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

Abstract

Variations in the interleukin 4 receptor A (IL4RA) gene have been reported to be associated with atopy, asthma, and allergy, which may occur less frequently in subjects with type 1 diabetes (T1D). Since atopy shows a humoral immune reactivity pattern, and T1D results from a cellular (T lymphocyte) response, we hypothesised that alleles predisposing to atopy could be protective for T1D and transmitted less often than the expected 50% from heterozygous parents to offspring with T1D. We genotyped seven exonic single nucleotide polymorphisms (SNPs) and the -3223 C4T SNP in the putative promoter region of IL4RA in up to 3475 T1D families, including 1244 Finnish T1D families. Only the À3223 C4T SNP showed evidence of negative association (P ¼ 0.014). There was some evidence for an interaction between À3233 C4T and the T1D locus IDDM2 in the insulin gene region (P ¼ 0.001 in the combined and P ¼ 0.02 in the Finnish data set). We, therefore, cannot rule out a genetic effect of IL4RA in T1D, but it is not a major one.

Lack of association of type 1 diabetes with the IL4R gene

“…This result is concordant with two independent family-based studies [10,12,14]. In the study of 309 US diabetic families, one nsSNP, rs1801275 (NP_000409/R576Q, deduced from the genotyping protocol of that study), was tested for type 1 diabetes association and no association was found [14].…”

“…In the study of 309 US diabetic families, one nsSNP, rs1801275 (NP_000409/R576Q, deduced from the genotyping protocol of that study), was tested for type 1 diabetes association and no association was found [14]. In the other study [12], one promoter SNP and seven nsSNPs were tested in 3,475 families, with the two largest subsets being 999 UK families and 1,231 Finnish families. None of the nsSNPs in that study was significantly associated with type 1 diabetes in the total family subjects, but in the Finnish subset the nsSNP rs1805012 was associated with type 1 diabetes, with p=0.03 and odds ratio 0.77 (95% CI 0.62-0.97) [12].…”

“…Some other autoimmune diseases or allergic conditions, such as asthma [4,5], primary Sjogren's syndrome [6], penicillin allergy [7] and atopic dermatitis [8], have been reported to be associated with the IL4R polymorphisms in recent years. However, the association between IL4R polymorphisms with type 1 diabetes has been addressed in several reports [9][10][11][12][13][14] with contradictory results. Two independent case-control studies [9,11] reported associations of the same three single-nucleotide polymorphisms (SNPs), E375A (rs1805011), L389L (rs2234898) and C406R (rs1805012), with type 1 diabetes.…”

“…One possible explanation for the discrepant results is population stratification. It was also found that allele frequencies in six of the eight IL4R SNPs (except for E375A and C406R) were different among European populations, with high statistical significance (p≤2×10 −4 ) [12], and it is not impossible that the Filipino population might also contain genetic diversity leading to population stratification. Population stratification may bias the real type 1 diabetes association and cause either false positive or false negative results [15].…”

“…An unequivocal answer to this question can only be given by a study design immune to population stratification, such as a family-based study employing the transmission disequilibrium test (TDT) [16]. However, even the available TDT studies on the association between IL4R and type 1 diabetes are contradictory [10,[12][13][14]. In this study, we tested the association between type 1 diabetes and each of six IL4R nsSNPs in a DNA collection from 830 families of European descent with one affected child; the study had a statistical power of >99% to detect the IL4R association with the effect size as most recently reported [9].…”