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-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.     

Genetic interaction of CTLA-4 with HLA-DR15 in multiple sclerosis patients

Multiple sclerosis is a chronic inflammatory disease of the central nervous system with a genetic component. Until now, the more consistent association with the disease is found with the major histocompatibility complex, especially HLA-DRB1*1501-DQB1*0602 haplotype. In this report, we demonstrate the interaction of Cytotoxic T Lymphocyte-associated antigen 4 (CTLA-4 [CD152]) gene with DRB1*15 haplotype in multiple sclerosis genetic susceptibility. Our data were obtained from two European independent family-based studies including 610 multiple sclerosis family trios. Ann Neurol 2003;54:119-122     

Evidence for the genetic role of human leukocyte antigens in low frequency DRB1*1501 multiple sclerosis patients in Israel

A strong association exists between multiple sclerosis (MS) and the DRB1*1501 haplotype, in most populations. Linkage of Multiple Sclerosis (MS) with the MHC or HLA region on chromosome 6p21 has previously been observed in DRB1*1501 positive MS families. A group of 13 Israeli multiplex MS families with a very low frequency of DRB1*1501 haplotype were examined in this study. Association and a linkage test were performed in order to identify a non-DRB1*1501 effect of HLA on susceptibility for MS. MS multiplex families and healthy controls were molecularly typed for six highly polymorphic markers located within the MHC region: DRB1, DQA1 and DQB1, BAT-2, MIB and D6S248. Data analyses included: (a) an association study comparing the patient group with both healthy relative, and healthy control groups (b) a transmission test for linkage disequilibrium (TDT) of the MS-associated alleles in the multiplex families, and (c) multipoint non-parametric linkage (NPL) and parametric LOD score analyses using the GENEHUNTER program. The DRB1*1303 allele was significantly more frequent among the MS patients. There was a trend towards transmission disequilibrium of DRB1*1303, but was not statistically significant. Allele sharing and LOD score analyses revealed no evidence for linkage. The high frequency of DRB1*1303 observed in our family patients provides evidence to support the association with this allele that previously described in sporadic non-Ashkenazi MS patients. Thus, DRB1*1303 may serve as genetic risk factor for MS. Our study exemplifies the genetic heterogeneity in MS as there is a genetic effect of HLA on MS susceptibility in our low frequency DRB1*1501 patients.     

Multiple sclerosis genetics 2010

Multiple sclerosis (MS) is a complex disease involving interactions among multiple genetic loci with modest effects and environment. The human leukocyte antigen (HLA) gene cluster in chromosome 6p21.3 represents by far the strongest MS susceptibility locus genome-wide, with the primary signal arising from the HLA-DRB1gene in the class II segment of the locus. Large, multicenter DNA collections have prospered as the development of new laboratory and analytical approaches has matured at a remarkable pace, allowing the pursuit of comprehensive "agnostic" genome-wide association studies to identify and characterize the non-HLA genetic component of MS. This article summarizes the new knowledge gained from this experimental approach.     

The genetics of multiple sclerosis

Epidemiological studies implicate an interplay between genetic and environmental factors in the aetiology of multiple sclerosis. The classical genetic observations suggest that multiple sclerosis is a complex trait in which susceptibility is determined by several genes acting independently or epistatically. The main dividend from understanding the genetic basis of susceptibility in multiple sclerosis will be an improved understanding of the pathogenesis. To date, candidate gene approaches have proved relatively unrewarding other than in establishing the association with alleles of the major histocompatibility complex (MHC). In common with most other complex traits, no major susceptibility gene has been identified through full genome screens but regions of interest have provisionally been identified. An important part of future studies in the genetics of multiple sclerosis will be to resolve the question of disease heterogeneity.     

Evidence for additional genetic risk indicators of relapse-onset MS within the HLA region

BACKGROUND: Human leukocyte antigen (HLA)-DR2 carriership is associated with an increased risk for MS. Genome searches using microsatellite markers have consistently shown that additional genetic factors contribute to susceptibility for MS. OBJECTIVE: To identify loci within the HLA region that predispose to relapse-onset MS independently of HLA-DR2. METHOD: A case-control study involving 159 patients with definite relapse-onset MS and 273 control subjects was conducted. Six highly polymorphic microsatellite markers encoded within the HLA-C to DR region, that is, D6S1014, D6S273, TNFa, MIB, C1_2_5, and C1_3_2, three single-nucleotide tumor necrosis factor (TNF) promoter gene polymorphisms at positions -238, -308, and -376, and HLA-DR2 carriership were typed. RESULTS: These data confirmed the well-known association between the HLA-DR2 haplotype and relapse-onset MS, yielding an odds ratio (OR) of 3.6 (95% CI: 2.4 to 5.4; p < 0.0001). Multivariate analyses revealed that C1_3_2*354 was also associated with an increased risk for developing relapse-onset MS independently of HLA-DR2 (OR: 2.0; 95% CI: 1.2 to 3.1; p = 0.004). This allele is encoded within an ancestral haplotype that is highly linked to HLA-DR3. The joint effect of this ancestral haplotype and HLA-DR2 resulted in an OR of 8.7 (95% CI: 2.7 to 29; p < 0.0001) to develop relapse-onset MS. In addition, a protective risk factor was found: carriers of TNFa*107 had a 0.5-fold lower risk to develop relapse-onset MS (95% CI: 0.3 to 0.9; p = 0.026). CONCLUSION: Within the HLA region, other loci besides HLA-DR2 haplotype modulate susceptibility for relapse-onset MS.     

Microsatellite polymorphisms in the gene promoter of monocyte chemotactic protein-3 and analysis of the association between monocyte chemotactic protein-3 alleles and multiple sclerosis development

Monocyte chemotactic protein 3 (MCP-3) is a chemokine that attracts mononuclear cells, including monocytes and lymphocytes, the inflammatory cell types that predominate in multiple sclerosis lesions. We studied the possible association between the presence of a CA/GA microsatellite repeat polymorphism in the promoter/enhancer region of the MCP-3 gene and the occurrence of multiple sclerosis. DNA samples from 192 Swedish multiple sclerosis (MS) patients and 129 healthy controls were analysed by an automated fluorescent technique. In the whole sample population, five MCP-3 allele variants (MCP-3*A1 to MCP-3*A5) were detected with an allele frequency ranging between 0.3% and 46%. The individual MCP-3 allele frequencies did not differ significantly between MS patients and control individuals. The relative MS risk, attributable to HLA-DRB1*15 was 3.05 (chi2 = 22.25, p < 0.0001). The phenotype frequency (PF) of none of the MCP-3 alleles was significantly altered in the population of controls versus unselected MS patients. When MS patients and control subjects were stratified according to positivity for HLA-DRB1*15, the MCP-3*A4-associated risk for developing MS decreased to 0.36 (p = 0.011). In the stratified groups of patients who were negative for both HLA-DRB1*15 and HLA-DRB1*03, and hence possessed a lower risk to develop MS, the MCP-3*A2-associated risk for MS development decreased significantly (p = 0.018). We conclude that the MCP-3*A4 allele might protect against MS development on the background of the increased risk in HLA-DRB1*15+ individuals and the MCP-3*A2 allele seems protective in low-risk individuals, who are both negative for DRB1*03 and DRB1*15.     

Non-random mating,parent-of-origin,and maternal–fetal incompatibility effects in schizophrenia

Although the association of common genetic variation in the extended MHC region with schizophrenia is the most significant yet discovered, the MHC region is one of the more complex regions of the human genome, with unusually high gene density and long-range linkage disequilibrium. The statistical test on which the MHC association is based is a relatively simple, additive model which uses logistic regression of SNP genotypes to predict case–control status. However, it is plausible that more complex models underlie this association. Using a well-characterized sample of trios, we evaluated more complex models by looking for evidence for: (a) non-random mating for HLA alleles, schizophrenia risk profiles, and ancestry; (b) parent-of-origin effects for HLA alleles; and (c) maternal–fetal genotype incompatibility in the HLA. We found no evidence for non-random mating in the parents of individuals with schizophrenia in terms of MHC genotypes or schizophrenia risk profile scores. However, there was evidence of non-random mating that appeared mostly to be driven by ancestry. We did not detect over-transmission of HLA alleles to affected offspring via the general TDT test (without regard to parent of origin) or preferential transmission via paternal or maternal inheritance. We evaluated the hypothesis that maternal–fetal HLA incompatibility may increase risk for schizophrenia using eight classical HLA loci. The most significant alleles were in HLA-B, HLA-C, HLA-DQB1, and HLA-DRB1 but none was significant after accounting for multiple comparisons. We did not find evidence to support more complex models of gene action, but statistical power may have been limiting.     

The HLA locus and multiple sclerosis in Sicily

The authors report the analysis of HLA-class II allelic heterogeneity in a well characterized multiple sclerosis (MS) Sicilian dataset. Family-based association analysis revealed evidence for excess transmission to affected individuals for alleles HLA-DRB1*1501, DRB1*04, and DQB1*0302. When analyzed as haplotypes, the authors observed excess transmission for the DRB1*0400-DQB1*0302 haplotype. Sicilian patients share the HLA-DRB1*1501 susceptibility allele with affected living in continental Italy, but also display the allelic heterogeneity that characterizes Mediterranean populations.     

HLA class II associated risk and protection against multiple sclerosis-a Finnish family study.

We analyzed the HLA class II haplotypes in 249 Finnish nuclear families and compared the frequencies of parental haplotypes transmitted or non-transmitted to multiple sclerosis (MS) patients. The most important predisposing haplotype was DRB1*15-DQB1*0602 (P<10(-6)) as expected and a weak predisposing effect of DRB1*04-DQB1*0302 was revealed after the elimination of DRB1*15-DQB1*0602. HLA-DRB1*01-DQB1*0501 and DRB1*13-DQB1*0603 were negatively associated with MS in transmission disequilibrium test, but only the DRB1*13-DQB1*0603 association remained significant (P=0.008) after the elimination of DRB1*15-DQB1*0602 haplotypes. Based on this study HLA class II haplotypes exhibit both predisposing and protective effects in MS.     

HLA-DM polymorphisms do not associate with multiple sclerosis: an association study with analysis of myelin basic protein T cell specificity

The MHC region on 6p harbors at least one susceptibility gene for multiple sclerosis (MS). Within this region, HLA-DM loci are of interest being involved in class II antigen processing. We investigated the association of HLA-DM polymorphisms with MS. Sixty-three patients with MS and 46 healthy controls from continental Italy were typed for HLA-DM polymorphisms and HLA-DRB1 alleles. Besides, among the donors characterized for the DM polymorphisms, we considered 6 MS patients previously studied for the fine specificity of their MBP-specific T lymphocyte lines (TLL). The frequencies of allelic variants at the DMA and DMB loci were similar between MS patients and controls, even when HLA-DRB1^*1501 positive and negative donors were analyzed separately. Patients with predominant responses to different MBP epitopes did not differ for their HLA-DM haplotype while patients with predominant responses to the same MBP epitope could present different HLA-DM haplotypes. HLA-DM polymorphisms do not associate with MS and may not affect specific patterns of T cell responses to MBP.     

HLA class II alleles and multiple sclerosis in Tunisian patients

Objective

The aim of our study was to investigate the association of HLA-DRB1 and -DQB1 alleles with multiple sclerosis (MS) in a Tunisian population and their effect on age at onset and disease severity.

Methods

58 MS patients and 105 healthy controls were genotyped for HLA class II alleles by PCR-SSP technique.

Results

An association of MS with HLA-DRB1*15 was found (14.7% vs 3.8%, OR (95% CI) = 4.34 (1.69–11.39), p_c = 2.5 × 10⁻³) after Bonferroni's correction. Moreover, the DRB1*15–DQB1*06 (13.8% vs 2.8%, OR (95% CI) = 5.44 (1.92–17.41), p_c = 1.1 × 10⁻³) and DRB1*04–DQB1*04 (8.6% vs 1.9%, OR (95% CI) = 4.86 (1.36–21.62), p_c = 0.028) haplotypes were found to confer a susceptibility to multiple sclerosis.

Conclusion

To our knowledge, this is the first study performed to analyze the association of HLA-DRB1/DQB1 alleles on MS susceptibility in Tunisia. The modern Tunisian gene pool shows some degree of heterogeneity and reflects a significant gene flow from Mediterranean regions.     

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.     

Molecular immunogenetic approach to the pathogenesis of multiple sclerosis]

In Japanese, there is no association of susceptibility to multiple sclerosis with any HLA class II alleles as a whole group. However, when we clinically classified MS patients into those having opticospinal form MS which presented selective involvement of the optic nerve and spinal cord and those with conventional form MS showing multiple involvement of the central nervous system including cerebrum, cerebellum and brainstem, the former showed a significant association with HLA-DPB1*0501 allele while the latter had an association with HLA-DRB1*1501 allele. The patients with opticospinal form MS showed a marked Th1/Tc1 shift both in the relapse phase and in the remission phase, as determined by an intracellular IFN-gamma/IL-4 ratio in peripheral blood CD4+ T cells and CD 8+ T cells. These findings suggest that opticospinal form MS is also an organ-specific autoimmune disease associated with a distinct HLA allele. By using SEREX method and brain proteomics approach, we have thus searched for any relevant autoantigens in the central nervous system in Japanese patients with MS. Heat shock proteins and neural proteins are found to be possible new candidate autoantigens in Japanese patients with MS.     

Primary association of a TNF gene polymorphism with susceptibility to multiple sclerosis.

The associations of three promoter polymorphisms in the tumor necrosis factor (TNFA) gene have been studied in 238 patients and 324 control subjects. A significant correlation was found between MS susceptibility and the TNFA-376 polymorphism. This association was independent of the human leukocyte antigen (HLA) class II association and the combined inheritance of HLA-DRB1*1501 and the TNFA-376A allele more than additively increased susceptibility to MS.     

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.     

Ethnicity-dependent association of HLA DRB1-DQA1-DQB1 alleles in Brazilian multiple sclerosis patients

OBJECTIVE: The present study focused on human leukocyte antigen (HLA) DQB1, DQA1 and DRB1 allelic variation according to ethnicity and analyzed whether susceptibility to multiple sclerosis (MS) depends on population characteristics. METHODS: Eighty-eight healthy African-Brazilians and 92 healthy white Brazilians living in Rio de Janeiro City were selected and the HLA phenotype between the two ethnic groups was compared with 44 MS patients of African descent and 40 patients of European descent. HLA class II genes were performed using polymerase chain reaction (PCR) and PCR-sequence-specific primer amplification. RESULTS: DQA1*0201-0301 alleles were associated with the white Brazilian population (P < 0.001). The DRB*1501 allele was present in White Brazilians (P=0.003), and DRB1*03-1503 in African-Brazilians. The DRB1*1501 allele confers an ethnicity-dependent MS susceptibility in White patients and the DQB1*0602 allele confers genetic susceptibility regardless of ethnicity. CONCLUSION: Heterogeneous phenotypes occur in both Brazilian ethnic groups. Taking into account that the response to immunomodulator drugs for MS treatment changes according to the DRB1*1501 allele and African-American MS patients presented poor response to the interferons, phenotype heterogeneity of HLA loci found in this study could influence therapeutic decisions in the Brazilian MS population.     

Histocompatibility antigens, aspirin use and cognitive performance in non-demented elderly subjects

HLA genotype and anti-inflammatory drug use have independently been associated with a lower risk of Alzheimer's disease (AD). We recently reported a negative association between aspirin use and AD. To investigate this further, we performed a cross-sectional study to investigate cognitive performance in 151 non-demented individuals in relation to HLA-DRB1 genotype and aspirin use. Aspirin and HLA-DRB1*01 were positive predictors of performance on logical memory (aspirin, p=0.04) and verbal fluency tests (HLA-DRB1*01, p=0.018), respectively. HLA-DRB1*05 had a negative impact on the Boston naming test (p=0.002). Our results suggest that aspirin use and inflammatory genotype may influence cognition in non-demented subjects.     

Association of HLA and T-cell receptor gene polymorphisms with Semple rabies vaccine-induced autoimmune encephalomyelitis.

Semple rabies vaccine is derived from brain tissue infected with rabies virus that is subsequently inactivated with phenol. Semple rabies vaccine-induced autoimmune encephalomyelitis (SAE) occurs in 1 in 220 immunized individuals. The immune response to myelin basic protein and pathological changes of demyelination in SAE suggest that this disease is the human homologue of experimental autoimmune encephalomyelitis (EAE). SAE and EAE are frequently studied as models for the human demyelinating disease multiple sclerosis. Major histocompatibility complex (MHC) class II and T-cell receptor (TCR) gene polymorphisms play important roles in rodent susceptibility to EAE and were analyzed to determine if the same was true in humans with SAE. HLA-DRB1, HLA-DQB1, and TCRBV gene polymorphisms were studied in Thai individuals with SAE (n = 18), with vaccination without neurological complications (n = 43), and without vaccination (n = 140). The allele frequencies of HLA-DR9 (DRB1*0901) and HLA-DR17 (DRB1*0301) were increased in SAE patients (DR9 = 22%, DR17 = 14%) compared with vaccinated controls (DR9 = 13%, DR17 = 6%) and with unvaccinated controls (DR9 = 9%, DR17 = 4%). The allele frequency of HLA-DQ7 (DQB1*0301) was decreased in SAE patients (8%) compared with vaccinated controls (15%) and with unvaccinated controls (25%). These susceptibilities are distinct from those associated with multiple sclerosis. The frequencies of TCRBV alleles and haplotypes were similar in SAE patients and vaccinated controls. These data suggest that genetic susceptibility associated with MHC class II alleles may have a role in the pathogenesis of SAE and its mechanism may be different from those involved in multiple sclerosis.