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David A Dyment

Publications and source records attributed to David A Dyment.

7 recordsLinked to original sources
PubMed2005

A predominant role for the HLA class II region in the association of the MHC region with multiple sclerosis.

Genetic susceptibility to multiple sclerosis is associated with genes of the major histocompatibility complex (MHC), particularly HLA-DRB1 and HLA-DQB1 (ref. 1). Both locus and allelic heterogeneity have been reported in this genomic region. To clarify whether HLA-DRB1 itself, nearby genes in the region encoding the MHC or combinations of these loci underlie susceptibility to multiple sclerosis, we genotyped 1,185 Canadian and Finnish families with multiple sclerosis (n = 4,203 individuals) with a high-density SNP panel spanning the genes encoding the MHC and flanking genomic regions. Strong associations in Canadian and Finnish samples were observed with blocks in the HLA class II genomic region (P < 4.9 x 10(-13) and P < 2.0 x 10(-16), respectively), but the strongest association was with HLA-DRB1 (P < 4.4 x 10(-17)). Conditioning on either HLA-DRB1 or the most significant HLA class II haplotype block found no additional block or SNP association independent of the HLA class II genomic region. This study therefore indicates that MHC-associated susceptibility to multiple sclerosis is determined by HLA class II alleles, their interactions and closely neighboring variants.

Canada↗
PubMed2005

Complex interactions among MHC haplotypes in multiple sclerosis: susceptibility and resistance.

Mechanisms for observed associations within the major histocompatibility complex (MHC) and autoimmune diseases including multiple sclerosis (MS) remain uncertain. Genotyping of the HLA Class II DRB1 locus in 4347 individuals from 873 multiplex families with MS highlights the genetic complexity of this locus. Excess allele sharing in sibling pair families lacking DRB1*15 and DRB1*17 (58.5% sharing; P=0.012) was comparable to that seen where parents were DRB1*15 positive (62%, P=0.0006). DRB1*17 (P=0.00027) was clearly established as an MS susceptibility allele in addition to DRB1*15 (P<10(-14)). DRB1*14 showed striking under-transmission (P=0.000032) to affected offspring newly establishing this allele as a broadly acting resistance factor. Trans interactions were seen in both DRB1*15 and non-DRB1*15 bearing genotype combinations. DRB1*08 was transmitted preferentially with DRB1*15 (P=0.0114) and, in the presence of DRB1*08, the transmission of DRB1*15 was almost invariable (37 transmissions to one non-transmission). DRB1*01 was under-transmitted to offspring in the presence of DRB1*15 (P=0.019). Both DRB1*01 and DRB1*14 haplotypes carry DQA1*01-DQB1*05 alleles, suggesting a common DQ-related mechanism for the protection mediated by these haplotypes. These studies demonstrate that it is the Class II genotype that determines susceptibility and resistance to MS. By analogy with celiac disease and type I diabetes, the pattern of susceptibility strongly supports an autoimmune aetiology.

Alleles↗
PubMed2004

Timing of birth and risk of multiple sclerosis: population based study.

OBJECTIVES: To determine if risk of multiple sclerosis (MS) is associated with month of birth in countries in the northern hemisphere and if factors related to month of birth interact with genetic risk. DESIGN: Population based study with population and family based controls and a retrospective cohort identified from death certificates. A post hoc pooled analysis was carried out for large northern datasets including Sweden and Denmark. SETTING: 19 MS clinics in major cities across Canada (Canadian collaborative project on the genetic susceptibility to multiple sclerosis); incident cases of MS from a population based study in the Lothian and Border regions of Scotland; and death records from the UK Registrar General. POPULATIONS: 17,874 Canadian patients and 11,502 British patients with multiple sclerosis. MAIN OUTCOME MEASURE: Diagnosis of multiple sclerosis. RESULTS: In Canada (n = 17,874) significantly fewer patients with MS were born in November compared with controls from the population census and unaffected siblings. These observations were confirmed in a dataset of British patients (n = 11, 502), in which there was also an increase in the number of births in May. A pooled analysis of datasets from Canada, Great Britain, Denmark, and Sweden (n = 42,045) showed that significantly fewer (8.5%) people with MS were born in November and significantly more (9.1%) were born in May. For recent incident data, the effect of month of birth was most evident in Scotland, where MS prevalence is the highest. CONCLUSIONS: Month of birth and risk of MS are associated, more so in familial cases, implying interactions between genes and environment that are related to climate. Such interactions may act during gestation or shortly after birth in individuals born in the northern countries studied.

Canada↗
PubMed2004

An extended genome scan in 442 Canadian multiple sclerosis-affected sibships: a report from the Canadian Collaborative Study Group.

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.

Canada↗
PubMed2004

Genetics of multiple sclerosis.

Multiple sclerosis (MS) is probably aetiologically heterogeneous. Systematic genetic epidemiological and molecular genetic studies have provided important insights. Both genetic and non-genetic (environment, stochastic) factors may be involved in susceptibility as well as outcome, but we have yet to understand their relative roles. Any environmental factor is likely to be ubiquitous and act on a population-basis rather than within the family microenvironment. Taken together, the results of genome screening studies provide strong evidence for exclusion of a major locus in MS. There are, however, many genes that seem to be associated with MS. These include, but are in no way limited to, HLA classes I and II, T-cell receptor beta, CTLA4, ICAM1, and SH2D2A. The future of MS genetics, as for most common complex disorders, will be dependent on the resources available, ranging from biological samples and comprehensive databases of clinical and epidemiological information to the development of new technologies and statistical methods.

Antigens, CD↗
PubMed2003

Significant linkage to migraine with aura on chromosome 11q24.

Migraine with aura (MA) is a prevalent neurological condition with strong evidence for a genetic basis. Familial hemiplegic migraine, a rare Mendelian form of MA, can be caused by mutations in the calcium channel gene, CACNA1A or in the ATP1A2 gene, a Na+/K+ pump. Susceptibility genes for the more prevalent forms of migraine have yet to be identified despite several reports of linkage including loci on 4q24, 1q31, 19p13 and Xq24-28. We have undertaken a genome-wide screen of 43 Canadian families, segregating MA with families chosen for an apparent autosomal dominant pattern of transmission. Diagnosis was based upon International Headache Society Criteria. Parametric linkage analysis revealed a novel locus on 11q24 with a two-point LOD score of 4.2 and a multi-point parametric LOD score of 5.6. We did not find any support for linkage at previously reported loci. The lack of consensus amongst linkage studies, including this study, is probably an indication of the heterogeneity that is inherent for MA. Nevertheless, the finding of a highly significant locus with a LOD score of 5.6 is powerful evidence that a gene increasing susceptibility to MA resides on 11q24. Several candidate genes map to this region of the genome including a number of ion channel genes such as GRIK4, SCNB2, KCNJ5 and KCNJ1.

Chromosome Mapping↗