Exploring the CLEC16A gene reveals a MS-associated variant with correlation to the relative expression of CLEC16A isoforms in thymus

Abstract

Genomewide association studies have implicated the CLEC16A gene in several autoimmune diseases, including multiple sclerosis (MS) and type 1 diabetes. However, the most associated single-nucleotide polymorphism (SNP) varies, and causal variants are still to be defined. In MS, two SNPs in partial linkage disequilibrium with each other, rs6498169 and rs12708716, have been validated at genomewide significance level. To explore the CLEC16A association in MS in more detail, we genotyped 57 SNPs in 807 Norwegian MS patients and 1027 Norwegian controls. Six highly associated SNPs emerged and were then replicated in two large independent sample sets (Norwegian and British), together including 1153 MS trios, 2308 MS patients and 4044 healthy controls. In combined analyses, SNP rs12708716 gave the strongest association signal in MS (P ¼ 5.3 Â 10 À8 , odds ratio 1.18, 95% confidence interval ¼ 1.11-1.25), and was found to be superior to the other SNP associations in conditional logistic regression analyses. Expression analysis revealed that rs12708716 genotype was significantly associated with the relative expression levels of two different CLEC16A transcripts in thymus (P ¼ 0.004), but not in blood, possibly implying a thymus-or cell-specific splice regulation.

Expression pattern and signalling pathways in neutrophil like HL-60 cells after treatment with estrogen receptor selective ligands

“…The verified genes are involved in a variety of vital functions. CLEC16A and CXCL5 are involved in various inflammatory and immune disorders (Mero et al, 2011;Szekanecz et al, 1998;Walz et al, 1997). PRKAG2, CNNM2 and NUP155 are associated with cardiovascular diseases (Gollob et al, 2002;Takeuchi et al, 2010;Zhang et al, 2008).…”

Functional evaluation of the role of C-type lectin domain family 16A at the chromosome 16p13 locus

“…Aside from the tight LD observed in the associated locus, the pursuit of revealing the diseasecausing variant has been hindered by the lack of association of nsSNPs [1,8,12] and inconclusive evidence that the associated intronic SNPs exert transcriptional effects on CLEC16A and its surrounding genes [1,[13][14][15] and Marchand et al 2009 and Zouk et al 2102 (unpublished results). Therefore, before uncovering such potential causal variants, it is imperative that we gain more insight into the largely unknown function of the CLEC16A protein to decipher how these variants, when discovered, would affect protein function and consequent disease pathology.…”

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

“…In addition, Todd et al [9] reported in a genome-wide association study that the G allele was associated with decreased risk of developing type 1 diabetes (OR = 0.77) and Graves' disease in English population. According with these data, Mero et al [30] determined the CLEC16A RNA expression based in two CLEC16A transcripts; a short (21 exons) and a full-length (24 exons) protein variants in the thymus tissue and peripheral blood samples from healthy controls considering their genotype. In this work, the authors found that the short isoform was overexpressed in the individuals with GG genotype, whereas individuals with AA genotype overexpressed the full-length isoform.…”