A novel polymorphism in the 5′ promoter region of the human interleukin-4 receptor α-chain gene is associated with decreased soluble interleukin-4 receptor protein levels

Abstract

Interleukin (IL)-4 exerts its biological effects through binding to the IL-4 receptor (IL4R) complex, plays a central role in stimulating B-cell differentiation, and is crucial for the development of T helper 2 cells. Recently, a soluble form of the human IL4R alpha chain (sIL4R alpha), which is produced by alternate mRNA splicing of exon 8, was discovered. sIL4R is thought to play an important role in either enhancing or inhibiting IL-4 signalling. We analyzed the 5' promoter region of the human IL4R alpha-chain gene (IL4RA) of healthy volunteers by DNA sequencing and found three novel single-nucleotide polymorphisms (SNPs; T-890C, T-1914C, C-3223T) and one novel short tandem repeat [(CAAAA)(5-7)-3600]. The two common promoter region SNPs T-1914C and C-3223T as well as six known coding SNPs in the IL4RA gene were genotyped in healthy blood donors by PCR with sequence-specific primers; total sIL4R levels were measured by ELISA. Results revealed a highly significant association of the -3223T variant with lowered sIL4R levels (two-tailed t-test, P=0.0002). Results remained highly significant after Bonferroni adjustment for multiple comparisons (P=0.0017). Moreover, the C-3223T variant was found to be in strong linkage disequilibrium with the extracellular 150V variant (P<0.001), which was recently described to be associated with atopic asthma in a Japanese population. Since this novel IL4RA promoter region SNP is common (allele frequency 29.8%), we conclude that it may be of importance for the genetic regulation of the IL-4 signalling pathway.

Testing the possible negative association of type 1 diabetes and atopic disease by analysis of the interleukin 4 receptor gene

“…29 There was no evidence that the potential disease association of À3223 C4T differed between the six populations (not shown). As shown by a linkage disequilibrium map in Figure 1, the disease association of the À3223 C4T SNP does not appear to be due to disease association of the +148 A4G (I50V) variant as previously reported, 20 since the À3223 C4T SNP is not in linkage disequilibrium with +148 A4G (I50V).…”

Identification of single-nucleotide and repeat polymorphisms in two candidate genes, interleukin 4 receptor (IL4RA) and signal transducer and activator of transcription protein 6 (STAT6), for Th2-mediated diseases

“…Similarly, the genomic region harboring the STAT6 gene (12q21.2) has also been found to be associated with such disorders (Tamura et al 2001). In addition, several functional polymorphisms that lead to aberrant expression and signal transduction resulted in atopic phenotypes (Hackstein et al 2001;Mitsuyasu et al 1999). In contrast, these genes were not found to be associated with atopy in a Caucasian and Japanese study (Duetsch et al 2002;Tanaka et al 2001).…”

Analysis of IL4R haplotypes in predisposition to multiple sclerosis

“…The potential regulatory role of the T(À1914)C SNP has not been as well characterized as that of the C(À3223)T SNP, which has been demonstrated to affect the level of soluble IL4R (sIL4R) protein in blood. 25 As these two promoter SNPs are in strong linkage disequilibrium, a role for the T(À1914)C SNP in sIL4R expression as well cannot be discounted, but alternatively its variation may be linked to other regulatory consequences. We speculate that it is the expression of an IL4R protein possessing only wild-type amino acids at polymorphic positions (haplotype H-1), expressed by one specific allelic arrangement of cisacting sequences, that confers the increased risk of MS.…”