Association of arthritis with a gene complex encoding C‐type lectin–like receptors

Abstract

Objective. To identify susceptibility genes in a rat model of rheumatoid arthritis (RA) and to determine whether the corresponding human genes are associated with RA.Methods. Genes influencing oil-induced arthritis (OIA) were position mapped by comparing the susceptibility of inbred DA rats with that of DA rats carrying alleles derived from the arthritis-resistant PVG strain in chromosomal fragments overlapping the quantitative trait locus Oia2. Sequencing of gene complementary DNA (cDNA) and analysis of gene messenger RNA (mRNA) expression were performed to attempt to clone a causal gene. Associations with human RA were evaluated by genotyping single-nucleotide polymorphisms (SNPs) in the corresponding human genes and by analyzing frequencies of alleles and haplotypes in RA patients and age-, sex-, and area-matched healthy control subjects.Results. Congenic DA rats were resistant to OIA when they carried PVG alleles for the antigenpresenting lectin-like receptor gene complex (APLEC), which encodes immunoregulatory C-type lectin-like receptors. Multiple differences in cDNA sequence and mRNA expression precluded cloning of a single causal gene. Five corresponding human APLEC genes were identified and targeted. The SNP rs1133104 in the dendritic cell immunoreceptor gene (DCIR), and a haplotype including that marker and 4 other SNPs in DCIR and its vicinity showed an indication of allelic association with susceptibility to RA in patients who were negative for antibodies to cyclic citrullinated peptide (anti-CCP), with respective odds ratios of 1.27 (95% confidence interval [95% CI] 1.06-1.52; uncorrected P ‫؍‬ 0.0073) and 1.37 (95% CI 1.12-1.67; uncorrected P ‫؍‬ 0.0019). Results of permutation testing supported this association of the haplotype with RA.

The rat antigen-presenting lectin-like receptor complex influences innate immunity and development of infectious diseases

“…Rat Dcar1 is a strong candidate as it appears functional in R17 rats but nonsense mutated in DA rats. 6 Interestingly, we discovered that Dcar1 mRNA expression was rapidly lost in vitro. The strikingly differential in vitro responses of DA-and R17-derived BMMF are therefore most likely not mediated by Dcar1, but rather by the other rat APLEC gene products, that is, Dcir1-4, Mcl and Mincle.…”

“…5,6 The cluster contains seven genes encoding C-type lectin-like receptors, that is, Mincle, Mcl, Dcar1 and Dcir1-Dcir4, which are expressed on leukocytes, to some extent on T lymphocytes, 7 but mainly on neutrophils and antigen-presenting cells, including macrophages. [5][6][7] The ligands and functions of the receptors remain unknown, but the receptor type has been implicated in diverse functions, such as microbial pattern recognition, cellular adhesion and migration, antigen uptake and presentation, T cell co-stimulation, and signal transduction through immunoreceptor tyrosine-based inhibitory or activating motifs (ITIMs and ITAMs, respectively). [8][9][10][11] Interestingly, we observed earlier that APLEC regulates clinical phenotypes in RA models induced by nonimmunogenic structures that activate the innate immune system, for example, incomplete Freund's adjuvant oil and yeast b-glucan.…”

“…We thus compared inbred DA rats with congenic DA rats (R17) that carry APLEC (o0.6 Mb substitution) derived from inbred PVG.1AV1 rats. 5,6 The phenotypes evaluated in DA and R17 rats were (i) S. aureus-induced septic arthritis; (ii) HSVinduced encephalitis; (iii) oxazalone-induced delayed type hypersensitivity (DTH) as well as olive oil-induced inflammation; and (iv) cellular responses of bone marrow (BM)-derived macrophages (BMMF) to different types of microbial adjuvants. We report a distinct genetic influence of APLEC on most of these phenotypes relating to innate immunity.…”

Replication of Associations of Genetic Loci Outside the HLA Region With Susceptibility to Anti–Cyclic Citrullinated Peptide–Negative Rheumatoid Arthritis

“…The novel associations at PRL and NFIA add to the list of suggestive or confirmed anti‐CCP–negative RA susceptibility loci: PTPN22, TNFAIP3, C5orf30, STAT4, BLK 8, SPP1 16, CLEC16A 17, IRF5 18, DCIR 19, 20, CLYBL 14, SMIM21 14, and ANKRD55 21. However, only a few of those associations have been independently replicated or confirmed at genome‐wide levels of significance.…”

“…We have previously tested markers of anti‐CCP–positive RA for their association with anti‐CCP–negative RA 8 and reported that several anti‐CCP–positive RA susceptibility loci (e.g., AFF3, CCR6, CCL21, IL2RA, and CD28 ) were not shared with anti‐CCP–negative RA, while markers at TNFAIP3, C5orf30, STAT4, ANKRD55, BLK, and PTPN22 were associated with both anti‐CCP–positive and anti‐CCP–negative RA. In addition, CLYBL 14, SMIM21 14, SPP1 16, CLEC16A 17, IRF5 18, and DCIR 19, 20 have been reported to be associated with anti‐CCP–negative RA. Of the markers reported to be associated with anti‐CCP–negative RA, only CLYBL 14, SMIM21 14, and ANKRD55 21 have been independently replicated or confirmed at genome‐wide levels of significance.…”