Revisiting the T-cell receptor alpha/delta locus and possible associations with multiple sclerosis.

A role for T cells in the pathogenesis of multiple sclerosis (MS) is well supported, evidenced by myriad immunological studies, as well as the unequivocal genetic influence of the major histocompatibility complex (MHC). Despite many attempts, no convincing genetic associations have been made between T-cell receptor (TCR) gene loci and MS. However, these studies may not be definitive because of small sample sizes and under-representative marker coverage of the chromosomal regions being investigated. To explore potential roles between the TCR alpha locus and MS, we have genotyped a large family-based cohort, including 1360 affected individuals and 1659 of their unaffected first-degree relatives, at 40 single-nucleotide polymorphism (SNP) markers within the TCR alpha/delta locus. This represents the largest TCR alpha-MS study to date. From this screen, we identified three potential loci of interest in TCR alpha variable and constant gene regions using the transmission disequilibrium test. Although SNPs implicating each of these regions of interest will require genotyping in independent replication cohorts, these findings suggest a role for TCR gene polymorphisms in MS susceptibility. In the context of these findings we review the evidence.

Genetic and environmental factors and the distribution of multiple sclerosis in Europe.

BACKGROUND: The observation that the incidence of multiple sclerosis (MS) increases further from the equator has prompted considerable interest in the factors that might underlie this latitude gradient. Potential candidates include population frequencies of disease-associated Human Leukocyte Antigen (HLA) alleles which are the major genetic component of MS susceptibility. Ultraviolet (UV) exposure and smoking have also been implicated as key environmental risk factors. METHODS: We used multiple sources of published data on MS prevalence, HLA allele frequencies, UV index and cigarette smoking to assess the contributions of both nature and nurture to the distribution of MS within Europe. RESULTS: We observed that HLA alleles unequivocally interact with a population-wide level to determine disease risk. The UV index and smoking behaviour was also shown to correlate with disease distribution in Europe. For countries with HLA, UV and smoking data, these three factors were shown to account for 75% of the variance in MS prevalence. CONCLUSIONS: Genetic (HLA) and environmental (UV and smoking) risk factors thus interact in a complex manner with each other to determine a large proportion of MS susceptibility within Europe.

HLA-DRB1 confers increased risk of pediatric-onset MS in children with acquired demyelination.

BACKGROUND: Multiple sclerosis (MS) in the pediatric age group is being increasingly recognized. In adults, complex interactions between genetic and environmental factors contribute to risk and the major genetic component of MS susceptibility localizes to the major histocompatibility complex (human leukocyte antigen [HLA]). Whether HLA alleles predict MS in at-risk children presenting with acquired demyelinating syndromes (ADS) of the CNS is unknown. METHODS: HLA-DRB1 alleles were typed using an allele-specific PCR amplification method on samples from 266 children presenting with ADS enrolled in the prospective Canadian Pediatric Demyelinating Disease Study and from 196 healthy controls. RESULTS: Sixty-four of 266 children with ADS met established criteria for a diagnosis of MS during a mean follow-up of 3.2 ± 1.5 years. Children harboring DRB1*15 alleles were more likely to be diagnosed with MS (χ(2) = 12.2, p < 0.001; OR = 2.7), an observation strengthened by children of European ancestry (χ(2) = 10.5, p = 0.001; OR = 3.3). DRB1*15 allele frequencies in children with ADS of European ancestry subsequently diagnosed with MS were greater than in children with monophasic ADS (χ(2) = 10.7, p = 0.001) or healthy controls (χ(2) = 12.5, p < 0.001). The proportion of children with non-European ancestry diagnosed with MS was not influenced by DRB1*15 status. CONCLUSION: DRB1*15 alleles confer increased susceptibility to pediatric-onset MS, supporting a fundamental similarity in genetic contribution to MS risk in both pediatric- and adult-onset disease. The specificity of the DRB1*15 risk allele for children with subsequent MS diagnosis, but not for all children with ADS, indicates that the risk conveyed by DRB1*15 relates to chronic CNS disease (MS), rather than acquired demyelination in general.

Relationship of UV exposure to prevalence of multiple sclerosis in England.

OBJECTIVE: To assess the potential relationship of ultraviolet B radiation (UVB) and Epstein-Barr virus (EBV) exposure in explaining the period prevalence of multiple sclerosis (MS) in England. METHODS: English national Hospital Episode Statistics covering all admissions to National Health Service hospitals in England in the 7 years from 1998 to 2005 were used to obtain the period prevalences of MS and infectious mononucleosis (IM) in England. The United States National Aeronautics and Space Administration's data on UVB intensity for England from the Nimbus 7 satellite was collected. The relationships among the 3 variables (MS prevalence, IM prevalence, and UVB intensity) were investigated. RESULTS: The regression of MS against UVB intensity for all seasons had an r(2) of 0.61; when including the interaction of IM with seasonal UVB, the r(2) rose to 0.72. CONCLUSIONS: UVB exposure and IM together can explain a substantial proportion of the variance of MS. The effect of UVB on generating vitamin D seems the most likely candidate for explaining its relationship with MS. There is a pressing need to investigate the role of vitamin D and EBV and how they might interact to influence MS risk to identify potential prevention strategies.

Multiple sclerosis and lung cancer: an unexpected inverse association.

Multiple sclerosis is associated with a decreased risk of cancer. Smoking is a risk factor both for multiple sclerosis and lung cancer. We performed a meta-analysis on studies of cancer frequency in multiple sclerosis. Surprisingly, we found that the risk of lung cancer is reduced in multiple sclerosis [odds ratio 0.67 (95% confidence interval 0.59-0.76) P < 0.00001]. Since this does not appear to be secondary to altered smoking behaviour, we hypothesise that this may be secondary to altered immune surveillance.