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.     

Comparison of clinical features in HLA-B27 positive and negative patients with ankylosing spondylitis

The clinical features of ankylosing spondylitis (AS) were compared in 63 HLA-B 27 positive (+) and 15 B27 negative (-) individuals with this disease. There were no differences in age at onset, functional class, degree of deformity, pain, severity of X-ray changes, or frequency of peripheral joint involvement or of reconstructive orthopedic surgery. These data demonstrated that skeletal manifestations of AS were essentially the same in B27(+) and (-) patients, and provide no evidence for the speculation that AS in B27(-) patients is milder or is a different disease from that occurring in B27(+) patients. On the other hand, acute anterior uveitis was found to be significantly more common in B27(+) patients, a fact suggesting that the "uveitis of AS" may in fact be an independent condition occurring in B27(+) individuals, rather than a manifestation of AS per se.     

Age at disease onset and diagnosis delay in HLA-B27 negative vs. positive patients with ankylosing spondylitis

OBJECTIVE: To investigate differences between HLA-B27(-) and HLA-B27(+) patients with ankylosing spondylitis (AS). METHODS: A total of 1080 patients with AS responded to a questionnaire containing 30 questions; 945 (87.5%) knew their HLA-B27 status, 10% of them being B27(-). RESULTS: The average age at disease onset was 27.7 years in B27(-) and 24.8 years in B27(+) AS (P < 0.01). The average age at diagnosis was 39.1 and 33.2 years and the average diagnosis delay 11.4 and 8.5 years, respectively. The distribution in age at disease onset was significantly wider in B27(-) (standard deviation 10.0 years) than in B27(+) AS (8.3 years). The percentages with childhood (age < 16 years) disease onset did not differ significantly (7.6% vs. 6.2%, respectively), whereas the percentage of late onset (age > 40 years) was significantly greater among B27(-) (13%) than among B27(+) (5%) patients with AS. There is a difference in average age at disease onset between male (25.7 years) and female (24.2 years) AS patients, and no difference between patients with primary AS and AS associated with psoriasis, inflammatory bowel disease, or reactive arthritis. Acute anterior uveitis was significantly less frequent in B27(-) (26%) than in B27(+) (41%) patients with AS. CONCLUSIONS. This study of a much larger number of B27(-) AS patients than have been studied previously confirms earlier reports indicating a significantly older average age at disease onset and a less frequent prevalence of acute anterior uveitis in B27(-) than in B27(+) AS. The frequency of late disease onset (after 40 years of age) is significantly higher in B27(-) AS. We provide the first report on significant differences in the distribution curves for the age at disease onset and for the age at diagnosis between B27(-)and B27(+) patients with AS. The average delay between the first spondyloarthritic symptoms and the diagnosis is significantly longer in B27(-) than in B27(+) AS. The frequency of juvenile disease onset (before age 16 years) is nearly the same, irrespective of the B27 status.     

TNF-238A promoter polymorphism contributes to susceptibility to ankylosing spondylitis in HLA-B27 negative patients.

OBJECTIVE: To investigate the relative contribution of MHC loci in their susceptibility to primary ankylosing spondylitis (AS) in HLA-B27 negative patients and to compare the clinical features and genetic factors with those of HLA-B27 positive AS. METHODS: DNA from patients with B27 negative primary AS (n = 28), B27 positive primary AS (n = 77), and matched healthy controls (B27-, n = 100; B27+, n = 70) were analyzed to investigate whether HLA genes determine the disease susceptibility, or whether other closely linked loci might play a role in disease development. HLA typing was carried out by serology and PCR/SSP (HLA-B, -DR), MICA-TM polymorphism in the transmembrane region by radioactive PCR, and tumor necrosis factor-alpha (TNF-alpha) promoter polymorphism at positions -238 and -308 by PCR-RFLP. RESULTS: Subtle clinical differences were found for primary AS, the B27 negative patients being less frequently complicated by acute anterior uveitis and more associated with peripheral arthritis than B27 positive. Differences were found in the distribution of TNF-alpha -238 genotypes among patients with primary AS (B27- vs B27+). The TNF-alpha -238(A) polymorphism was present in 50% of the B27 negative patients carrying the -238 G/A and A/A genotypes and was significantly increased compared with B27 positive AS (odds ratio 4.3) and with the B27 negative control group (OR 5.9). The TNF-alpha genotypes were equally prevalent in B27 positive AS and healthy matched B27 positive controls. No significant HLA and MICA typing differences were found between the populations under study. CONCLUSION: Our results indicate that the polymorphism variation in the TNF-alpha promoter -238.2(A) influences disease susceptibility in B27 negative primary AS but had no effect in our B27 positive AS population.     

LMP2 polymorphism is associated with extraspinal disease in HLA-B27 negative Caucasian and Mexican Mestizo patients with ankylosing spondylitis

OBJECTIVE: To determine the effects of HLA Class II genes, particularly LMP2 and previously implicated Class I genes, on susceptibility and disease expression in HLA-B27 negative ankylosing spondylitis (AS). METHODS: Patients included 41 HLA-B27 negative Caucasians from a total AS population of 546 and 17 HLA-B27 negative Mexican Mestizo. Controls included 4352 random HLA-B27 negative Caucasians. LMP2 genotype assignments were made on all patients and 282 random Caucasian controls by polymerase chain reaction-restriction fragment length polymorphism with the Cfo I restriction enzyme while HLA typing was performed on patients and controls using microcytotoxicity assays for Class I, and sequence specific probe-PCR for HLA-B60, B39, B38, and DR. RESULTS: The LMP2BB genotype was significantly decreased in Caucasian AS patients without extraspinal (ES) disease (25%) compared to AS patients with ES (64.7%) (p = 0.01) and random Caucasian controls (53.9%) (p = 0.007), even when those with colitis and psoriasis were excluded from analysis (ES+ 55.6% versus ES- 22.2%). This finding remained significant after stratification by HLA-DR. Similar trends were noted in the Mexican population. A potential role for HLA-DR8 and DR2 in susceptibility to disease was observed in Caucasian patients, although this observation requires confirmation. We could not confirm reported associations with HLA-B60 or B39. Peripheral arthritis was significantly more commonly observed in those who had had acute anterior uveitis (AAU) (75%) than in those who had not developed AAU (27.3%) (p = 0.04). CONCLUSION: HLA Class II encoded genes may have effects on disease susceptibility and/or phenotype in HLA-B27 negative individuals similar to those noted in HLA-B27 positive AS. Eccentric and axial phenotypes of disease may be immunogenetically determined.     

Clinical features of ankylosing spondylitis may correlate with HLA-B27 polymorphism

The objective of this study is to investigate the relationship between clinical features of ankylosing spondylitis (AS) and HLA-B27 status or its subtypes. Clinical data and blood samples were collected with patients’ informed consent. Luminex liquid array combining polymerase chain reaction-sequence specific oligonucleotide probe was used to do the low-resolution HLA-B genotype typing. Polymerase chain reaction-sequence specific primer was applied to do the high resolution HLA-B27 typing. In 98 subjects, 93 were HLA-B27 positive, of which three subtypes were detected: B*2704 (n = 76), B*2705 (n = 12), and B*2715 (n = 5). The onset age for B27 negative and positive group was 28 ± 7.9 and 21.1 ± 6.2 years, respectively (χ² = −2.047, P = 0.041). The onset age for B*2704, B*2705 and B*2715 group was 20.45 ± 4.50, 26.67 ± 9.95 and 17.8 ± 11.12 years, respectively (χ² = 7.888, P = 0.019). No significant difference was found between B27 positive and negative group, or among three B27 subtypes groups for other clinical features. In conclusion, the clinical features of AS may be correlated with HLA-B27 status and its polymorphism.     

Cross-reacting HLA-B alleles as genetic markers of HLA-B27 negative ankylosing spondylitis

15 east Austrian patients (EUC) with HLA-B27-negative ankylosing spondylitis (AS) were tissue-typed for HLA-B-antigens. HLA-B-alleles of the B27-CREG (B7, B13, Bw22, B40) were found in 14/15 patients (= 93,3%; RR = 37,8; Chi2 = 23,21; p less than 0.05) of this group. We may postulate a common partial-antigen for AS, carried by HLA-alleles belonging to the B27-CREG. This partial-antigen may either react in a direct pathway with the unknown pathogenic agent of AS or represent a marker for the "disease-susceptibility genes" of AS.     

The risk of developing ankylosing spondylitis in HLA-B27 positive individuals

The present study was performed on 61 HLA-B27 positive first-degree relatives and 40 HLA-B27 negative relatives of 20 HLA-B27 positive probands with ankylosing spondylitis (AS). Of 24 HLA-B27 positive relatives 45 years or older, 21% had AS and 38% sacroiliitis. The HLA-B27 negative relatives did not have features of either disease. In the population study of 2,957 individuals 45 years or older, we found 5 cases of HLA-B27 positive sacroiliitis (according to the New York criteria) and 3 of these fulfilled the New York criteria for diagnosis of AS. In 2 of these 3 individuals, the diagnosis was made on clinical grounds. The pheno-type frequency of HLA-B27 in this population is 7.8%, or about 230 HLA-B27 positive individuals in this population sample. Since AS was found in only 3 individuals, 1.3% of the HLA-B27 positive individuals in the population at large have AS; therefore, our data show that among individuals 45 years or older, 21% of HLA-B27 positive relatives of HLA-B27 positive AS patients have AS as compared with 1.3% of the HLA-B27 positive individuals in the population at large. Thus, the risk for AS is 16 times greater in the HLA-B27 positive relatives compared with HLA-B27 positive individuals in the population at large. The discriminatory value of the New York criterion of history of pain or the presence of pain at the dorsolumbar junction or in the lumbar spine was analyzed in the population and family studies and was found to be too nonspecific.     

Ankylosing spondylitis and HLA-B27: restriction fragment length polymorphism and sequencing of an HLA-B27 allele from a patient with ankylosing spondylitis.

Two groups of patients with ankylosing spondylitis (AS) from England and Poland were examined for restriction fragment length polymorphisms (RFLPs) associated with the disease. No preferential association was found between the 9.2 kb PvuII fragment in HLA-B27 positive patients with AS compared with HLA-B27 healthy subjects as had been previously reported. In the English group, however, a 14 kb PvuII fragment was more common in HLA-B27 positive subjects with AS than in normal controls. Also 4.6 and 3.7 kb PvuII fragments were more prevalent in subjects without AS than in the group with AS, but these results were confined to the English group. Furthermore, the sequence of an HLA-B*2705 gene isolated from a patient with AS was examined, and no significant differences were found compared with the sequence isolated from a healthy subject. There do not seem to be significant genetic differences in the coding or in the regulatory region in HLA-B27 alleles, in subjects with or without AS.     

Is HLA-B27 the ankylosing spondylitis susceptibility gene?

We studied a family in which the mother and her son had primary ankylosing spondylitis (AS). The mother carried the HLA-B27 allele, but did not pass this to her son. It is possible that the son is a coincidental, sporadic, non-B27 patient with spondylitis and the presence of B27 in the mother is relevant to the disease. Alternatively, it is possible that B27 in the mother is coincidental and the non-B27 haplotype, inherited by the son, carries the disease susceptibility gene. The results would then support the hypothesis that the B27 antigen may not be the AS gene, but rather a marker for another closely linked AS gene.     

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.     

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).     

HLA-B27 positive ankylosing spondylitis and polyarteritis nodosa: a case report

Summary A35-year-old man, with positive HBV and HCV markers, showed clinical and histopathological features of polyarteritis nodosa (PAN), in the course of HLA-B27 positive ankylosing spondylitis (AS). The possible occurrence of both diseases in genetically susceptible subjects is discussed.Although the role of HBV surface antigen in the pathogenesis of PAN is well established, there is still a large proportion of PAN patients with no evidence of HBV infection. In the present case, the coexistence of HCV infection led us to speculate about a possible role of this virus in the pathogenesis of PAN.In our case we were able to verify the sensitivity of single photon emission computed tomography (SPECT) in the diagnosis and the clinical evaluation of the ischaemic cerebral lesions.     

HLA-B27 in possible ankylosing spondylitis with peripheral arthritis

Summary Among 86 patients selected as possibly having ankylosing spondylitis because of clinical symptoms and radiologically normal sacroiliac joints, HLA-B27 was positive in 41%. Four years later a representative sample of 38 individuals were re-examined and radiographed. HLA-B27 positive patients developed sacroiliitis as defined by radiological criteria twice as often (P<0.05). They also showed increased uptake of technetium 99 m upon quantitative scintigraphy with a region of interest method and more often probable or definite ankylosing spondylitis as defined by the New York criteria. Further differences between the HLA-B27 positive and negative follow-up groups concerned the frequency of clinical symptoms and peripheral arthritis. It is suggested that HLA-B27 typing may be helpful both in diagnosis and in judging the prognosis of possible or abortive ankylosing spondylitis.     

Whipple's disease and ankylosing spondylitis simultaneous occurrence in HLA-B27 positive male.

A 57 year old male had recurrent arthritis and uveitis for 34 years, spinal symptoms for 10 years, and malabsorption for four months leading to the diagnosis of ankylosing spondylitis and Whipple's disease. HLA-B27 was positive. Out of the four cases of Whipple's and ankylosing spondylitis in the literature, only one had been tested for HLA-B27 and was found to be negative.