS group and 319 (88.6%) in AAS group. There was no significant difference for B27 subtypes distribution between JAS (B*2704, 05, 15) and AAS (B*2704, 05, 15, 02) groups. The frequency of B*2715 in two groups was 3 (2.24%) and 3 (0.94%), respectively. The onset age of three JAS patients carrying B*2715 was 5, 9 and 13 years old, respectively. Our results suggested that B*2704 was the predominant subtype in AS patients in Southern China. B*2715 was observed in AS group only and slightly more in JAS than in AAS, and the patients carrying this allele tended to have early onset, B*2715 may be disease-association subtype.     

ERAP1-ERAP2 haplotypes are associated with ankylosing spondylitis in Polish patients

The objective of this case-control study was to evaluate the role of four single-nucleotide polymorphisms in the ERAP1 (rs2287987, rs30187, rs27044) and ERAP2 (rs2248374) genes and their haplotypes in predicting the risk for ankylosing spondylitis (AS) on a well-defined Polish population. Our study confirmed the strong association between the HLA-B*27 allele and the disease. For all tested ERAP1 SNPs we found significant differences in the minor allele and genotype distribution between patients and controls. The strongest association with AS was observed for rs30187. The minor T allele and homozygous TT genotype of this SNP significantly increased disease risk (OR = 1.56, 95%CI = 1.22–1.99, p = 0.0004 and OR = 2.52, 95%CI = 1.50–4.25, p = 0.001, respectively). In the case of rs2287987, minor C allele exerted a protective effect (OR = 0.64, 95%CI = 0.46–0.88, p = 0.008). In contrast to ERAP1, we observed no effect of rs2248374 in ERAP2 on the disease. We also carried out ERAP1-ERAP2 haplotype analysis to demonstrate a possible association of both genes with AS. Results showed that the haplotype H4, containing ERAP1 SNPs associated with high enzymatic activity, together with the presence of ERAP2 expression, significantly increased the risk of AS (OR = 1.97, 95% CI = 1.21–3.21, p_corr = 0.048). By contrast, the haplotype H5 coding for low activity of ERAP1 and the lack of ERAP2 expression was strongly protective (OR = 0.41, 95% CI = 0.23–0.72, p_corr = 0.008).     

Allelic variation at the TAP 1 locus influences disease phenotype in HLA-B27 positive individuals with ankylosing spondylitis

Abstract: The objective was to determine the role of the TAP 1 gene in influencing the phenotype of disease in adult patients with ankylosing spondylitis (AS). The distribution of TAP 1 gene alleles was determined using the PCR RFLP method and restriction enzymes Bcl I and Ace I. The study population included 115 HLA-B27 positive patients with well-documented AS and 41 HLA-B27 positive normal controls. No significant difference in distribution of TAP 1 alleles was noted in comparisons of all AS patients with normal controls. However, AS patients with extraspinal disease were noted to have a significantly increased prevalence of the TAP 1B allele (17.0%) as compared to AS patients without extraspinal disease (2.9%) (P=0.005) or normal controls (1.9%) (P=0.005). Polymorphism at the TAP 1 locus may influence disease outcome in patients with AS.     

Polymorphism of TAP1 and TAP2 in Japanese patients with rheumatoid arthritis

Contribution of polymorphism of transporter associated with antigen processing 1 and 2 (TAP1 and 2) alleles to pathogenesis of Japanese rheumatoid arthritis (RA) was studied in 92 RA patients by PCR-RFLP. The allele frequency of TAP2A was slightly low (38.0%) and the frequencies of TAP2B and TAP2C were slightly high (39.7% and 17.9%) in RA, but these differences were not significant. These increases and decrease were due to the positive or negative associations with HLA-DRB1*0405. It was very likely that slight differences in TAP2A, TAP2B and TA2C in RA were secondary phenomenon reflecting an increase in HLA-DRB1*0405. The prevalence of TAP2E allele was low (3.3%, P <0.01, P_c=not significant) and not correlated with HLA-DRB1*0405.     

TAP1 and TAP2 gene polymorphisms in Korean patients with allergic rhinitis

Antigen peptides are actively transported across the endoplasmic reticulum by the transporters associated with antigen presentation (TAP). TAP genes polymorphism could influence the selection process that determines which antigen peptides play a role in the pathogenesis of allergic rhinitis. The aim of this study was to investigate the association of TAP genes polymorphism with allergic rhinitis. TAP1 and TAP2 genotyping were performed on 110 allergic rhinitis patients and 107 healthy controls. TAP1 polymorphic residues at codons 333 and 637, and TAP2 polymorphic residues at codons 379, 565, 651, and 665 were analyzed by the amplification refractory mutation system-polymerase chain reaction (ARMS-PCR). Analysis of TAP1 gene polymorphism demonstrated decreased frequencies of Ile/Val genotype at codon 333, Asp/Gly genotype at codon 637, and haplotype A and B in allergic rhinitis patients when compared to controls (p<0.05). However, there was no significant difference in the genotype, phenotype, or allele frequencies at four TAP2 codons between controls and allergic rhinitis patients. In conclusion, TAP1 gene polymorphism may be an important factor contributing to the genetic susceptibility in the development of allergic rhinitis in the Korean population.     

Early-onset ankylosing spondylitis is associated with a functional MICA polymorphism

Major histocompatibility complex (MHC) class I chain-related A (MICA) molecules deliver activating signals through the NKG2D receptor expressed on the surface of natural killer (NK), CD8alphabeta and gammadelta T cells, and the MICA gene is polymorphic. The recently described MICA amino acid substitution at position 129 (MICA-129) seems to affect its binding to NKG2D. We investigated whether this dimorphism (MICA-129met [methionine] and MICA-129val [valine]) is associated with susceptibility to ankylosing spondylitis (AS) in a cohort of Algerian patients stratified according to their HLAB27 status and the age of onset of the disease. DNA from 129 patients and 76 healthy individuals were analyzed to determine the HLA-B generic type as well as MICA-129 polymorphism. Statistical analysis revealed: (1) a weaker association between AS and HLA-B27 in Algerians than in that reported for European patients (63% versus 80-90%), suggesting a possible influence of other genetic/environmental determinants in the studied population and (2) an association between MICA-129 met/met genotype and juvenile AS (p = 0.02) independent of HLA-B27 status. These data suggest a potential role for a functionally relevant MICA gene polymorphism in autoimmune/inflammatory disease susceptibility.     

HLA-B27 polymorphism and worldwide susceptibility to ankylosing spondylitis

HLA-B27 is strongly associated to ankylosing spondylitis (AS) and represents a family of eleven B27 alleles (B*2701–11). Our aim was to analyze the distribution of B27 subtypes by PCR/SSOP and genomic sequencing in a large group of populations ( n =17). 711 B27-positive samples from Caucasoid, Asian, African, Amerindian and Polynesian populations were selected to ascertain transracial gene mapping of the B27 subtypes. 476 of these were AS patients, chosen to investigate the contribution of B27 alleles to AS susceptibility. Some significant new findings have arisen from this study: 1) B*2705 was the predominant subtype in circumpolar and subarctic areas. B*2702 was found to be practically restricted to Caucasian populations, showing a higher frequency in Middle-East (Jews) and North Africa (Arabs/Berbers) groups. 2) B*2703 appears associated with AS in Western Africans. This is of remarkable interest since it was suggested that B*2703 would be negatively disease-associated. 3) Although B*2706 appears negatively associated with AS in Thais, we identified two patients from northern China carrying it. This may be a reflection of a disease heterogeneity and could indicate that more than one pathogenic agent can be involved in AS. B*2709 has been recently described as negatively associated with AS in Sardinians. The molecular changes His 114Asp (B*2706) and Asp 116His (B*2709) could modify the genetic susceptibility to AS.     

TAP1 and TAP2 gene polymorphism in rheumatoid arthritis in a population in eastern France

The ‘transporter associated with antigen processing’ (TAP) gene products are involved in the processing of endogenous peptides that bind to class I molecules. Polymorphism within these genes could alter the level of the immune response, a phenomenon relevant to the development of autoimmune diseases. In this study, we examined the polymorphism of TAP1 and TAP2 genes in patients with rheumatoid arthritis (RA). TAP1 and TAP2 typing was performed for 138 Caucasian RA patients and 100 healthy controls, all originating from eastern France. TAP1 polymorphic residues at positions 333 and 637 and amino acid variants 379, 565, 651 and 665 in the TAP2 gene were found using amplification refractory mutation system–polymerase chain reaction (ARMS‐PCR). This method enabled us to determine four TAP1 alleles (TAP1A to TAP1D) and eight TAP2 alleles (TAP2A to TAP2H). All patients and controls had been HLA‐DRB1* genotyped. The polymorphic residues TAP1³³³ and TAP1⁶³⁷ did not show any difference in their distribution between patients and controls. Similar findings were obtained for TAP2³⁷⁹ and TAP2⁶⁶⁵. However, we found an increased frequency of Thr homozygosity and heterozygosity at position 565 in the TAP2 gene in RA patients (RA vs. controls: 25.3 vs. 14%; P = 0.032; OR = 2.09; CI = 1.01–4.38). Similarly, the prevalence of subjects who were homozygote and heterozygote for Cys⁶⁵¹ was increased in the RA group (RA vs. controls: 36.8 vs. 11%; P = 0.02). The dimorphic site TAP2⁵⁶⁵ defines TAP2D and TAP2E alleles, while the site at position 651 characterizes TAP2F. Thus, we found that TAP2D and TAP2E alleles were more prevalent in RA, but not significantly so (RA vs. controls: TAP2D: 10 vs. 3.6%; P = 0.24; TAP2E: 3.6 vs. 0%; P = 0.19). Similarly, the frequency of TAP2F was higher in RA patients (24.5%) than in controls (11.3%), but this was not significant after correction (P = 0.029; P_corr = 0.17). Finally, we found no linkage disequilibrium between DRB1* RA‐associated alleles and amino acid substitution Thr⁵⁶⁵ or TAP2D and TAP2E alleles, whereas Cys⁶⁵¹ (and TAP2F) was not independent of DRB1*04, a strongly RA‐associated allele. Finally, Thr at position 565 in the TAP2 gene was associated with manifestations of disease severity in only a few patients. Examination of TAP1 and TAP2 gene polymorphisms in RA patients revealed an association between a particular amino acid residue, namely Thr⁵⁶⁵ in the TAP2 gene, and RA. This association was found to be weak and did not seem to be a predictor for the severity of the disease.     

MCP-1 promoter polymorphism in Spanish patients with rheumatoid arthritis

To investigate the possible role of the polymorphism located in the regulatory region of monocyte chemoattractant protein-1 (MCP-1) gene in the susceptibility to rheumatoid arthritis (RA), a total of 141 Spanish RA patients and 194 controls, previously typed for human leukocyte antigen DRB1* (HLA-DRB1*), were genotyped for -2518 (A/G) MCP-1 gene polymorphism using polymerase chain reaction-restriction fragment length polymorphism. No association between -2518 (A/G) MCP-1 polymorphism and susceptibility to RA was found. Nevertheless, when patients and controls were stratified according to their HLA shared epitope (SE) status, a significant increase in the frequency of genotype GG was found among SE negative (SE-) patients with respect to both SE positive (SE+) patients and SE- controls (16% versus 4% in SE+ patients, pFisher=0.04, odds ratio [OR]=4.4, 95% confidence interval [95%CI]=1.03-21.48; and 4% in SE- controls, pFisher=0.02, OR=4.13, 95%CI=1.10-15.72). In conclusion, MCP-1 polymorphism is slightly associated with the susceptibility to RA in patients lacking the HLA SE.     

Association of TAP1 and TAP2 gene polymorphisms with systemic sclerosis in Korean patients

We sought to determine whether transporter associated with antigen processing (TAP) gene polymorphism is associated with susceptibility to systemic sclerosis (SSc). TAP1 and TAP2 gene polymorphisms were analyzed in 61 Korean patients with SSc and 100 ethnically matched healthy Koreans by polymerase chain reaction-restriction fragment length polymorphism. Human leukocyte antigen (HLA)-DRB1 genotyping data of the patients from our previous study was used for the assessment of independent role of TAP genes to SSc susceptibility. Patients were stratified according to anti-topoisomerase I (anti-topo I) antibody status and clinical subsets of diffuse and limited cutaneous SSc (dcSSc and lcSSc). TAP1 and TAP2 gene polymorphisms were associated with different subsets of SSc: TAP1*A/A genotype with anti-topo I-positive dcSSc (p = 0.01, p corrected = 0.04), TAP2*A1/C genotype with anti-topo I-positive lcSSc (p < 0.05), TAP2*Bky2 and *C alleles with anti-topo I-negative dcSSc (both p < 0.05), and TAP2*B/E genotype with anti-topo I-negative lcSSc (p = 0.004). Although TAP gene associations were generally weak, some associations (TAP2*A1/C, TAP2*C, and TAP2*B/E) with different subsets of SSc were independent of HLA-DR associations, revealing even stronger associations (TAP2*A1/C and TAP2*C) among individuals not possessing the risk HLA-DR alleles. These results suggest the possible role of TAP gene polymorphisms in the genetic susceptibility to SSc.     

强直性脊柱炎患者气道管理分析

目的分析强直性脊柱炎患者的气道管理。方法对2004年1月至2014年12月在北京协和医院因强直性脊柱炎行骨科手术的171名患者的气道管理资料进行回顾性分析。结果 96.5%患者选择全麻手术。Macintosh喉镜和Glidescope喉镜声门暴露Cromack分级Ⅲ-Ⅳ级分别占9.6%和6.6%。90.9%的患者首次插管成功。9例患者需要更换插管工具,并有2例出现困难通气。5例患者选择椎管内麻醉,其中1例因效果不佳而改为全身麻醉。结论强直性脊柱炎患者由于脊柱和关节受累,属于困难气道高危,术前应充分评估和准备,选择最佳麻醉方案,减少并发症的发生。     

Ultrasonographic evaluation of enthesitis in patients with ankylosing spondylitis

The aim of this study was to assess sensitivity and responsiveness of power Doppler ultrasound (PDUS) in detecting enthesitis for ankylosing spondylitis (AS) patients compared to clinical examinations. Twenty AS patients initiating etanerceptunderwent clinical and PDUS examinations of six bilateral entheseal sites at baseline and after 1, 2 and 3 months of treatment. Clinical and PDUS examinations identified at least one entheseal lesion in nine (45%) and 19 (95%) patients, respectively. Furthermore, of 240 entheseal sites examined in these 20 patients, PDUS detected 123 entheseal lesions (51.3% of sites), compared with only 47 entheseal lesions (19.6%) detected by clinical examination (P < 0.05). The entheseal lesions found on PDUS were most commonly identified by calcification (33.3%), tendon edema (29.2%), abnormal blood flow (25.8%), a thickened tendon (22.1%), cortical irregularity (12.9%), bony erosions (9.6%) and bursitis at the tendon insertion to the bone cortex (7.1%). Improvements in clinical symptoms and laboratory parameters, and significant decreases in PDUS scores were observed following treatment with etanercept. Improvements in PDUS scores continued during follow-up in patients who entered remission following treatment. In conclusion, PDUS improve detection of structural and inflammatory abnormalities of the enthesis in AS compared to physical examination. In addition, PDUS may be useful inascertaining medications.     

HLA-B27 subtypes in chinese patients with ankylosing spondylitis

The HLA-B27 allele has been extensively studied due to its strong association with ankylosing spondylitis (AS). In order to identify B27 alleles in Chinese patients with AS from the Shanghai area, we joined the AHS#5 of the 12 IHW and total of 68 B27 positive patients and 7 B27 positive normal persons have been investigated using polymerase chain reaction and Dig-ddTUP labeled oligonucleotides. Three primer pairs, E403 and E90as, E91As and E136as, E91Bs and E18as, were used to amplify codons 40-90 of HLA-B related alleles, codon 91 to 136 of HLA-B^*2701-B^*2706 and B^*2708 and codons 91-180 of B^*2707. A total of 11 probes were used to distinguish 8 B^*27 alleles from B^*2701 to B^*2708. 68 AS patients contain 69 B27 alleles because one patient is heterozygous B^*2704/B^*2705. A total of 4 alleles of B^*27 were detected in the AS-patient group. B^*2704 is the most common B^*27 allele in both AS patients and controls with similar frequency, 76.8% and 71.4%, respectively. We found a high proportion of B^*2705 in both AS patient (20.3%) and control (28.6%) groups. Although the control group is quite small we are still able to deduce that B^*2704 and probably also B^*2705 seem to be associated with AS in Shanghai area patients We also found one AS allele typed as B^*2707. Interestingly, for the first time we detected B^*2706 in an AS patient, which would argue against a protective effect of B^*2706 on AS susceptibility in Shanghai Chinese. The conclusion from this study is that the distribution of B^*27 alleles is not significantly different between AS patients and controls. Expanded numbers of AS patients and especially of healthy controls in different ethnic groups will be necessary to assess the contribution of different B27 subtypes to AS susceptibility.     

TAP1 and TAP2 gene polymorphism in rheumatoid arthritis in a population in eastern France.

The 'transporter associated with antigen processing' (TAP) gene products are involved in the processing of endogenous peptides that bind to class I molecules. Polymorphism within these genes could alter the level of the immune response, a phenomenon relevant to the development of autoimmune diseases. In this study, we examined the polymorphism of TAP1 and TAP2 genes in patients with rheumatoid arthritis (RA). TAP1 and TAP2 typing was performed for 138 Caucasian RA patients and 100 healthy controls, all originating from eastern France. TAP1 polymorphic residues at positions 333 and 637 and amino acid variants 379, 565, 651 and 665 in the TAP2 gene were found using amplification refractory mutation system-polymerase chain reaction (ARMS-PCR). This method enabled us to determine four TAP1 alleles (TAP1A to TAP1D) and eight TAP2 alleles (TAP2A to TAP2H). All patients and controls had been HLA-DRB1* genotyped. The polymorphic residues TAP1333 and TAP1637 did not show any difference in their distribution between patients and controls. Similar findings were obtained for TAP2379 and TAP2665. However, we found an increased frequency of Thr homozygosity and heterozygosity at position 565 in the TAP2 gene in RA patients (RA vs. controls: 25.3 vs. 14%; P = 0.032; OR = 2.09; CI = 1.01-4.38). Similarly, the prevalence of subjects who were homozygote and heterozygote for Cys651 was increased in the RA group (RA vs. controls: 36.8 vs. 11%; P = 0.02). The dimorphic site TAP2565 defines TAP2D and TAP2E alleles, while the site at position 651 characterizes TAP2F. Thus, we found that TAP2D and TAP2E alleles were more prevalent in RA, but not significantly so (RA vs. controls: TAP2D: 10 vs. 3.6%; P = 0.24; TAP2E: 3.6 vs. 0%; P = 0.19). Similarly, the frequency of TAP2F was higher in RA patients (24.5%) than in controls (11.3%), but this was not significant after correction (P = 0.029; Pcorr = 0.17). Finally, we found no linkage disequilibrium between DRB1* RA-associated alleles and amino acid substitution Thr565 or TAP2D and TAP2E alleles, whereas Cys651 (and TAP2F) was not independent of DRB1*04, a strongly RA-associated allele. Finally, Thr at position 565 in the TAP2 gene was associated with manifestations of disease severity in only a few patients. Examination of TAP1 and TAP2 gene polymorphisms in RA patients revealed an association between a particular amino acid residue, namely Thr565 in the TAP2 gene, and RA. This association was found to be weak and did not seem to be a predictor for the severity of the disease.