Common variants within the interleukin 4 receptor ? gene (IL4R) are associated with susceptibility to osteoarthritis

Abstract

Primary osteoarthritis (OA) is a common late-onset arthritis that demonstrates a complex mode of transmittance with both joint-site and gender-specific heterogeneity. We have previously linkage-mapped an OA susceptibility locus to a 12-cM interval at chromosome 16p12.3-p12.1 in a cohort of 146 affected female sibling-pair families ascertained by total hip replacement (female-THR families), with a maximum multipoint LOD score of 1.7. Despite the low LOD score, we were encouraged to investigate this interval further following the report of a linkage to the same interval in an Icelandic pedigree with an early-onset form of hip OA. Using public databases, we searched the interval for plausible candidates and concluded that the gene encoding the interleukin 4 receptor alpha chain (IL4R) was a particularly strong candidate based on its known role in cartilage homeostasis. We genotyped nine common single nucleotide polymorphisms (SNPs) from within IL4R, including six non-synonymous SNPs, in the 146 probands from our female-THR families (stage 1) and in an independent cohort of 310 female-THR cases (stage 2). We compared allele frequencies with those of 399 age-matched female controls. All individuals were UK Caucasians. The minor alleles of two SNPs demonstrated association in both stages, with the most significant association having a P-value of 0.004 with an odds ratio (OR) of 2.1. These two SNPs defined two associated SNP groups. Inheriting a minor SNP allele from both groups was a particular risk factor (OR=2.4, P=0.0008). Our data suggest that functional variants within the IL4R gene predispose to hip OA in Caucasian females.

Linkage to nodal osteoarthritis: quantitative and qualitative analyses of data from a whole-genome screen identify trait-dependent susceptibility loci

“…30 The suggestive locus we identified on chromosome 16 at 52.3 cM (for U-JSN) also seems concordant with a locus for hip osteoarthritis reported by two independent studies, 31 32 and encompasses the interleukin 4 receptor a (IL4R) gene, which has been associated with osteoarthritis in women. 33 As hip and isolated hand osteoarthritis have not been strongly associated, we compared the frequency of people in our study with hip osteoarthritis in those families who contributed to the chromosome 16 linkage and those who did not, and found no difference (results not shown).…”

Polymorphism in the β 2 -Adrenergic Receptor and Lipoprotein Lipase Genes as Risk Determinants for Idiopathic Venous Thromboembolism

“…Allelic variations in this gene have been associated with atopy, 23 type 1 diabetes mellitus, 24,25 serum IgE response, 26,27 and osteoarthritis. 28 However, future studies are needed to provide further evidence for an association.…”

Interleukin‐4 antagonizes oncostatin M and transforming growth factor beta‐induced responses in articular chondrocytes

“…Antiinflammatory activity of IL-4 was also attributed to its ability to induce apoptosis in monocytes [Mangan et al, 1992]. Interestingly, mutations of IL-4 receptor have been recently linked to increased susceptibility to hip osteoarthritis in Caucasian females [Forster et al, 2004].…”