The impact of HLA-A and -DRB1 on age at onset, disease course and severity in Scandinavian multiple sclerosis patients

The human leucocyte antigen (HLA) class II haplotype DRB1*15–DQB1*06 (DR15–DQ6) is associated with susceptibility to multiple sclerosis (MS), and HLA class I associations in MS have also been reported. However, the influence of HLA class I and II alleles on clinical phenotypes in MS has not yet been completely studied. This study aimed at evaluating the impact of HLA-A and -DRB1 alleles on clinical variables in Scandinavian MS patients. The correlation between HLA-A or -DRB1 alleles and age at onset, disease course and Multiple Sclerosis Severity Score (MSSS) were studied in 1457 Norwegian and Swedish MS patients by regression analyses and Kruskal–Wallis rank sum test. Presence of HLA-DRB1*15 was correlated with younger age at onset of disease (corrected P  = 0.009). No correlation was found between HLA-A and the variables studied. This study analysed the effect of HLA-A on clinical variables in a large Scandinavian sample set, but could not identify any significant contribution from HLA-A on the clinical phenotype in MS. However, associations between HLA-DRB1*15 and age at onset of MS were reproduced in this extended Scandinavian MS cohort.     

HLA-DRB1基因型与北方汉族多发性硬化易感性的研究

目的 探讨人类白细胞抗原(HLA)-DRB1基因型与中国北方汉族多发性硬化(MS)的关联.方法 应用序列特异性引物-聚合酶链反应(PCR-SSP)技术检测58例中国北方汉族MS患者及63名健康对照者的HLA-DRB1基因型分布;同时将MS患者分为西方型MS和视神经脊髓炎(NMO)两亚组,对其DR4和DR15基因频率进行比较.结果 与对照组比较,MS患者DR15和DR4等位基因频率显著升高(分别为P=0.025,P=0.003);此外,NMO亚组DR4频率显著高于西方型MS(P=0.013).结论 我国北方汉族人MS与HLA-DRB1等位基因的关联与西方人群有所不同,DR15可能是MS的易感基因,而DR4则可能为我国汉族人NMO的易感基因.关联基因的差异可能是导致东西方MS病变部位不同的原因.     

HLA-DRB1 and multiple sclerosis in Argentina

Background:  The association of multiple sclerosis (MS) with HLA DR subtypes, and particularly human leukocyte antigen (HLA)-DRB1*15 has been a consistent finding across nearly all Caucasian MS populations. In South America, scarce data exist about this issue. As the complete characterization of the HLA association range around the world is important to understand the role of this locus in MS susceptibility, we analyzed the frequency of HLA-DRB1* allelic groups in an MS population in Argentina.
Methods:  HLA-DRB1 locus was genotyped using PCR and sequence-specific primer amplification in 61 MS patients born in Buenos Aires, Argentina and 1216 healthy controls. Allele frequencies were compared between groups.
Results:  The HLA-DRB1*15 allele frequency significantly differed between controls and patients (13.5% and 33.9% respectively, P  < 0.001, OR 2.51, 95% CI: 1.7–3.0). The other allele frequencies did not show significant differences between patients and controls.
Conclusions:  The present HLA class II population study is in accordance with other Caucasian MS surveys which have found that HLA-DRB1*15 allele is strongly associated with MS disease. In Argentina, this is the first study performed to analyze the association of HLA-DRB1*15 and MS susceptibility in a Caucasian population and therefore contributes with new data to the immunogenomic global MS map.     

人类白细胞抗原DRB1基因与多发性硬化遗传易患性研究

目的　分析多发性硬化遗传易患的分子免疫遗传背景。方法　采用聚合酶链反应序列特异性引物（ＰＣＲＳＳＰ） 联合技术对４５ 例病例组和１０５ 例正常对照组人类白细胞抗原ＤＲＢ１ 基因（ＨＬＡＤＲＢ１） 进行基因分型。结果　病例组ＨＬＡＤＲ２ 基因频率高于正常对照组，优势比为３．３２１ ，有统计学意义（ Ｐ＜ ０．０１）。结论　ＨＬＡＤＲ２ 基因与多发性硬化遗传易患相关联，提示可能还存在保护性基因。     

The role of HLA-DRB1 alleles on susceptibility and outcome of a Portuguese Multiple Sclerosis population

BACKGROUND: The association between susceptibility to multiple sclerosis (MS) and HLA-DRB1*15 has been reported in various European populations. OBJECTIVE: To investigate the relationship between MS, HLA-DRB1*15 and other DRB1 alleles in a Portuguese population and their association with clinical course of MS. METHODS: The HLA-DRB1 alleles were analyzed by PCR-SSP in 248 MS patients and 282 healthy controls. In order to relate HLA-DRB1 alleles to disease aggressiveness, patients with relapsing remitting MS and secondary progressive MS were subdivided into 3 groups: 'benign' MS patients who maintain an Extended Disability Status Scale (EDSS) score of 3 after the same period and 'aggressive' MS those with EDSS>or=6 within 15 years of disease onset. RESULTS: As expected, a higher frequency of HLA-DRB1*15 was found in MS patients (29.8% vs 19.9%, odds ratio (OR)=1.72, 95% CI=1.15-2.56, p=0.008). The HLA-DRB1*03 allele was positively associated with MS in the overall patient population (22.6% vs 15.6%, OR=1.58, 95% CI=1.02-2.45). Concerning disease aggressiveness, HLA-DRB1*15 occurred more frequently in the group with benign disease (42.6% vs 19.9%, OR=2.99, 95% CI=1.56-5.72) and in the group with non-benign disease (34.1% vs 19.9%, OR=2.09, 95% CI=1.05-4.16) compared with controls. When time to reach an EDSS=3 or EDSS=6 was considered as end point, HLA-DRB1*15 negative patients were found to have a worse prognosis. CONCLUSIONS: In this population of Portuguese MS patients, the HLA-DRB1*15 allele is established as a genetic marker for susceptibility to MS and is also associated with a better outcome.     

HLA-DRB1 and disease outcome in multiple sclerosis

The association between susceptibility to multiple sclerosis (MS) and the class II MHC allele HLA-DRB1*15 is well established although a possible relationship between this allele and outcome in MS is less clear. HLA-DRB1 typing was performed on 375 unrelated white patients with clinically definite MS and on 367 healthy controls. Putative associations of the gene with outcome were examined by dividing patients into two groups: those with an EDSS of 0-5.5 (mild/moderate disease) and those with an EDSS of 6-10 (severe disease). In order to minimise the effects of disease variability patients with a disease duration of at least 10 years or 15 years were examined. As subsidiary HLA-DRB1*03 and HLA-DRB1*04 associations have been previously reported, the effect of these alleles was also examined. As expected, HLA-DRB1*15 was found more frequently in patients than in controls (P < 0.000001). HLA-DRB1*15 positive patients had a significantly earlier age at onset than HLA-DRB1*15 negative patients. No significant associations were noted between HLA-DRB1*15 and outcome in the total patient group or in patients with a disease duration of 10 years or longer. In patients with a disease duration of at least 15 years HLA-DRB1*15 negative status was associated with a worse prognosis, although this did not remain significant after correction for multiple testing. It is thus likely that the contribution of HLA in MS is primarily towards onset and initial triggering mechanisms rather than influencing disease progression, chronicity and severity.     

HLA-multiple sclerosis association in continental Italy and correlation with disease prevalence in Europe

The association with HLA-DRB1 alleles was tested in 609 Continental Italian MS patients and 836 controls. The phenotype frequency of DRB1*15 in the patients was significantly higher (0.316 vs. 0.112; p(c)<10(-6); Odds Ratio (OR)=3.64) with no dose effect. DRB1*10 was also significantly increased (OR=2.19; p(c)=0.047) and DRB1*07 decreased (OR=0.60; p(c)=1.3 x 10(-3)) independently of DR15 and of each other. We did not detect an influence of the DR phenotype on disease course, age at onset/diagnosis, gender or familiarity. No association with Class I was detected in a random subset of patients and controls. A comparison of the HLA association data in Northern and Southern European populations shows a parallel between disease prevalence and DR15 frequency.     

HLA determinants of susceptibility to multiple sclerosis in an Arabian Gulf population

BACKGROUND: An association between HLA antigens and susceptibility to multiple sclerosis (MS) has been established, especially in Caucasian populations. Such associations have not been as clearly defined in many Arab populations, where even the frequencies of specific HLA antigens remain unclear OBJECTIVE: The study was designed to (i) investigate the frequencies of HLA Class I and II antigens in Kuwaiti Arabs with MS, and; (ii) assess possible inter-relationships between HLA Class II antigens and such clinical phenotypic variables in MS as age at onset, gender, disease subtype and scale of disability. SUBJECTS AND METHODS: HLA Class I (A, B, C) and Class II (DR, DQ) antigens' tissue-typing was performed by the standard complement-dependent microlymphocytotoxicity technique in two groups of age- and sex-matched Kuwaiti subjects: (i) 67 patients with definite MS (48 relapsing remitting, 19 relapsing-progressive) and (ii) 145 unrelated healthy controls. The frequencies of specific HLA types were then compared between patients with controls, and in the former, related to specified clinical parameters. RESULTS: The frequencies for the Class I antigens: A9, A10, A19, A33, B5 and CW4 appeared higher with the presence of MS, although the numbers of positive subjects were rather low. For the Class II antigens, frequencies of DR4, DQ5, DQ6, DQ7 and DQ8 were increased while those for DR6 and DR1 were decreased in the patients with MS. HLA types DR15 and DR4 were present at higher frequencies in patients with a younger age at disease onset; DR15 also appeared more frequent in the female patients. CONCLUSION: There is a trend towards an association between HLA Class II antigens (DR4, DQ6, DQ7 and DQ8) and MS in Kuwaiti subjects. Additionally, it appeared that DR4 and DR15 were more frequent in females and those with an early onset of the disease. These patterns of HLA Class II determinants of susceptibility to MS differ from reports in some other populations, and may reflect the recognized variability in genetic influence on HLA and disease expression.     

Human leucocyte antigen (HLA) class I and II typing in Belgian multiple sclerosis patients

This is one of the first studies to compare the frequencies of different human leucocyte antigen (HLA) class I and II alleles and haplotype HLA-DRB1*15-DQB1*06 in a cohort of 119 patients with multiple sclerosis (MS) and a cohort of 124 healthy controls in Belgium. An association with MS was found for the HLA-DRB1*15 (odds ratio [OR] 2.60 [95% confidence interval (CI) 1.51–4.50]) and HLA-DQB1*06 (OR 1.97 [95% CI 1.18–3.29]) alleles, and for haplotype DRB1*15-DQB1*06 (OR 2.63 [95% CI 1.52–4.56]). The HLA-B*07 allele also tended to be more frequent in MS patients (OR 1.46 [95% CI 0.80–2.65]) and more frequent among MS patients with than in those without the HLA-DRB1*15 allele (26/54 [48.1%] versus 6/65 [9.2%]; p value <0.0001). Other alleles were underrepresented in MS patients, such as the HLA-DRB1*07 (OR 0.39 [95% CI 0.21–0.73]) and HLA-A*02 (OR 0.56 [95% CI 0.34–0.94]), showing a protective role against the disease. The HLA-B*44 (OR 0.58 [95% CI 0.31–1.09]) and HLA-DRB1*04 (OR 0.75 [95% CI 0.42–1.34]) alleles tended to be less frequent in MS patients. Altogether, the significant results observed in this population are in line with those from other countries and confirm that propensity to MS can be due to a complex presence of various HLA class I and class II alleles.     

Heterogeneous immunogenetic background in Japanese adults with myasthenia gravis

The aim of this study was to elucidate the roles of human leukocyte antigen (HLA) class II genes in disease susceptibility in Japanese adult patients with myasthenia gravis (MG). A number of studies have shown that MG is correlated with DR3 in Caucasians. In Japanese, infantile MG is associated with DR9, but the HLA class II alleles associated with adult MG remains unclear. HLA-DRB1 and DQB1 alleles were determined by genotyping in 75 Japanese adult patients with MG and in 115 race-matched healthy adults. No statistically significant difference was observed in the overall prevalences of DRB1 and DQB1 alleles between MG patients and healthy controls, even when the patients and controls were stratified on the basis of their gender. MG patients with DQB1*0604 were younger and those with DQB1*0402 were older at disease onset than those without (P=0.03 and 0.008, respectively). Concomitant autoimmune thyroid disease was associated with DRB1*0803 (P=0.0009, corrected P=0.04). In addition, anti-acetylcholine receptor antibody levels were significantly higher in patients with DQB1*0604 than in those without (P=0.045). These findings indicate that immunogenetic backgrounds in Japanese adult MG patients are heterogeneous and are apparently different from those in Caucasian patients.     

Influence of HLA on progression of optic neuritis to multiple sclerosis: results of a four-year follow-up study

BACKGROUND: Genetic predisposition in multiple sclerosis (MS) has always been a critical concern in aetiology and progress of the disease. The present study looks into the relations between human leukocyte antigen (HLA), optic neuritis (ON) and MS in the Iranian population. METHODS: Patients with potential diagnosis of acute ON underwent a standardized clinical examination for confirming the diagnosis. Selected patients were gathered for HLA typing and clinical follow up. RESULTS: Of the 55 patients, 46 (83.6%) were female. The mean age was 25(+/-7.3) with a range of 12-43. Twenty of the 55 (36%) were confirmed for the diagnosis of clinically definite MS (CDMS). Results show that A23, B21, A11 and B51 alleles were present in 4 (20%), 6 (30%), 2 (10%) and 1 (5%) of the CDMS patients, respectively. Ten (50%) and 17 (85%) CDMS patients were positive for HLA class II alleles, DR2 and DQ1, correspondingly. CONCLUSIONS: The study strongly suggests the association among DR2, A23 and B21 allele and the evolution of ON to MS. High prevalence of A23 and DR2 alleles in CDMS patients compared with the normal population may suggest an important role for these alleles in the development of MS. The study suggests B51 as a protective factor against development of ON in the normal population. In addition, results do not confirm previous studies considering A11 as a predisposing factor. The present study finally evokes that different classes of HLA have different roles in susceptibility to MS and confirms disease heterogeneity as an important emerging concept in MS.     

Multiple sclerosis and HLA class II susceptibility and resistance genes

Probes to the HLA class II genes DRβ, DQβ, and DQα were used to study DNA from unrelated Caucasian multiple sclerosis (MS) patients by sequential restriction fragment length polymorphism (RFLP) analysis in Taq1 restriction enzyme digests. Comparison of 104 patients and 108 controls, who were not matched for DR type, has identified for the first time a linked series of allele-specific RFLPs or allogenotypes which form an extended haplotype that is preferentially associated with MS. These allogenotypes include DRw15 or DR2(15);DQβlb, which corresponds at the DNA level to the DQwl (DQw6) serotype; a DQA1 allogenotype termed DQα1b; and a 2.2kb DX (DQA2) allogenotype termed DXαU (DQA2U). The role of HLA class II genes in susceptibility to MS was found to be complex. First, 23 of 104 MS patients showed DR-DQ linkages which were not observed in our control population. We suggest these anomalous associations may be important in the pathogenesis of MS. Second, homozygosity of a 2.0 KB DX (DQA2) gene, termed DXαL (DQA2L), Showed a strong negative association with MS. DXαL (DQA2L) is in strong linkage disequilobrium with DR1, 5(w11)7, and a subset of DR4, all of which also showed a negative association with MS, Since DXαL (DQA2L) does not code for any known product, DR1, 5(11), 4, and 7 become candidates for disease resistance genes. Third, in EcoR1 and EcoRV digests of DNA from both controls and patients homozygous for DQβ1b a number of different RFLP patterns were identified and these RFLPs patterns were identified and these RFLPs were associated with either relapsing-remitting or progressive MS. This suggests there may be HLA sequence differences between individuals bearing a particular class II allele and these may correlate with the clinical course of MS.     

Association between Parkinson's disease and the HLA-DRB1 locus

Two genome-wide association studies (GWASs) recently highlighted the HLA-DRA and HLA-DRB5 genes as associated with Parkinson disease (PD). However, because HLA-DRA displays a low level of polymorphisms and HLA-DRB5 is only present in approximately 20% of the population, these findings are difficult to interpret. Our aims were: (1) to replicate and investigate in greater detail the association between PD and the HLA-DR region; (2) to identify PD-associated HLA alleles; and (3) to perform a meta-analysis of our top finding. As part of 2 French population-based case-control studies of PD including highly ethnically homogeneous participants, we investigated the association between PD and 51 Single-nucleotide polymorphisms (SNPs) in the HLA-DR region. HLA-DRB1 alleles were imputed using the HLA(*) IMP software. HLA typing was performed in a subsample of the participants. We performed a meta-analysis of our top finding based on 4 GWAS data sets. Among 499 cases and 1123 controls, after correction for multiple testing, we found an association with rs660895 (OR/minor allele, 0.70; 95% CI, 0.57-0.87) within the HLA-DRB1 gene, which encodes the most polymorphic HLA-DR chain (DRβ). A meta-analysis (7996 cases, 36455 controls) confirmed this association (OR, 0.86; 95% CI, 0.82-0.91; P < .0001). SNP-based imputation of HLA alleles showed an inverse association between PD and the HLA-DRB1(*) 04 allele. We replicated an association between PD and the HLA-DR region and provided further insight into the loci and alleles involved. The highly polymorphic HLA-DRB1 locus contains rs660895, which represents a more legitimate candidate than previous ones. Our finding is in agreement with the hypothesis of an immune component in PD pathophysiology. ? 2012 Movement Disorder Society.     

Association and linkage of juvenile MS with HLA-DR2(15) in Russians

The aim of this study was to determine the role of the HLA-DRB1 gene [6p21] in susceptibility to juvenile MS (JMS) (age at onset < or =15 years) of children of Russian descent. Association of DR2(15) with JMS has been found by the comparison of patients with JMS with both unrelated and affected family-based healthy controls. The linkage of DR2(15) with JMS was shown by transmission disequilibrium test. There were no significant differences in the frequencies of DRB1 alleles and genotypes between 56 patients with JMS and 234 patients with MS with age at onset > or =16 years.     

HLA antigens-linked genetic control in multiple sclerosis patients resistant and susceptible to infection

Patients with multiple sclerosis (MS) from the two Montreal MS clinics, were divided into two groups: one group of 61 patients (MS type I) who had no clinical history of susceptibility to recurrent respiratory tract infections and a second group of 58 patients (MS type II) who had persistent susceptibility to such infections since childhood. All patients were typed for the HLA tissue antigens. The HLA antigen frequencies of the total MS patient population, and of MS type I and MS type II patients were compared to those of a normal control population and each other. The HLA-DR2 and B7 antigen frequencies were significantly increased compared to the normal controls for all MS patients. MS type I patients had an increased frequency for HLA-Bw42 and DRw8 antigens; the frequency of HLA-A29 was lower than in the controls and MS type II patients. MS type II patients had a significantly increased frequency for DR3 and some HLA-DR3-associated phenotypes (A1 + DR3; B8 + DR3; A1 + B8 + DR3) as compared to controls and MS type I patients. These results are consistent with the existence of genes linked to the HLA antigens, such as immune response genes, which control the resistance or susceptibility of the patients to infection, and suggest that these HLA antigens could be associated with a difference in the evolution of MS, as observed in the MS type I and II patients [21].     

Abnormal cervical vestibular-evoked myogenic potential in anterior inferior cerebellar artery territory infarction: frequency, pattern, and a determinant

BackgroundThere have been few magnetic resonance imaging (MRI) studies of the spinal cord in large multiple sclerosis (MS) patient cohorts and little is known about correlations between cord lesions and human leukocyte antigen (HLA) alleles.ObjectiveTo investigate the spectrum of MRI changes in the spinal cord in MS and associations with the HLA-DRB1 genotype.MethodsTwo hundred and fifty two consecutive MS patients from the Perth Demyelinating Diseases Database had MRI of the spinal cord and brain and high-resolution HLA-DRB1 genotyping. The numbers, locations, shape and segmental extent of cord lesions were analysed and were correlated with carriage of individual HLA-DRB1 alleles and diplotypes.ResultsFocal cord lesions were present in 82.9% of cases, with numbers being maximal in the cervical cord and increasing with disease duration. Focal lesions were usually round or oval in shape but in 35% of cases subpial wedge-shaped lesions were present. Diffuse cord involvement was present in 10% of cases and correlated with carriage of HLA-DRB1*1501 and with higher disability. Carriage of the minor allele HLA-DRB1*0701 was significantly associated with numbers of wedge-shaped lesions and lesions in the cervical cord, while HLA-DRB1*1104 and DRB1*0103 were significantly associated respectively with higher and lower numbers of thoracic cord lesions. HLA-DRB1*1501 and the HLA-DRB1*11 sub-alleles DRB1*1101 and DRB1*1104 were significantly associated with the segmental length of cord lesions.ConclusionsOur study is the first to investigate the frequency of subpial wedge-shaped lesions in the cord in vivo and has provided preliminary evidence that HLA-DRB1 alleles may play a role in determining the severity and extent of spinal cord involvement in MS.     

DQB1*0602 allele shows a strong association with multiple sclerosis in patients in Malaga,Spain

BACKGROUND: The human leukocyte antigen (HLA) class II DR2 haplotype (DRB1*1501, DQA1*0102, DQB1*0602) has been associated with multiple sclerosis (MS) in all ethnic groups and very strongly in Caucasians. AIM: To investigate the possible HLA class II (DRB1, DQA1 and DQB1) associations with MS in Malaga, southern Spain. METHODS: We analysed the HLA class II sub-regions DRB1, DQA1 and DQB1 by polymerase chain reaction (PCR) and sequence-specific oligonucleotide probe hybridization (PCR/SSO) for DRB1 and DQB1 and with sequence-specific primers (PCR/SSP) for DRB1 subtypes and DQA1. Possible HLA class II associations with clinical MS characteristics were investigated in 149 subjects with and 160 without MS. RESULTS: Associations were detected between MS and the HLA class II alleles DRB1*1501 (45.6 % vs. 21.3%, p=0.001), DQA1*0102 (44% vs. 29.4%, p=0.001) and DQB1*0602 (45% vs. 20.6%, p=0.001). The DR2 haplotype (DRB1*1501, DQA1*0102, DQB1*0602) was associated with MS (43.6 % vs. 20%, p=0.002). DQB1*0602 was the only allele that maintained an association with MS in a logistic regression model. No HLA class II alleles or genotypes were significantly associated with any clinical characteristics of MS. CONCLUSIONS: Our results confirm the positive association of the DR2 haplotype with MS, particularly the allele DQB1*0602, in the population studied. DR4 was not associated with the disease in Malaga. HLA class II alleles or haplotypes were not associated with clinical or demographic characteristics, or clinical form or severity of MS.     

HLA-DR 15 is associated with female sex and younger age at diagnosis in multiple sclerosis.

BACKGROUND: The association between multiple sclerosis and class II alleles of the major histocompatibility complex, in particular the DRB1*1501-DQB1*0602 haplotype, is well established but their role in determining specific features of this clinically heterogeneous disease is unknown as few studies involving large sample sizes have been performed. METHODS: 729 patients with multiple sclerosis were typed for the HLA DR15 phenotype. All patients underwent clinical assessment and a detailed evaluation of their clinical records was undertaken. RESULTS: The presence of DR15 was associated with younger age at diagnosis and female sex but there was no association with disease course (relapsing-remitting or secondary progressive v primary progressive type), disease outcome, specific clinical features (opticospinal v disseminated form), diagnostic certainty (clinically and laboratory supported definite v clinically probable multiple sclerosis), and paraclinical investigations including the presence of oligoclonal bands in the CSF or characteristic abnormalities on MRI imaging of the central nervous system. CONCLUSION: Even though DR15 carriers are more likely to be female and prone to an earlier disease onset, the results indicate that there is no association with other specific clinical outcomes or laboratory indices examined here. This suggests that DR15 exerts a susceptibility rather than disease modifying effect in multiple sclerosis.     

A study of the HLA-DR region in clinical subgroups of multiple sclerosis and its influence on prognosis.

OBJECTIVE: To investigate the HLA-DR associations in relapsing-remitting/secondary progressive multiple sclerosis (RR/SPMS) and primary progressive MS (PPMS). The HLA-DR2 allele (or its split, HLA-DRB1*15) is felt to be a risk factor for MS, rather than a genetic marker for the population of origin. Some studies have indicated a different HLA-DR antigen profile in PPMS patients compared with those having an initially relapsing-remitting course, only those with relapsing disease showing an increase in HLA-DR2. Association of PPMS with DR4 has been suggested. Several DR alleles have also been felt to influence the prognosis in MS. METHODS: Genomic DNA was prepared from peripheral blood of 202 RR/SPMS patients identified in a population-based prevalence study, 102 PPMS patients identified throughout Northern Ireland and 398 normal controls (Nor) matched for the postcode areas of those identified in the prevalence study. Samples were typed for the HLA-DR antigens using polymerase chain reaction (PCR) technology and sequence specific oligonucleotide probes (SSOP). RESULTS: A high incidence of HLA-DRB1*15 was found in each MS group - PPMS (63.73%), RR/SPMS (66.83%) - compared with normals (32.41%), (PPMS vs. Nor, P<0.0001: RR/SPMS vs. Nor, P<0.0001). HLA-DRB1*04 occurred at a lower incidence in both MS groups compared with controls - RR/SPMS (22%), PPMS (30%), Nor (35%). Overall, highly significant differences existed across the full HLA-DR allele distribution (RR/SPMS vs. Nor, P<0.0001, df=12: PPMS vs. Nor, P=0.0007, df=12). No significant differences existed between PPMS and RR/SPMS (P=0.47, df=12), and the allele distributions in benign and aggressive MS were similar. CONCLUSIONS: These data suggest that in this population, HLA-DRB1*15 is indeed associated with PPMS and that PPMS has a HLA-DR profile distinct from the normal population but not from those with an initially relapsing-remitting course. No single allele is associated with either a good or poor prognosis.