Multiple Sclerosis: A Modifying Influence Of HLA Class I Genes In An HLA Class II Associated AutoImmune Disease
Fogdell-Hahn A, Ligers A, Gronning M, Hillert J, Olerup O
Tissue Antigens 2000 Feb;55(2):140-8
Karolinska Institute, Dept of Biosciences at NOVUM, Huddinge, Sweden
PMID# 10746785; UI# 20208574
Multiple Sclerosis (MS) is a presumed AutoImmune Disease of the Central Nervous System, shown to be associated with the HLA Class II haplotype DRB1*15,DQB1*06.
Carrying the HLA Class II haplotype DRB1*15, DQB1*06 increases the risk of MS by 3.6.
By adopting a Polymerase Chain Reaction (PCR)-based typing technique for HLA Class I and Class II Genes, 200 Swedish MS patients and 210 Swedish healthy controls were analyzed for their HLA alleles.
Additional HLA Class I alleles that increase and decrease the Genetic susceptibility to MS were identified:
- HLA-A*0301 allele increases the risk of MS (odds ratio=2.1) independently of DRB1*15
- DQB1*06, HLA-A*0201 decreases the overall risk (odds ratio= 0.52)
- Presence of A*0201 reduces the risk of MS for DRB1*15
and DQB1*06 carriers from 3.6 to 1.5
Our findings are the first to identify a major modulating effect of HLA Class I alleles on the susceptibility to a human AutoImmune Disease; a phenomenon that has previously only been observed in animal models.
Genomic HLA Profiles Of MS in Hokkaido, Japan: Important Role Of DPB1*0501 Allele
Fukazawa T, Kikuchi S, Sasaki H, Yabe I, Miyagishi R, Hamada T, Tashiro K
J Neurol 2000 Mar;247(3):175-8
Hokuyukai Neurology Hospital, Sapporo, Japan
PMID# 10787110; UI# 20246791
The PolyMorphism of the HLA Class II Genes was investigated in 97 patients with Multiple Sclerosis (MS) in Hokkaido, the northernmost main island of Japan.
Of these, 80 patients were classified as having conventional MS and 17 as having OpticoSpinal MS (OS-MS).
Our findings confirmed a previous report that the DPB 1*0501 allele is positively associated with OS-MS (P = 0.0043).
The frequency of DPB 1*0501 was also found to be higher in conventional MS patients than in controls (79% vs. 58%, P = 0.0084), although the differences were not statistically significant.
Our results indicate that OS-MS is a DPB 1*0501-associated subgroup of MS, and that DPB1*0501 is also correlated with risk of conventional MS in Japanese.
Linkage Of The MHC To Familial Multiple Sclerosis Suggests Genetic Heterogeneity
The Multiple Sclerosis Genetics Group
Haines JL; Terwedow HA; Burgess K; Pericak-Vance MA; Rimmler JB; Martin ER; Oksenberg JR; Lincoln R; Zhang DY; Banatao DR; Gatto N; Goodkin DE; Hauser SL
Hum Mol Genet 7: 1229-34 (1998)
Massachusetts General Hospital, Molecular NeuroGenetics Unit, Boston, MA, USA
Multiple Sclerosis (MS) is a DeMyelinating AutoImmune Disease of the Central Nervous System. While its Etiology is not well understood, Genetic factors are clearly involved.
Until recently, most Genetic studies in MS have been association studies using the case-control design testing specific candidate Genes and studying only sporadic cases.
The only consistently replicated finding has been an association with the HLA-DR2 allele within the Major Histocompatibility Complex (MHC) on Chromosome 6.
Using the Genetic linkage design, however, evidence for and against linkage of the MHC to MS has been found, fostering suggestions that Sporadic and Familial MS have different Etiologies.
Most recently, two of four genomic screens demonstrated linkage to the MHC, although specific allelic associations were not tested.
Here, a dataset of 98 multiplex families was studied to test for an association to the HLA-DR2 allele in Familial MS and to determine if Genetic linkage to the MHC was due solely to such an association.
Three highly polymorphic markers (HLA-DR, D6S273 and TNF-beta) in the MHC
demonstrated strong Genetic linkage (parametric lod scores of 4.60, 2.20 and 1.24, respectively).
And a specific association with the HLA-DR2 allele was confirmed (TDT; P < 0.001).
Stratifying the results by HLA-DR2 status showed that the linkage results were limited to families segregating HLA-DR2 alleles.
These results demonstrate that Genetic linkage to the MHC can be explained by the HLA-DR2 allelic association. They also indicate that Sporadic and Familial MS share a common Genetic susceptibility.
In addition, preliminary calculations suggest that the MHC explains between 17 and 62% of the Genetic Etiology of MS.
This Heterogeneity is also supported by the minority of families showing no linkage or association with loci within the MHC.
HLA Class II Susceptibility To Multiple Sclerosis Among Ashkenazi And Non-Ashkenazi Jews
Kwon OJ, Karni A, Israel S, Brautbar C, Amar A, Meiner Z, Abramsky O, Karussis D
Arch Neurol 1999 May;56(5):555-60
Hadassah Univ Hospital, Hebrew UnivHadassah Medical School, Tissue Typing Unit and,
The Lautenberg Center for General and Tumor Immunology, Jerusalem, Israel
PMID# 10328250; UI# 99258802
To look for HLA Class II alleles and haplotypes conferring susceptibility to Multiple
Sclerosis (MS) in the Jewish population of Israel.
Design & Setting
Population-based cohort of Clinically Definite patients with MS tested prospectively over 7 years. Referral center in a Neurology clinic at a university hospital in the greater Jerusalem area in Israel.
A total of 162 consecutive patients with Clinically Definite MS from the 2 main ethnic Jewish groups in Israel:
- 104 Ashkenazi (80 with a Relapsing/Remitting or Secondary/Progressive and 24 with a Chronic Primary/Progressive course of the disease)
- 58 Non-Ashkenazi (36 with a Relapsing/Remitting or Secondary/Progressive course and 22 with a Chronic Primary/Progressive course of the disease), matched with 132 Ashkenazi and 120 Non-Ashkenazi healthy controls.
Main Outcome Measures
The relationship between the various MHC Class II alleles and haplotypes and MS
As defined by the polymerase chain reaction and sequence-specific OligoNucleotide probe hybridization, among the Ashkenazi and the Non-Ashkenazi Jewish sections and with respect to the different clinical courses of the disease.
The haplotype DRB1*1501, DQA1*0102, DQB1*0602 was found to be associated with MS among both Ashkenazi and Non-Ashkenazi patients (P<.001 and P =.04, respectively).
Among the Non-Ashkenazi patients, a new association of haplotypes DRB1*1303, DQA1*05, and DQB1*030 with MS was detected (P = .03).
The MS susceptibility alleles, DRB1*1501, DQA1*0102, and DQB1*0602, were found in association with the Ashkenazi patients (P<.001, P=.02, and P=.01, respectively).
DRB1*1501 and DRB1*1303 were more frequently observed among the Non-Ashkenazi patients (P = .03, P = .04, respectively).
On subdivision of the patients into clinical subgroups, associations of DRB1*0801, DQA1*0102, DQA1*0401, and DQB1*0602 with Chronic Primary/Progressive MS among the Ashkenazi patients were evident (P = .03, P = .04, P = .04 and P = .05, respectively).
Whereas DRB1*1501, DRB1*03011, and DQB1*0602 were associated with Relapsing/Remitting or Secondary/Progressive among the Non-Ashkenazi patients (P = .05, P = .05, and P = .03, respectively).
This study, unlike previous ones, is the first to show a significant association between MHC Class II alleles and MS in the Jewish population.
The association with the HLA-DR2-related haplotype is similar to that among Non-Jewish white patients with MS.
Moreover, our data support the possibility that DRB1*1501 is the susceptibility allele responsible for the association between this haplotype and MS in the Jewish population.
Our study also underscores differences in HLA profiles between Ashkenazi and Non-Ashkenazi patients, and between the different clinical courses of the disease.
The latter may indicate that the clinical courses of MS are influenced by the Genetic background.
Evidence Of Linkage Between Susceptibility To Multiple Sclerosis And HLA-Class II Loci In Italian Multiplex Families
Eoli M., Pandolfo M., Amoroso A., Salmaggi A., Zaffaroni M., Gasparini P., DiDonato S., Milanese C., Zeviani M.
Eur J Hum Genet (1995) 3(5):303-11
To verify whether MultiAllelic PolyMorphisms belonging to HLA Class II Genes are linked to Multiple Sclerosis (MS) in the Italian population, we studied 28 multiplex MS families originating from different areas of Italy.
Allelic characterization was carried out by analysis of RFLPs and OligoNucleotide typing.
Evidence supporting the existence of linkage between MS susceptibility and the MHC Class II loci DRB1, DQA, 1and DQB1 was provided using two non-parametric tests, affected sib-pair analysis, and Affected-Pedigree-Member (APM) analysis.
The APM analysis also suggested the existence of Genetic heterogeneity for the HLA Class II loci and MS susceptibility in our series.
Linkage disequilibrium between MS susceptibility and the haplotype DRB1*1501, DQA1*0102, DQB1*0602 was demonstrated by applying the transmission linkage disequilibrium test to our families.
Finally, lod score analysis suggests that in our Italian families, MS susceptibility is conferred by MHC Class II alleles according to a low-penetrance autosomal recessive mode of inheritance.
An Extended Genome Scan In 442 Canadian Multiple Sclerosis-Affected Sibships: A Report From The Canadian Collaborative Study Group
Canadian Collaborative Study Group
Dyment DA, Sadovnick AD, Willer CJ, Armstrong H, Cader ZM, Wiltshire S, Kalman B, Risch N, Ebers GC
Hum Mol Genet 2004 May 15;13(10):1005-15
The Wellcome Trust Center for Human Genetics, Oxford, UK
Multiple Sclerosis (MS) is a complex trait with a sibling relative risk (lambda(sibs)) between 18 and 36. We report a multistage Genome scan of 552 sibling pairs from 442 families, the largest MS family sample assessed for linkage.
The first stage consisted of a Genome scan for linkage with 498 MicroSatellite markers at an average spacing of 7 cM in 219 sibling pairs.
The second stage involved further GenoTyping of markers from positive regions in an independent sample of 333 affected sibling pairs.
The global distribution of Allele sharing for all markers showed a shift towards greater sharing within the affected sibling pair group but not in the discordant sibling pair group.
This shift indicates that the number of contributing genetic factors is likely to be moderate to large.
Only markers at Chromosome 6p showed significant evidence for linkage (MLOD=4.40), while other regions were only suggestive (1p, 2q, 5p, 9q, 11p, 12q, 18p, 18q and 21q) with MLODs greater than 1.0.
The replication analysis involving all 552 affected sibling pairs confirmed suggestive evidence for five locations, namely, 2q27 (MLOD=2.27), 5p15 (MLOD=2.09), 18p11 (MLOD=1.68), 9q21 (MLOD=1.58) and 1p31 (MLOD=1.33).
Suggestive linkage evidence for a previously reported location on Chromosome 17q (MLOD=1.67) and a prior association with marker D17S789 was replicated.
We showed that the overall excess Allele sharing we observed for the entire sample was due to increased Allele sharing within the DRB1*15 negative subgroup alone.
This observation is most consistent with a model of genetic heterogeneity between HLA and other genetic loci.
These findings offer guidance for future genetic studies including dense SNP linkage disequilibrium analysis.
Heterogeneity At The HLA-DRB1 Locus And Risk For Multiple Sclerosis
Barcellos LF, Sawcer S, Ramsay PP, Baranzini SE, Thomson G, Briggs F, Cree BC, Begovich AB, Villoslada P, Montalban X, Uccelli A, Savettieri G, Lincoln RR, DeLoa C, Haines JL, Pericak-Vance MA, Compston A, Hauser SL, Oksenberg JR
Hum Mol Genet 2006 Sep 15;15(18):2813-24
University of California, School of Public Health, Division of Epidemiology, Berkeley 94720, USA, and University of Cambridge, Addenbrooke's Hospital, Department of Clinical NeuroSciences, UK
Variation in Major Histocompatibility Complex genes on chromosome 6p21.3, specifically the Human Leukocyte Antigen HLA-DR2 or -DRB1*1501 -DQB1*0602 extended haplotype, confers risk for Multiple Sclerosis (MS).
Previous studies of DRB1 variation and both MS susceptibility and phenotypic expression have lacked statistical power to detect modest genotypic influences, and have demonstrated conflicting results.
Results derived from analyses of 1339 MS families indicate DRB1 variation influences MS susceptibility in a complex manner.
DRB1*15 was strongly associated in families (P=7.8x10(-31)), and a dominant DRB1*15 dose effect was confirmed (OR=7.5, 95% CI=4.4-13.0, P < 0.0001).
A modest dose effect was also detected for DRB1*03; however, in contrast to DRB1*15, this risk was recessive (OR=1.8, 95% CI=1.1-2.9, P=0.03).
Strong evidence for under-transmission of DRB1*14 (P=5.7x10(-6)) even after accounting for DRB1*15 (P=0.03) was present, confirming a protective effect.
In addition, a high risk DRB1*15 genotype bearing DRB1*08 was identified (OR=7.7, 95% CI=4.1-14.4, P < 0.0001), providing additional evidence for trans DRB1 allelic interactions in MS.
Further, a significant DRB1*15 association observed in Primary/Progressive MS families (P=0.0004), similar to Relapsing/Remitting MS families, suggests that DRB1-related mechanisms are contributing to both phenotypes.
In contrast, results obtained from 2201 MS cases argue convincingly that DRB1*15 genotypes do not modulate age of onset, or significantly influence disease severity measured using Expanded Disease Disability Score and disease duration.
These results contribute substantially to our understanding of the DRB1 locus and MS, and underscore the importance of using large sample sizes to detect modest genetic effects, particularly in studies of genotype-phenotype relationships.