Identification of previously unrecognized predisposing factors for ankylosing spondylitis from analysis of HLA–B27 extended haplotypes in sardinia

Objective

To define the contribution of HLA genes other than HLA–B27 in conferring susceptibility to ankylosing spondylitis (AS), through analysis of HLA–B27 haplotypes in Sardinian subjects.

Methods

Ninety‐eight patients with AS, 133 HLA–B27–positive controls (of whom 33 were positive for HLA–B*2709), and 190 randomly selected controls were genotyped for microsatellites and single‐nucleotide polymorphisms (SNPs) spanning the HLA region.

Results

Haplotypes carrying either the B*2705 or the B*2709 allele were found to share a conserved region downstream of the HLA–B gene and a functional polymorphism in the HLA–E gene (R128G), while differing in all other markers. Notably, the presence of an A at SNP rs1264457, encoding for Arg‐128, was significantly increased in the cohort of patients (P = 6 × 10⁻⁶, corrected P = 3 × 10⁻⁵) but not in B*2705‐ or B*2709‐positive controls. Comparing the alleles co‐occurring at each HLA marker, we identified a region differentiating patients with AS and B*2705‐matched controls. In particular, there was a markedly increased prevalence of heterozygosity at rs1264457 among B27‐positive controls (74%, versus 47% in patients and 54% in random controls), suggesting a protective role of G128 in AS. Moreover, other markers around the HLA–B gene were also differentially represented.

Conclusion

These results demonstrate a significant difference in the frequency of some HLA markers between AS patients and B*2705‐positive controls, which could be attributed to the opposite chromosome. In particular, the differential distribution of a functional polymorphism in the HLA–E gene suggests a possible role of natural killer function in AS pathogenesis.

     

Two distinctive HLA haplotypes harbor the B27 alleles negatively or positively associated with ankylosing spondylitis in Sardinia: implications for disease pathogenesis

OBJECTIVE: To compare haplotype distribution in HLA-B27-positive patients with ankylosing spondylitis (AS) and healthy control subjects possessing either AS-associated HLA-B27 alleles or the non-AS-associated HLA-B*2709 allele. METHODS: DNA samples from 47 HLA-B27-positive patients with AS and 76 HLA-B27-positive healthy controls (19 positive and 57 negative for B*2709) living in different areas of Sardinia were collected and typed for HLA class I and class II alleles. The third exon of the B27 gene was analyzed for the presence of Asp(116) or His(116), which differentiates B*2709 from the other two B27 subtypes (B*2705 and B*2702) that are mostly found in Sardinia. The parents of 6 subjects positive for B*2709 were also typed for HLA class I and class II alleles. Statistical analysis was performed by Fisher's exact test. RESULTS: In Sardinia, the B27 alleles conferring susceptibility to AS appear to be more frequently carried by a haplotype (A2;B27;Cw2;DR16) that reaches its highest frequency in patients with AS (A2 80.8%, B27 100%, Cw2 83%, and DR16 74.5%). Conversely, the non-AS-associated B*2709 allele is more frequently found together with other HLA alleles whose frequencies are inversely correlated with the disease (A32 or A30, Cw1, and DR12). Familial analysis of 6 subjects positive for HLA-B*2709 confirmed the existence of a "Sardinian" haplotype that is not associated with AS (A32;B*2709;Cw1;DR12). CONCLUSION: In Sardinia, 2 distinct haplotypes harbor the non-AS-associated HLA-B*2709 allele or the AS-associated B27 alleles. Our findings are compatible with the hypothesis that other genes within the HLA region besides HLA-B27 may play some role in conferring susceptibility to AS.     

HLA-B27 subtypes in Turkish patients with ankylosing spondylitis and healthy controls

The aim of this study was to determine human leukocyte antigen (HLA)-B27 subtypes frequency in ankylosing spondylitis (AS) and related spondyloartropathy (SpA) patients. Therefore, we investigated the differences in HLA-B27 subtypes between HLA-B27-positive patients and controls. Sixty six patients were included in this study (51 AS and 15 SpA). Thirty-five individuals were diagnosed with leukemia or chronic renal failure, and their donors without any rheumatological problem (no SpA history) were selected as the control group. HLA-B27 subtyping was performed by PCR-SSP (polymerase chain reaction with sequence-specific primer) method in serologically HLA-B27-positive 46 AS patients, 9 SpA patients and control group. When the frequency of HLA-B27 was 4.5% in Turkish population, this frequency was 90.2% in AS patients. Four different HLA-B27 subtypes found in AS patients were B*2705 (65.2%), B*2702 (26.1%), B*2704 (6.5%) and B*2707 (2.2%). In SpA patients, B*2705 and B*2702 found in equal frequency. Five B27 alleles were identified in our control group: B*2705 (54.3%), B*2702 (31.4) %, B*2703 (2.9%), B*2704 (2.9%) and B*2702/B*2705 (8.5%). Both in the patient group and in the control group, we also observed B*2705 as most frequent allele, and B*2702 was second common allele. Our results show that the frequency of HLA-B27 subtypes is not significantly different between patients and controls (P?>?0.10).     

MICA gene triplet repeat polymorphism in patients with HLA-B27 positive and negative ankylosing spondylitis from Sardinia

OBJECTIVE: We investigated the distribution of MICA triplet repeat polymorphism in a random population and in patients with seronegative spondyloarthritis from Sardinia compared to continental Italy. METHODS: We analyzed the distribution of MICA triplet repeat polymorphism in HLA-B*2709 [not associated with ankylosing spondylitis (AS)] and B*2705 (associated with AS) haplotypes, to verify whether the strong association of MICA-A4 with HLA-B27 reported in other populations is maintained in Sardinia, and compared the distribution of MICA-A alleles in HLA-B27 negative versus HLA-B27+ patients with AS. RESULTS: We found that the frequency of MICA-A4 triplet repeat allele in a random Sardinia population is higher (53.2%) than in other Caucasian populations (around 20%); this allele is strongly associated with both HLA-B*2709 and B*2705. No significant difference between HLA-B27+ patients with AS and healthy controls was found: the MICA-A4 allele was present in more than 90% of subjects. MICA-A4 was found in 16 out of 20 HLA-B27 negative Sardinian patients with AS, with a frequency (80%) more similar to that of the HLA-B27+ group of patients than that of controls. CONCLUSION: The high frequency of MICA-A4 allele in HLA-B27 negative patients with AS from Sardinia, suggests the presence within the HLA region of a susceptibility factor other and certainly weaker than B27. This factor is likely to be more easily found by analyzing genetically homogeneous populations like the Sardinian, characterized by a small number of very frequent haplotypes.     

Distribution of HLA-B27 and its alleles in patients with reactive arthritis and with ankylosing spondylitis in Tunisia

The purpose of the present study is to investigate the frequency of HLA-B27 and its alleles in reactive arthritis (ReA) and in ankylosing spondylitis (AS) in Tunisia. HLA-B27 alleles were typed by PCR amplification with sequence-specific primers. We studied 17 patients with ReA associated with urethritis or with gastrointestinal infection; 42 HLA-B27-positive patients with AS and 100 healthy controls. Eleven ReA patients (67.7%) were HLA-B27 positive. There was an increased frequencies of HLA-B27 (P = 7.76 × 10⁻¹², OR = 59.30) and a moderate increase of HLA-B51 (P = 0.015; OR = 4.91) alleles in ReA patients when compared with healthy controls. Four B27 subtypes were identified: B*2702, 05, 09 and B*2712. The distribution of these alleles in the ReA patients was 37.5% for B*2702 and B*2705. Only these two subtypes were detected in 18 (42.8%) and 24 (57.1%), respectively, of the AS patients. B*2709 and B*2712 were relatively rare in ReA patients and were identified in one case each. Our results showed a restricted number of HLA-B27 subtypes associated with ReA and AS. B*2702 and 2705 were common in ReA and AS patients.     

The association of HLA-B*27 subtypes with ankylosing spondylitis in Wuhan population of China

The aim of this study was to investigate the association of the B27 subtypes with ankylosing spondylitis (AS) in the Wuhan population of China. We selected 317 HLA-B27-positive individuals (145 controls and 172 patients with ankylosing spondylitis). The B27 subtypes were characterized using a PCR-SSP method. Six B27 subtypes were determined: B*2702, 03, 04, 05, 06 and B*13. HLA-B*2704 and HLA-B*2705 were the two high frequency genotypes in controls and patients. Compared with the controls, the AS patients had high frequency of B*2704 (patients 69.2% vs. controls 53.8%) and low frequency of B*2705 (patients 23.8% vs. controls 33.1%). B*2703 was detected in 10 (5.8%) patients and in 13 (8.9%) controls. B*2702, 06 and B*2713 were relatively rare. Our results show that the allele conferring risk to AS in the Wuhan population of China was B*2704 and B*2705. B*2704 is strongly associated with AS.     

Prevalence of HLA-B27 and subtypes of HLA-B27 associated with ankylosing spondylitis in Galicia, Spain

OBJECTIVE: To assess the prevalence of HLA-B27 and its subtypes in both the normal population and in patients with Ankylosing Spondylitis (AS) in Galicia, Northwest Spain. METHODS: The prevalence of HLA-B27 in the normal population was determined by checking the number of HLA-B27 positive samples in 308 subjects from different areas of Galicia who had donated organs over a period of 4 years. A total of 106 patients with the diagnosis of AS, according to the modified New York clinical criteria for definitive ankylosing spondylitis, were collected from three very representative areas of Galicia. HLA-B27 was determined by PCR using the primers E91s and E136as, while 11 subtypes of HLA-B27 were analyzed using a commercial kit. RESULTS: The prevalence of HLA-B27 in organ donors was 9.34%. HLA-B27 was present in 94.3% of patients with AS. Subtypes B*2701, B*2709 and B*2710 were not found. The subtypes found in the normal population were; B*2705 (79.5%), B*2702 (18%) and B*2708 (2.5%). The subtypes associated with AS were B*2705 (88%) and B*2702 (12%). CONCLUSION: The prevalence of HLA-B27 in Galicia was 9.34%, which is higher than previously published in Spain. The frequency of the subtypes associated with AS was similar to that reported for other Spanish regions.     

HLA class I associations of ankylosing spondylitis in the white population in the United Kingdom.

OBJECTIVE: To investigate the HLA class I associations of ankylosing spondylitis (AS) in the white population, with particular reference to HLA-B27 subtypes. METHODS: HLA-B27 and -B60 typing was performed in 284 white patients with AS. Allele frequencies of HLA-B27 and HLA-B60 from 5926 white bone marrow donors were used for comparison. HLA-B27 subtyping was performed by single strand conformation polymorphism (SSCP) in all HLA-B27 positive AS patients, and 154 HLA-B27 positive ethnically matched blood donors. RESULTS: The strong association of HLA-B27 and AS was confirmed (odds ratio (OR) 171, 95% confidence interval (CI) 135 to 218; p < 10(-99)). The association of HLA-B60 with AS was confirmed in HLA-B27 positive cases (OR 3.6, 95% CI 2.1 to 6.3; p < 5 x 10(-5)), and a similar association was demonstrated in HLA-B27 negative AS (OR 3.5, 95% CI 1.1 to 11.4; p < 0.05). No significant difference was observed in the frequencies of HLA-B27 allelic subtypes in patients and controls (HLA-B*2702, three of 172 patients v five of 154 controls; HLA-B*2705, 169 of 172 patients v 147 of 154 controls; HLA-B*2708, none of 172 patients v two of 154 controls), and no novel HLA-B27 alleles were detected. CONCLUSION: HLA-B27 and -B60 are associated with susceptibility to AS, but differences in HLA-B27 subtype do not affect susceptibility to AS in this white population.     

Etiopathogenic role of HLA‐B27 alleles in ankylosing spondylitis

HLA‐B27 is the major genetic susceptibility factor for ankylosing spondylitis (AS). However, its precise role in the pathogenesis of AS still remains unclear, even though its gene has been cloned and sequenced, and its crystallographic structure has been defined. Arthritogenic peptide and molecular mimicry hypotheses propose mechanisms related to an antigen‐presenting function of HLA‐B27 to be responsible for disease development. However, peculiar aspects of its immunobiology, such as its misfolding and heavy chain dimerization raise the possibility of involvement of pathogenic mechanisms unrelated to its physiological function. Moreover, HLA‐B27 is not a single allele, but a family of 31 different alleles, named HLA‐B*2701 to HLA‐B*2727. Studies worldwide indicate that the relatively common alleles (subtypes) HLA‐B*2705, B*2704, and B*2702 are strongly associated with AS, whereas HLA‐B*2706 which is prevalent in South‐east Asia and HLA‐B*2709 which is prevalent on the Italian island of Sardinia, seem to lack such an association. The distinction between the disease‐associated subtypes and those that are not associated, may provide clues to the actual role of HLA‐B27 in disease pathogenesis. B*2706 differs from B*2704 by only two residues, and B*2709 differs from B*2705 by only one residue. Moreover, both B*2706 and B*2709 bind an endogenous peptide (derived from vasoactive intestinal peptide type 1 receptor) and also an exogenous peptide (latent membrane protein 2 of Epstein‐Barr virus) but in two drastically diverse conformations. These recent X‐ray diffraction studies of individual peptides in the context of different HLA‐B27 alleles broaden our perception of the possible pathogenetic role of this molecule in the development of AS and related spondyloarthopathies. In summary, the pathogenetic role of HLA‐B27 in AS seem to be quite heterogenous, and cannot be explained by a single mechanism, and new ideas have been raised based on the aberrant immunobiologic features of HLA‐B27.     

Correlation of HLA B27 subtypes with clinical features of ankylosing spondylitis

Aim: The aim of the present study was to identify the B*27 subtypes associated with ankylosing spondylitis (AS) in our population and correlate them with clinical features of AS. Method: Whole blood samples were collected from 81 HLA‐B27 positive AS patients and 29 controls (asymptomatic healthy unrelated individuals) positive for HLA‐B27. Clinical details of the patients were recorded which included history of inflammatory back pain, sacroiliitis, spine involvement, enthesitis, peripheral arthritis and uveitis. HLA‐B27 subtypes were detected using commercially available techniques. Fisher’s exact test was used for statistical analysis. Results: The subtypes observed in AS patients were B*2705 (67.9%, 55/81), B*2704 (28.4%, 23/81), B*2707 (2/81) and B*2702 (1/81). Subtypes in the controls were B*2705 (62.07%, 18/29), B*2707 (27.59%, 8/29) and B*2704 (10.34%, 3/29). Uveitis was observed more in B*2704‐positive AS patients (34.78%, 8/23) compared to B*2705‐positive AS patients (16.36%, 9/55). However, the difference was not statistically significant (P = 0.130). No major differences were found between B*2705 and B*2704 for other clinical features. Conclusion: B*2705 was the main subtype observed in both patient and control groups. Frequency of B*2704 was more in AS patients compared to controls. Occurrence of AS‐associated uveitis was more often in B*2704‐positive AS patients compared to B*2705‐positive ones.     

Undifferentiated spondyloarthropathies in Brazilians: importance of HLA-B27 and the B7-CREG alleles in characterization and disease progression

OBJECTIVE: To analyze the profile of the HLA-B27 and B7 cross-reactive group (CREG) alleles and the role of these markers in disease characterization and progression in patients with undifferentiated spondyloarthropathies (uSpA). METHODS: A total of 80 patients with a diagnosis of uSpA (40 HLA-B27 positive and 40 HLA-B27 negative) were prospectively studied for 2 years. The control group consisted of 66 HLA-B27 positive and 112 HLA-B27 negative individuals without a history of seronegative SpA. HLA-B alleles were typed at low (B7-CREG alleles, i.e., B*7, B*54, B*55, B*56, B*40, B*42) or high resolution (B*27 alleles) using polymerase chain reaction-amplified DNA hybridized with sequence-specific oligonucleotide probes. RESULTS: HLA-B*2705 was the most frequent allele, observed in 92.5% of the patients and in 77% of the controls, followed by the HLA-B*2702, observed in 5% of the patients and in 12% of the controls. HLA-B*2704 was observed in only one patient (2.5%), and was absent in the control population. HLA-B*2703 (6%) and HLA-B*2707 (5%) alleles were observed only in controls. No associations between HLA-B*27 alleles or B7-CREG alleles and any specific manifestation of uSpA were observed. HLA-B27 positive patients more frequently presented juvenile onset SpA (p = 0.002) and progression to ankylosing spondylitis (AS) (p = 0.03) than did HLA-B27 negative patients. The B7-CREG alleles were observed in 5% of the HLA-B27 positive uSpA group, in 25% of the HLA-B27 negative uSpA group, in 7% of the HLA-B27 positive controls, and in 13% of the HLA-B27 negative controls; a significant association was observed between the presence of the B7-CREG and the HLA-B27 negative uSpA group (p = 0.012). CONCLUSION: The frequency of the HLA-B*2705 allele among the B27 positive uSpA patients of this series was closely similar to that reported for patients with ankylosing spondylitis (AS). The presence of HLA-B*27 alleles was associated with the progression to AS, and the presence of B7-CREG was associated with uSpA in the HLA-B27 negative group.     

Major histocompatibility genes and ankylosing spondylitis

The association of HLA-B27 with ankylosing spondylitis accounts for nearly 40% of the total disease risk. However, fewer than 5% of B27-positive individuals in the general population become affected. Genomewide scans suggest that other major histocompatibility complex genes further heighten this risk, although linkage disequilibrium with HLA-B27 has confounded their precise identification. Over 31 variants of HLA-B27 have been identified to date, which have evolved from the original B27 allele (B*2705) along three geographic lines. HLA-B*2705 and B*2702 are the primary subtypes in Caucasians with spondylitis, and B*2704 and B*2707 are the primary subtypes in Asians. HLA-B*2706 and B*2709 are not disease associated. There are four theories of how HLA-27 causes spondyloarthritis: (1) HLA-B27 presents a bacterially derived 'arthritogenic peptide' (not yet identified); (2) misfolding or homodimerization of HLA-B27 heavy chains results in a pro-inflammatory response; (3) HLA-B27-positive individuals have deficient intracellular killing of arthritogenic organisms; and (4) HLA-B27 itself, due to sequence homology with bacterial proteins, becomes autoantigenic.     

HLA-B27 polymorphism in Turkish patients with ankylosing spondylitis

The aim of this study was to determine the distribution of human leukocyte antigen (HLA)-B27 subtypes in serologically HLA-B27-positive ankylosing spondylitis (AS) patients and healthy controls from the Turkish population and to compare this with other reports from other populations. We subtyped HLA-B27 in 38 HLA-B27-positive Turkish patients with AS and 47 HLA-B27-positive healthy controls without AS by polymerase chain reaction with specific sequence primers (PCR-SSP). The results demonstrated that: B*2705 was the predominant subtype among both of the patients (71.1%) and controls (68.0%). B*2702 was observed in 26.3% and 32.0% of the patients and controls, respectively. B*2708 subtype was found in 2.6% of the patients but not among the control group. When the distribution of B27 subtypes in Turkish populations was compared with that in other populations, similar frequencies with the Caucasian–Europe groups were noted. However, this should be interpreted carefully because of the small number of individuals in our study.     

Association of ankylosing spondylitis with HLA-B*1403 in a West African population

OBJECTIVE: To investigate the contribution of HLA class I alleles in the susceptibility to primary ankylosing spondylitis (AS) in West African patients living in Togo. METHODS: A large epidemiologic analysis of 9,065 West African rheumatology patients living in Togo was performed in order to identify those who had AS. Eight Togolese patients with AS were identified. HLA was typed by polymerase chain reaction using sequence-specific oligonucleotide probes. DNA typing was also performed on a control population of 85 healthy subjects matched for ethnic background. RESULTS: A significant association between AS and B*14 was identified. This allele was found in 62.5% of the AS patients (odds ratio 69), but was carried by only 2% of the healthy controls. Analysis for B14 subtypes showed that B*1403 was the predominant allele in AS patients (odds ratio 171), and that this allele was absent in healthy controls. B27 was virtually absent, being observed in only 1 AS patient (B*2705). CONCLUSION: HLA-B*1403 shows the B27 "supertype" motif and may exert an effect on AS susceptibility according to the arthritogenic peptide model. The association of B*1403 with AS has not previously been reported in either population.     

HLA–B27 heavy chains distinguished by a micropolymorphism exhibit differential flexibility

Objective

Although the products of the HLA subtypes B*2705 and B*2709 differ only in residue 116 (Asp versus His) within their peptide‐binding grooves, they are differentially associated with inflammatory rheumatic diseases such as ankylosing spondylitis (AS): B*2705 occurs in AS patients, whereas B*2709 is only rarely encountered. The reasons for this distinct association are still unclear but could include subtype‐specific conformational and dynamic properties of these antigens. The present study was undertaken to investigate structural and dynamic differences between B*2705 and B*2709 and their possible relationship to subtype‐specific disease association.

Methods

The membrane‐distal segments of the B*2705 and B*2709 heavy chains were expressed in vitro and reconstituted together with β₂‐microglobulin and a peptide. HLA–B27 complexes loaded with 2 self peptides (TIS [RRLPIFSRL] and pVIPR [RRKWRRWHL]) and a sequence‐related viral peptide (pLMP2 [RRRWRRLTV]) were studied by isotope‐edited infrared spectroscopy to detect differences in their structure and flexibility at physiologic temperature.

Results

Our analyses revealed the existence of subtype‐specific conformational differences between the 2 HLA–B27 heavy chains at physiologic temperature, which are undetectable using x‐ray crystallography. Irrespective of the bound peptide, the heavy chain of the B*2705 complex exhibited higher conformational flexibility than the B*2709 heavy chain.

Conclusion

The present study demonstrates the existence of previously undetected systematic conformational and dynamic differences between the heavy chains of the 2 HLA–B27 subtypes. Since effector cell recognition of cells expressing HLA antigens is dependent on the dynamic properties of the interacting cell surface molecules, this HLA–B27 subtype–specific heavy chain flexibility could have a role in the distinct association of HLA–B27 subtypes with spondylarthritides.

     

中国汉族强直性脊柱炎患者人类白细胞抗原-B27多态性研究

目的 本研究拟利用最新的人类白细胞抗原(HLA)-B27亚型数据,调查中国汉族强直性脊柱炎(AS)患者HLA-B27及其亚型的分布情况.方法 从我院脊柱关节炎患者数据库中随机抽取100例AS患者.用luminex液态芯片,结合聚合酶链反应-序列特异性寡核苷酸探针(PCR-SSOP)技术对HLA-B位点作低分辨分型.HLA-B27阳性者进一步用聚合酶链反应-序列特异性引物(PCR-SSP)法做高分辨HLA-B27亚型检测.结果 经随机抽样纳入无关AS患者98例,其中HLA-B27阳性93例,阳性率94.9%,其中B*2704亚型76例(81.7%),B*2705亚型12例(12.9%),B*2715亚型5例(5.4%).与另外2篇文献报道的HLA-B27阳性汉族健康人群比较,没有一致的证据表明HLA-B27亚型分布在AS患者和健康人群中存在差异.但这2项汉族健康人群中的研究均未发现B*2715亚型.结论 中国汉族AS患者B27亚型以B*2704为主,其次是B*2705.B*2715作为一个频率极低的等位基因,本组病例中发现5例,提示B*2715与AS发病存在关联.     

Determination of HLA-B27 subtypes in Iranian patients with ankylosing spondylitis

The human leukocyte antigen-B27 is one of the class I molecules of the major histocompatibility complex which is strongly associated with ankylosing spondylitis (AS). The strength of the disease association with B27 varies markedly among racial and ethnic populations. It is an allele family, which constitutes about 31 subtypes, with a considerable geographic and ethnic difference in distribution. It is important to know whether certain subtypes show any preferential association with AS. Because there is no report regarding HLA-B27 subtypes in Iranian patients with AS, the main purpose of the present study was to assess the frequency of subtypes of human leukocyte antigen (HLA)-B27 in patients with ankylosing spondylitis in Iranian populationOne hundred and nineteen AS patients (82 HLA-B27 positive and 37 HLA-B27 negative) were selected for this study. HLA-B27 positive patients were screened by polymerase chain reaction amplification with sequence-specific primers (PCR-SSP) for B*27 subtyping.The results of present study revealed that only two subtypes were detected in Iranian patients, including B*2705 (52 patients, 63.4%) and B*2702 (30 patients, 36.6%). Our results showed a restricted number of HLA-B27 subtypes associated with AS in Iran and an elevated frequency of the B*2705 allele in these patients similar to other Euro-Caucasoid (Aryan) groups in the world.     

Does HLA‐B*2706 protect against ankylosing spondylitis? A meta‐analysis

The human leukocyte antigen (HLA)-B*2706 is a relatively rare subtype of HLA-B27. In contrast to most HLA-B27 subtypes, some studies have reported HLA-B*2706 to be protective against ankylosing spondylitis (AS). A systematic review and a meta-analysis of available studies was performed to investigate the association of HLA-B*2706 with AS. After literature review a random effect meta-analysis was performed. No studies were found comparing the frequency of HLA-B*2706 in AS patients and controls. Meta-analysis of seven studies using HLA-B27-positive AS patients and controls showed a protective effect of HLA-B*2706 on development of AS in HLA-B27 individuals (odds ratio = 0.128, 95% CI = 0.043-0.378, P < 0.001). The results of the meta-analysis of HLA-B*2706 in HLA-B27-positive patients and controls is preliminary evidence of a protective effect of HLA-B*2706 against AS in the population. There is a clear need for additional studies on HLA-B*2706 in AS. Due to the fact that HLA-B*2706 is more or less restricted to Southeast Asia, researchers in this part of the world may have an essential role in performing these studies.     

Distribution of HLA-B*27 Alleles in Pa-tients with Ankylosing Spondylitis in Iran

Background: HLA-B*27 is strongly associated with ankylosing spondylitis (AS). It represents a family of alleles that differ among ethnic groups. Objective: The aim of this study was to determine the distribution of HLA-B*27 alleles in AS patients and healthy controls in Isfahan (Iran). Methods: Sixty AS patients and 430 healthy blood donors were selected. All subjects were HLA-B*27 positive by flow cytometry. HLAB* 27 subtypes were determined by PCR-SSP. Results: Forty patients (66.7%) and 17 controls (3.95%) were HLA-B*27 positive. Subtypes detected by PCR-SSP were B*2705, B*2702, B*2704 and B*2707. One patient was B*2702/B*2710. No significant difference was found in the distribution of these alleles between AS patients and controls. Conclusion: Although Caucasian subtypes are predominant among Iranians, this population is characterized by a combination of both specific Caucasian and Oriental subtypes. However such results should be interpreted carefully because of the small sample size in our investigation and definitive conclusion awaits more ethnicgroup studies.     

Update: the twenty subtypes of HLA-B27

HLA-B27 is a serologic specificity that encompasses 20 different alleles-HLA-B*2701 to B*2720. These alleles are also called subtypes of HLA-B27, and they have evolved from the B*2705 subtype, mostly from changes in exons 2 and 3 (which encode the alpha 1 and alpha 2 domains of the peptide binding groove, respectively). Occurrence of ankylosing spondylitis (AS) or related spondyloarthropathy (SpA) has thus far been documented in subjects possessing any one of the first 10 subtypes. However, B*2706 in Southeast Asian and B*2709 in the Italian island population of Sardinia may have a relatively much weaker association with AS. The 10 most recent subtypes have not yet been studied for disease association. There may exist a hierarchical ranking, resulting, in part, from differences in other co-inherited genetic factors, or due to environmental factors; eg, B*2705 is clearly disease-associated throughout the world, but not among the West Africans of Senegal and Gambia. It is important to investigate whether certain subtypes show any preferential association with some of the clinical features or forms of AS and related SpA among the various ethnic/racial populations and geographic regions of the world. This may help to identify the polymorphic positions of HLA-B27 that may have a disease-predisposing role.