Genetic studies of multiple sclerosis and neuromyelitis optica: Current status in European, African American and Asian populations

Abstract

Multiple sclerosis (MS) pathogenesis results from both genetic and environmental factors. Genome-wide association studies (GWAS) have contributed considerably to our understanding of MS susceptibility through identification of genetic variants influencing risk and quantitation of their effect sizes. Immunologically relevant genes, including genes in the major histocompatibility complex region, are the primary genetic contributors to MS susceptibility. MS prevalence differs according to population, and most GWAS carried out to date have used datasets from people of European descent. Interpretation and application of GWAS results from Europeans to other populations require a good understanding of the genetic characteristics of each population, such as linkage disequilibrium patterns. The heterogeneity in global MS prevalence is partially explained by differences in risk allele frequencies in populations, which are due to the effects of migration, adaptation to new environments and genetic heterogeneity. Genetic studies of different populations can be expected to narrow down the putative causative regions and improve our understanding of MS pathogenesis. The literature record of genetic studies of neuromyelitis optica is much shorter than that of MS. Genes associated with neuromyelitis optica have been reported in the major histocompatibility complex region, as well as at other genetic loci, but only the susceptibility associated with the HLA-DPB1*05:01 and HLA-DRB1*03 alleles, and the association of a CYP7A single nucleotide polymorphism have been replicated. Here, we describe important genetic studies of MS and neuromyelitis optica in Europeans, African Americans, and Asians, and discuss the implications for disease incidence and future directions for genetic research. (Clin. Exp. Neuroimmunol.

Copy number variations in multiple sclerosis and neuromyelitis optica

“…44 The deletion-type CNV is associated with negative/low titers of anti-AQP4 antibodies and high brain lesion load in NMO/NMOSD, suggesting the importance of T cells with a specific TCR repertoire in AQP4 antibody-seronegative NMO, which often has more brain lesions than seropositive cases. 10,11 This difference might be caused by distinct genetic and environmental backgrounds. First, the CNV boundaries cannot be accurately specified, even with high-density SNP microarrays, because probes are set at specific intervals.…”

“…50 There were some limitations and implications in our study. 10,11 Therefore, the CNVs at TRG and TRA may not be common variations in all MS and NMO patients globally. That the TCR delta locus is located within the telomeric end of TRA, and that they exist adjacently, may also make it difficult to precisely detect CNVs in this genomic region and interpret the results.…”

“…The prevalence and disease manifestations of MS are significantly different between Caucasians and Asians. 10,11 This difference might be caused by distinct genetic and environmental backgrounds. 10,11 Therefore, the CNVs at TRG and TRA may not be common variations in all MS and NMO patients globally.…”

“…5 Furthermore, cerebrospinal fluid (CSF) from NMO patients at relapse shows increased T helper (Th)1 and Th17 cytokine levels. [9][10][11] Certain polymorphisms of human leukocyte antigen genes have strong associations with susceptibility to MS 12 and NMO. 8 MS and NMO are not thought to be hereditary diseases, but a number of genetic variations increase the risk of developing disease.…”

“…8 MS and NMO are not thought to be hereditary diseases, but a number of genetic variations increase the risk of developing disease. [9][10][11] Certain polymorphisms of human leukocyte antigen genes have strong associations with susceptibility to MS 12 and NMO. 13 Genome-wide association studies (GWASs) of European descendants have identified >100 immunologically relevant genes associated with MS that are outside the major histocompatibility complex region.…”