A Second-Generation Association Study of the 5q31 Cytokine Gene Cluster and the Interleukin-4 Receptor in Asthma

Abstract

We have analyzed a dense set of single-nucleotide polymorphisms (SNPs) and microsatellites spanning the T-helper cytokine gene cluster (interleukins 3, 4, 5, 9, and 13, interferon regulatory factor-1, colony-stimulating factor-2, and T-cell transcription factor-7) on 5q31 and the gene encoding the interleukin-4 receptor (IL4R) on 16p12 among Finnish families with asthma. As shown by haplotype pattern mining analysis, the number of disease-associated haplotype patterns differed from that expected for the 129Q allele polymorphism in IL13 for high serum total immunoglobulin (Ig) E levels, but not for asthma. The same SNP also yielded the best haplotype associations. For IL4R, asthma-associated haplotype patterns, most spanning the S411L polymorphism, showed suggestive association. However, these haplotypes consisted of the major alleles for the intracellular part of the receptor and were very common among both patients and controls. The minor alleles 503P and 576R have been reported to be associated with decreased serum IgE levels and changes in the biological activity of the protein, especially when inherited together. In the Finnish population, these two polymorphisms segregated in strong linkage disequilibrium. Our data support previous findings regarding IL4R, indicating that 503P and 576R may act as minor protecting alleles for IgE-mediated disorders.Key Words: asthma, atopy, haplotype pattern mining, polymorphism, association families). The study showed suggestive linkage for asthma (LOD = 2.6) but no evidence for atopy [8]. Although it is not known whether human genes in the 5q31 cytokine cluster are genetic regulators for atopic disorders, experimental models of asthma have shown the importance of both IL4 and IL13 signaling. Administration of either exogenous IL4 or IL13 induced the asthma phenotype in mice [9]. However, neither of these cytokines was able to induce the asthma phenotype in mice deficient in the IL4 receptor (IL4R) [9]. The IL4 receptor is a heterodimer consisting of a common ␥-chain that is shared by several other interleukin receptors (IL2, IL7, IL9, and IL13) and a ligand-specific ␣-chain encoded by IL4R. An IL4R␣-IL13R␣ heterodimer is also able to transduce IL13 signaling [10] and is an important signaling pathway in the asthma model. All this indicates the importance of IL4R␣ in IL4/IL13-mediated signaling.

Allergy-Related Polymorphisms Influence Glioma Status and Serum IgE Levels

“…Versions of this haplotype (using some but not all the same SNPs) were previously linked to increased atopic asthma, decreased type I diabetes, and increased sensitivity of the IL4R receptor or decreased IL4R activity (19)(20)(21)(22). However, the minor alleles 503P and 576R have been associated with decreased IgE levels and atopy in other studies (23,24). These minor alleles comprise the fourth and fifth position of the haplotype 111110.…”

Association of ADAMTS12 polymorphisms with rheumatoid arthritis

“…COMP degradation mediated by ADAMTS7 and ADAMTS12 is inhibited by α-2-macroglobulin (22). The chromosomal location of the ADAMTS12 gene has been suggested to contain susceptibility loci for autoimmune or inflammatory diseases, such as Crohn's disease, asthma and RA (13)(14)(15)(16)(17)(18). A few studies have been published on the role of ADAMTS12 SNPs.…”

“…The ADAMTS12 gene is located on chromosome 5q35 and spans approximately 365 kb. The chromosome 5q region has been suggested to contain susceptibility loci for autoimmune or inflammatory diseases, such as Crohn's disease, asthma and RA (13)(14)(15)(16)(17)(18). Despite the potential importance of ADAMTS12 on RA pathogenesis, there have been no published studies on the relationship between the genetic variants of ADAMTS12 and RA.…”

miR-146ais a significant brake on autoimmunity, myeloproliferation, and cancer in mice

“…Histologically, these neoplasms were characterized as diffuse large cell neoplasms (Fig. 7, B-E) that stained negatively with pan-B, -T, and -myeloid cell markers (CD19, CD3, and CD11b, respectively) while displaying positive immunostaining only with anti-CD45 antibody, indicating a hematolymphoid origin note that the distal region of chromosome 5q, which contains the miR-146a gene (5q33) in man, has been previously suggested to harbor susceptibility loci for autoimmune diseases such as rheumatoid arthritis (Tokuhiro et al, 2003), Crohn's disease , asthma (Kauppi et al, 2001), and psoriasis (Friberg et al, 2006).…”