From Identification to Characterization of the Multiple Sclerosis Susceptibility Gene CLEC16A

Abstract

Multiple sclerosis (MS) is an inflammatory, demyelinating disorder of the central nervous system that develops in genetically susceptible individuals, probably triggered by common environmental factors. Human leukocyte antigen (HLA) loci were early shown to confer the strongest genetic associations in MS. Now, more than 50 non-HLA MS susceptibility loci are identified, of which the majority are located in immune-regulatory genes. Single nucleotide polymorphisms (SNPs) in the C-type lectin-like domain family 16A (CLEC16A) gene were among the first non-HLA genetic variants that were confirmed to be associated with MS. Fine-mapping has indicated a primary association in MS and also other autoimmune diseases to intronic CLEC16A SNPs. Here, we review the identification of MS susceptibility variants in the CLEC16A gene region, functional studies of the CLEC16A molecule and the recent progress in understanding the implications thereof for MS development. This may serve as an example of the importance for further molecular investigation of the loci identified in genetic studies, with the aim to translate this knowledge into the clinic.

Understanding the genetic and epigenetic basis of common variable immunodeficiency disorder through omics approaches

“…[41] The CLEC16A locus is pleiotropic, which was first found to be associated Type I Diabetes [42], then association was established with several other immune-related diseases, including autoimmunity, allergy. [43] By studying gene expression in human blood samples and Clec16a conditional knockout mouse model, we further found the correlation between CLEC16A gene expression and genotype status, and demonstrated the potential role of Clec16a in B cell development. [41] …”

Association of the C-type lectin-like domain family-16A (CLEC16A) gene polymorphisms with acute coronary syndrome in Mexican patients

“…Association studies have identified several SNPs in CLEC16A gene (previously called KIAA0350) associated with the risk of developing several inflammatory diseases [10,[16][17][18][19][20][21][22][23][24]. In the present paper, we studied four polymorphisms (146529 A > G, 155804 G > C, 47905 C > G and 64135 C > T) located in the CLEC16A gene.…”

“…CLEC16A presents four important SNPs, two in the intron 19 [position 146529 A > G (rs12708716) and position 155804 G > C (rs12917716)] and two in the introns 10 and 11, respectively [position 47905 C > G (rs6498142) and position 64135 C > T (rs9925481)]. These SNPs have been associated with risk to developing several inflammatory diseases as type 1 diabetes, multiple sclerosis, juvenile arthritis, rheumatoid arthritis, IgA deficiency [10,[16][17][18][19], Addison's disease, myocardial infarction, hypertension, metabolic syndrome [20][21][22], chronic kidney disease [23], and inflammatory bowel diseases [24].…”

Contribution of Rare and Common Genetic Variants to Plasma Lipid Levels and Carotid Stiffness and Geometry

“…rs2903692 is located at a distance of 58 910 bp from rs12708716, the lead SNP associated with type 1 diabetes mellitus, and both SNPs are in tight LD (R 2 =0.96). The mechanism of implication of CLEC16A in immune diseases is not clearly established, 30,31 and it is possible that other genes in the region are responsible for the association of this locus with immune diseases. It is interesting that Chromosome Conformation Capture studies have demonstrated physical proximity of the promoter of the nearby DEXI gene and intron 19 of CLEC16A.…”

“…rs2903692 is located in intron 22 of CLEC16A at position 16:11144926. The 3 intronic variants on the CLEC16A sequence were added to the exome array because they have been reported to be associated with several immunity-related diseases, 30 particularly type 1 diabetes mellitus and multiple sclerosis. rs2903692 is located at a distance of 58 910 bp from rs12708716, the lead SNP associated with type 1 diabetes mellitus, and both SNPs are in tight LD (R 2 =0.96).…”