Multiple sclerosis: a modifying influence of HLA class I genes in an HLA class II associated autoimmune disease

Fogdell‐Hahn, Anna; Ligers, Arturs; Grønning, Marit; Hillert, Jan; Olerup, Olle

doi:10.1034/j.1399-0039.2000.550205.x

Cited by 243 publications

(193 citation statements)

References 31 publications

(29 reference statements)

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“…The frequency of MOG-142L and HLA-A*02-positive individuals was significantly lower in cases than in controls, confirming the previously reported protective effect, 9,10,12,13 whereas the association with Cw*05 was not significant. To eliminate the possible confounding effect of linkage disequilibrium (LD) with HLA-DRB1*15, we performed the same analysis in DRB1*15-negative individuals.…”

Section: Resultssupporting

confidence: 85%

“…8 Conversely, other studies have detected the effect at least of one class I genetic factor independently of HLA-DRB1. Brynedal et al 9 confirmed in a Nordic cohort of 1084 MS patients and 1347 controls the results of a previous study performed in a smaller Swedish panel, 10 showing that HLA-A*02 is negatively associated with MS (OR ¼ 0.63, P ¼ 7 Â 10 À12 ). Yeo et al 11 analyzed over 1600 UK MS patients and 3600 controls and found that HLA-Cw*05 exerts an MS-protective effect (OR ¼ 0.49, 95% confidence intervals, CI ¼ 0.34-0.69, P ¼ 3.3 Â 10 À5 ) after excluding all individuals carrying DRB1 alleles associated with MS.…”

Section: Introductionmentioning

confidence: 63%

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HLA-class I markers and multiple sclerosis susceptibility in the Italian population

et al. 2009

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Previous studies reported an association with multiple sclerosis (MS) of distinct HLA-class I markers, namely HLA-A*02, HLA-Cw*05 and MOG-142L. In this work, we tested the association with MS of A*02 and Cw*05 in 1273 Italian MS patients and 1075 matched controls, which were previously analyzed for MOG-142, and explored the relationship among these three markers in modulating MS risk. HLA-A*02 conferred a statistically robust MS protection (odds ratio, OR ¼ 0.61; 95% confidence intervals, CI ¼ 0.51-0.72, Po10 À9 ), which was independent of DRB1*15 and of any other DRB1* allele and remained similar after accounting for the other two analyzed class I markers. Conversely, the protective effect we previously observed for MOG-142L was secondary to its linkage disequilibrium with A*02. Cw*05 was not associated considering the whole sample, but its presence significantly enhanced the protection in the HLA-A*02-positive group, independently of DRB1: the OR conferred by A*02 in Cw*05-positive individuals (0.22, 95% CI ¼ 0.13-0.38) was significantly lower than in Cw*05-negative individuals (0.69, 95% CI ¼ 0.58-0.83) with a significant (P ¼ 4.94 Â 10 À5 ) multiplicative interaction between the two markers. In the absence of A*02, Cw*05 behaved as a risk factor, particularly in combination with DRB1*03 (OR ¼ 3.89, P ¼ 0.0006), indicating that Cw*05 might be a marker of protective or risk haplotypes, respectively.

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Section: Resultssupporting

confidence: 85%

Section: Introductionmentioning

confidence: 63%

HLA-class I markers and multiple sclerosis susceptibility in the Italian population

et al. 2009

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“…Furthermore, HLA class II-independent associations with HLA-A and -B have also been reported with other AIDs. In particular, HLA-A has been implicated in multiple sclerosis [34][35][36] and juvenile idiopathic arthritis, 37,38 whereas HLA-B is a well-known risk factor in ankylosing spondylitis 39 and has been implicated in systemic lupus erythematosus. 40 This raises the possibility that these genes represent susceptibility loci that are involved in common, autoimmune processes.…”

Section: Confirmation Of Mhc Class I Associationsmentioning

confidence: 99%

Genetic variants of the HLA-A, HLA-B and AIF1 loci show independent associations with type 1 diabetes in Norwegian families

et al. 2008

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The main genetic predisposition to type 1 diabetes (T1D) is known to be conferred by the HLA-DRB1, -DQA1 and -DQB1 genes in the major histocompatibility complex (MHC). Other genetic factors within this complex are known to contribute, but their identity has often been controversial. This picture is shared with several other autoimmune diseases (AIDs). Moreover, as common genetic factors are known to exist between AIDs, associations reported with other AIDs may also be involved in T1D. In this study, we have used these observations in a candidate gene approach to look for additional MHC risk factors in T1D. Using complementary conditional methods (involving conditional logistic regression and family-based haplotype tests) and analyses of linkage disequilibrium (LD) patterns, we confirmed association for alleles of the HLA-A and HLA-B genes and found preliminary evidence for a novel association of a single-nucleotide polymorphism (rs2259571) in the AIF1 gene, independent of the DRB1-DQA1-DQB1 genes and of each other. However, no evidence of independent associations for a number of previously suggested candidate polymorphisms was detected. Our results illustrate the importance of a comprehensive adjustment for LD effects when performing association studies in this complex.

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“…3 Within the MHC, the human leukocyte antigen (HLA) DRB1*1501-DRB5*0101-DQA1*0102-DQB1*0602 haplotype has a pre-eminent role, especially for populations of Northern European descent. [4][5][6][7] However, there is now robust, validated evidence that other variants within the MHC have independent roles in rendering individuals susceptible to MS, 8 and there is evidence for a role of the MHC in age at onset 9 and disease course. 10,11 Many studies have used clinical measures of severity to explore this aspect, but MRI-derived measures (such as brain atrophy and T 2 -weighted lesion volume or T2LV) appear to be more sensitive in capturing the course of disease, particularly in the early years after symptom onset.…”

Section: Introductionmentioning

confidence: 99%

HLA (A-B-C and -DRB1) alleles and brain MRI changes in multiple sclerosis: a longitudinal study

et al. 2010

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Several major histocompatibility complex (MHC) alleles have been postulated to influence the susceptibility to multiple sclerosis (MS), as well as its clinical/radiological course. In this longitudinal observation, we further explored the impact of human leukocyte antigen (HLA) class I/II alleles on MS outcomes, and we tested the hypothesis that HLA DRB1*1501 might uncover different strata of MS subjects harboring distinct MHC allele associations with magnetic resonance imaging (MRI) measures. Five hundred eighteen MS patients with two-digit HLA typing and at least one brain MRI were recruited for the study. T2-weighted hyperintense lesion volume (T2LV) and brain parenchymal fraction (BPF) were acquired at each time point. The association between allele count and MRI values was determined using linear regression modeling controlling for age, disease duration and gender. Analyses were also stratified by the presence/absence of HLA DRB1*1501. HLA DRB1*04 was associated with higher T2LV (P ¼ 0.006); after stratification, its significance remained only in the presence of HLA DRB1*1501 (P ¼ 0.012). The negative effect of HLA DRB1*14 on T2LV was exerted in DRB1*1501-negative group (P ¼ 0.012). Longitudinal analysis showed that HLA DRB1*10 was significantly protective on T2LV accrual in the presence of HLA DRB1*1501 (P ¼ 0.002). Although the majority of our results did not withstand multiple comparison correction, the differential impact of several HLA alleles in the presence/absence of HLA DRB1*1501 suggests that they may interact in determining the different phenotypic expressions of MS.

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Multiple sclerosis: a modifying influence of HLA class I genes in an HLA class II associated autoimmune disease

Cited by 243 publications

References 31 publications

HLA-class I markers and multiple sclerosis susceptibility in the Italian population

HLA-class I markers and multiple sclerosis susceptibility in the Italian population

Genetic variants of the HLA-A, HLA-B and AIF1 loci show independent associations with type 1 diabetes in Norwegian families

HLA (A-B-C and -DRB1) alleles and brain MRI changes in multiple sclerosis: a longitudinal study

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