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. Author manuscript; available in PMC: 2010 Jan 24.
Published in final edited form as: Genes Immun. 2009 Dec;10(Suppl 1):S33–S41. doi: 10.1038/gene.2009.89

Association analysis of SNPs in the IL4R locus with type I diabetes

HA Erlich 1,2, K Lohman 3, SJ Mack 2, AM Valdes 4, C Julier 5, D Mirel 6, JA Noble 2, GE Morahan 7, SS Rich 8, for the Type I Diabetes Genetics Consortium
PMCID: PMC2810494  NIHMSID: NIHMS163335  PMID: 19956098

Abstract

The Type I Diabetes Genetics Consortium (T1DGC) has collected thousands of multiplex and simplex families with type I diabetes (T1D) with the goal of identifying genes involved in T1D susceptibility. These families have all been genotyped for the HLA class I and class II loci and a subset of samples has been typed for an major histocompatibility complex (MHC) single-nucleotide polymorphism (SNP) panel. In addition, the T1DGC has genotyped SNPs in candidate genes to evaluate earlier reported T1D associations. Individual SNPs and SNP haplotypes in IL4R, which encodes the α-chain of the IL4 and IL13 receptors, have been associated with T1D in some reports, but not in others. In this study, 38 SNPs in IL4R were genotyped using the Sequenom iPLEX Gold MassARRAY technology in 2042 multiplex families from nine cohorts. Association analyses (transmission-disequilibrium test and parental-disequilibrium test) were performed on individual SNPs and on three-SNP haplotypes. Analyses were also stratified on the high-risk HLA DR3/DR4-DQB1*0302 genotype. A modest T1D association in HBDI families (n = 282) was confirmed in this larger collection of HBDI families (n = 424). The variant alleles at the non-synonymous SNPs (rs1805011 (E400A), rs1805012 (C431R), and rs1801275 (Q576R)), which are in strong linkage disequilibrium, were negatively associated with T1D risk. These SNPs were more associated with T1D among non-DR3/DR4-DQB1*0302 genotypes than DR3/DR4-DQB1*0302 genotypes. This association was stronger, both in terms of odds ratio and P-values, than the initial report of the smaller collection of HBDI families. However, the IL4R SNPs and the three-SNP haplotype containing the variant alleles were not associated with T1D in the total data. Thus, in the overall families, these results do not show evidence for an association of SNPs in IL4R with T1D.

Keywords: polymorphism, genotype, haplotype

Introduction

Type I diabetes (T1D), an autoimmune disease involving destruction of the insulin-producing cells of the pancreas, has a significant genetic component (λs = 15).1 On the basis of linkage and association analyses, the strongest contribution (40–50%) comes from the HLA region.2,3 Although alleles at the HLA-DR and -DQ-encoding loci are the major determinants of genetic risk for T1D,4,5 association studies have revealed that multiple genes within the HLA region contribute to T1D risk.6–12 In addition, many T1D susceptibility regions and genes outside the HLA region have been identified by linkage and by associations analyses.13–15 Of the genes identified by association, some have been detected by hypothesis-free genome-wide approaches,15 whereas others have been identified in candidate gene studies, on the basis of biological plausibility of the gene and/or of the specific polymorphism. Many of the candidate gene studies investigated a limited number of single-nucleotide polymorphisms (SNPs) and samples and, consequently, had very modest statistical power. The results of many of the reported candidate genes studies of T1D association are discordant. To address the issue of limited statistical power in the published candidate gene-association studies, the Type I Diabetes Genetics Consortium (T1DGC), an international collaboration that has collected thousands of multiplex and simplex T1D families,16 has performed genotyping and association analysis of multiple SNPs in 21 T1D candidate genes.

One of the 21 candidate genes studied in the Rapid Response Project is IL4R, which encodes the α-chain of the IL4 and IL13 receptors. Polymorphisms in IL4R have been reported to be associated with allergy and asthma17 and cervical cancer,18 as well as with T1D;19,20 several IL4R non-synonymous SNPs have been associated with differences in signaling.21 A study of the multiplex HBDI families (n = 282) investigated eight SNPs in IL4R and, on the basis transmission–disequilibrium test (TDT) analysis, reported a modest protective effect of the variant allele at several tightly linked non-synonymous SNPs.19 SNP rs1805015 (S503P) was the only individual SNP that exhibited nominal significance in this small study. This significance emerged only after stratification on families in which neither affected sib had the high-risk DR3/DR4-DQB1*0302 genotype. The percent transmission for the 503P variant allele was 44.6% (P = 0.06) for all families. In contrast, transmission of the 503P allele was 47.8% (P = 0.61) in families with a DR3/DR4-DQB1*0302-affected child and 42% (P = 0.03) in families in which neither affected sib had DR3/DR4-DQB1*0302. TDT analysis of an eight-SNP haplotype that included the variant alleles at rs1805011 (E400A), rs2234898 (L414L), rs1805012 (C431R), rs1805015 (S503P), and rs1801275 (Q576R) head a 33% transmission and an odds ratio (OR) of 0.49 (95% confidence interval (CI) = 0.28–0.81).

A small study of Filipino T1D cases and controls also reported an association of IL4R SNPs with T1D.20 The association analysis in this study was performed without stratification on the DR3/DR4-DQB1*0302 genotype because this high-risk genotype is very rare in the Filipino population. Consistent with the earlier results,19 this study reported a modest protective effect of a seven-SNP haplotype that included the same five variant alleles (400A 414L 431R, 503P, and 576R) (OR = 0.4; 95% CI = 0.2–0.8; P = 0.005). Four of the five SNPs are non-synonymous.

Two studies, one in Caucasian multiplex families and one in Filipino cases and controls, suggested that the variant alleles at a series of linked SNPs in IL4R were associated with protection from T1D. Small sample sizes and multiple testing, however, limited statistical power. An earlier report found no association with IL4R (only rs1801275 and Q576R were genotyped).22 More recently, a much larger study consisting of 3475 T1D families, including 1244 Finnish families, genotyped eight IL4R SNPs and found no significant evidence for association with T1D.23 Subsequent to this report, another large study examined the IL4R SNPs and T1D in large family and case/control datasets and earlier published data and found no single-SNP association with T1D.24

In addition to the analysis of IL4R SNPs, the study of Filipino T1D cases and controls also investigated the possible association of SNPs in IL4 and IL13, genes that encode the ligands of the IL4 receptor, and possible gene–gene interaction between SNPs in these genes and SNPs in IL4R. On the basis of the earlier small case–control data, risk for T1D might be determined by specific combinations of genotypes at IL4R, IL4, and IL13. However, the large study found no evidence for association or interaction between SNPs in IL4R, IL4, and IL13.24

The T1DGC carried out SNP genotyping on 38 SNPs in IL4R, 10 SNPs in IL4, and 5 SNPs in IL13 on a collection of 2042 multiplex families from nine different populations. The data were subjected to TDT and parental TDT (PDT) analyses. An association analysis of the T1DGC genotyping data for 19 candidate genes, including the IL4R, IL4, and IL13, found no evidence of association for any of the SNPs in these three genes in the overall dataset.25 Here, we present association analyses on the results from the individual cohorts in the IL4R T1DGC dataset.

Results

A panel of 38 SNPs in IL4R was genotyped using the Sequenom iPLEX platform on the nine cohorts (multiplex family collections from nine geographic locations) listed in Table 1. IL4R SNPs, their positions, and minor allele frequencies are shown in Table 2. Although 38 tagging SNPs in IL4R were attempted for genotyping in this study, two of the SNPS for which T1D associations were reported earlier, rs2234898 (L414L) and rs1805015 (S503P),19 were not genotyped. The association analyses were performed using the TDT and PDT methods that used meiotic transmissions to each affected sib compared with expectation under the hypothesis of ‘no association’. In addition, the analyses were stratified on the high-risk DR3/DR4-DQB1*0302 haplotype.

Table 1.

Cohorts used for the study (proportions of DR3/DR4 vs non-DR3/DR4 are shown, as well as average age of onset in each cohort)

Region Cohort N pedigrees N pedigrees
MHC		 Not DR3/DR4
trios		 DR3/DR4
trios		 Age of
onset mean		 s.d. n T1D
patients age
of onset		 Num peds
with age
of onset
1 AP 169 118 130 109 10.34 7.94 366 169
2 DAN 130 94 106 85 14.99 11.23 293 130
2 EUR 428 329 429 232 11.83 8.26 893 428
4 HBDI 424 413 540 342 12.28 8.67 937 415
4 JOS 71 53 56 52 11.83 7.53 148 71
4 NA 295 217 263 172 8.76 6.62 637 295
5 BDA 393 0 0 0 12.60 9.76 853 391
5 SAR 74 52 51 52 12.75 8.71 150 74
5 UK 108 91 93 90 8.22 5.29 242 108
Total 2092 1367 1668 1134
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Abbreviations: MHC, major histocompatibility complex; T1D, type I diabetes.

Table 2.

IL4R SNPs tested, their locations, alleles, and functions

Marker
number		 SNP ID Reference assembly
chromosome position		 Major allele Minor
allele		 Minor allele
frequency		 SNP functiona
1 rs2057768 27229596 C T 0.2874 Not reportedb
2 rs2107356 27230905 G A 0.4125 5′ near gene
3 rs6498012 27239475 C G 0.379 Intron
4 rs1110470 27243928 C T 0.4733 Intron
5 rs4787948 27248560 A G 0.2933 Intron
6 rs2283563 27253855 G A 0.3121 Intron
7 rs3024537 27260320 G A 0.1438 Intron
8 rs1805010 27263704 A G 0.4466 I75V
9 rs3024560 27264168 T G 0.3536 Intron
10 rs3024571 27265428 C T 0.0891 N167N
11 rs2301807 27265599 G T 0.0499 Intron
12 rs3024578 27265852 G A 0.0826 Intron
13 rs2239347 27266522 A C 0.4548 Intron
14 rs3116578 27267337 C T 0.0201 Intron
15 rs3024613 27271754 G A 0.4816 Intron
16 rs3024614 27271846 A G 0.0562 Intron
17 rs3024622 27272954 C G 0.3448 Intron
18 rs4787423 27274835 T C 0.1368 Intron
19 rs3024668 27279450 C T 0.0524 Intron
20 rs2234897 27281113 T C 0.0244 F313F
21 rs1805011 27281373 A C 0.1137 E400A
22 rs1805012 27281465 T C 0.1053 C431R
23 rs1801275 27281901 A G 0.2114 Q576R
24 rs1805016 27282428 A C 0.0558 S752A
25 rs2074570 27282658 A G 0.0405 3′ UTR
26 rs8832 27283288 G A 0.4423 3′ UTR
27 rs3024685 27284411 A G 0.3923 Not reportedb
28 rs12102586 27285554 C T 0.0914 Not reportedb
29 rs4787956 27285750 T C 0.3439 Not reportedb
30 rs16976728 27289213 G A 0.3831 Not reportedb
31 rs4787426 27292232 T G 0.1271 Not reportedb
32 rs12445135 27293007 C T 0.0298 Not reportedb
33 rs4787427 27293895 C G 0.324 Not reportedb
34 rs7191188 27296912 C T 0.2386 Not reportedb
35 rs6498015 27299125 C T 0.1287 Not reportedb
36 rs6498016 27299289 G A 0.1842 Not reportedb
37 rs2382722 27300127 A G 0.4611 Not reportedb
38 rs9944340 27301092 T C 0.2699 Not reportedb
39 rs6498017 27302359 G A 0.1396 Not reportedb
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a

Single-nucleotide polymorphism (SNP) location relative to the IL4R gene and function in the context of changes to the peptide sequence of the IL4R gene, as described in the GeneView ‘Function’ entries of the relevant entry for each rs number in the NCBI’s Entrez dbSNP database.

b

No data was available in the GeneView entry describing this SNP as resulting in either a synonymous or non-synonymous replacement, or describing a change in an untranslated region as being in a 5′ UTR, 3′ UTR, or intron.

The patterns of LD among 38 IL4R SNPs are shown in Figure 1. None of the individual SNPs showed a statistically significant association with T1D in the overall dataset. All the IL4R SNPs that exhibited a nominally significant (<0.05) association with T1D by either TDT or PDT analysis in one or more of the different cohorts (before or after stratification) are shown in Table 3. No consistent pattern of association with T1D was observed across all cohorts.

Figure 1.

Figure 1

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Linkage disequilibrium (R2) values between all SNPs across all cohorts.

Table 3.

RR in IL4R SNPs with significant TDT or PDT P-values

Cohort Stratification Marker
number		 SNP Over-
transmitted
allele		 IS TU % Trans TDT
P-value		 PDT
P-value		 RR
minor		 CI_minor
EUR DR3/DR4-DQB1*0302+ 1 rs2057768 C Major 110:82 0.5729 0.0429 0.2782 0.75 (0.56–0.99)
EUR No stratification 1 rs2057768 C Major 244:198 0.5520 0.0285 0.0365 0.81 (0.67–0.98)
EUR DR3/DR4-DQB1*0302+ 2 rs2107356 A Minor 154:118 0.5662 0.0288 0.0652 1.31 (0.60–0.97)
EUR No stratification 2 rs2107356 A Minor 361:300 0.5461 0.0176 0.0186 1.20 (0.71–0.97)
NA DR3/DR4-DQB1*0302− 2 rs2107356 A Minor 123:92 0.5721 0.0342 0.0204 1.34 (0.57–0.98)
SAR No stratification 2 rs2107356 G Major 66:44 0.6000 0.0353 0.0972 0.67 (0.45–0.98)
EUR DR3/DR4-DQB1*0302+ 3 rs6498012 C Major 136:102 0.5714 0.0273 0.0975 0.75 (0.58–0.97)
EUR No stratification 3 rs6498012 C Major 304:245 0.5537 0.0117 0.0158 0.81 (0.68–0.95)
EUR No stratification 4 rs1110470 T Minor 325:277 0.5399 0.0503 0.0285 1.17 (1.00–1.38)
SAR No stratification 4 rs1110470 C Major 71:48 0.5966 0.0344 0.0985 0.68 (0.47–0.97)
AP DR3/DR4-DQB1*0302− 5 rs4787948 A Major 54:29 0.6506 0.0057 0.0851 0.54 (0.34–0.84)
AP No stratification 5 rs4787948 A Major 106:65 0.6199 0.0016 0.2415 0.61 (0.45–0.83)
DAN DR3/DR4-DQB1*0302− 5 rs4787948 A Major 29:23 0.5577 0.4049 0.0411 0.79 (0.46–1.37)
NA DR3/DR4-DQB1*0302− 6 rs2283563 A Minor 104:72 0.5909 0.0156 0.0010 1.44 (0.51–0.93)
NA No stratification 6 rs2283563 A Minor 159:130 0.5502 0.0878 0.0017 1.22 (0.65–1.03)
AP DR3/DR4-DQB1*0302− 7 rs3024537 G Major 35:13 0.7292 0.0012 0.3410 0.37 (0.20–0.70)
AP DR3/DR4-DQB1*0302+ 7 rs3024537 G Major 47:16 0.7460 0.0001 0.0006 0.34 (0.19–0.60)
AP No stratification 7 rs3024537 G Major 82:29 0.7387 0.0000 0.0009 0.35 (0.23–0.54)
HBDI DR3/DR4-DQB1*0302− 7 rs3024537 G Major 134:103 0.5654 0.0437 0.0274 0.77 (0.60–0.99)
HBDI No stratification 7 rs3024537 G Major 239:188 0.5597 0.0135 0.0088 0.79 (0.65–0.95)
JOS DR3/DR4-DQB1*0302+ 7 rs3024537 A Minor 17:7 0.7083 0.0382 0.0772 2.43 (0.17–0.99)
NA DR3/DR4-DQB1*0302− 7 rs3024537 G Major 51:31 0.6220 0.0264 0.1452 0.61 (0.39–0.95)
BDA DR3/DR4-DQB1*0302− 8 rs1805010 G Minor 169:132 0.5615 0.0327 0.1089 1.28 (1.02–1.61)
JOS DR3/DR4-DQB1*0302− 8 rs1805010 A Major 23:13 0.6389 0.0934 0.0254 0.56 (0.29–1.11)
NA DR3/DR4-DQB1*0302− 8 rs1805010 A Major 115:81 0.5867 0.0149 0.0166 0.70 (0.53–0.93)
EUR DR3/DR4-DQB1*0302+ 9 rs3024560 T Major 130:100 0.5652 0.0476 0.2078 0.77 (0.59–1.00)
NA DR3/DR4-DQB1*0302− 10 rs3024571 C Major 40:20 0.6667 0.0091 0.0327 0.50 (0.29–0.85)
NA No stratification 10 rs3024571 C Major 71:48 0.5966 0.0344 0.0416 0.68 (0.47–0.97)
NA DR3/DR4-DQB1*0302− 12 rs3024578 G Major 36:18 0.6667 0.0134 0.0631 0.50 (0.28–0.88)
JOS DR3/DR4-DQB1*0302− 13 rs2239347 A Major 20:12 0.6250 0.1551 0.0455 0.60 (0.29–1.23)
NA DR3/DR4-DQB1*0302− 13 rs2239347 A Major 129:83 0.6085 0.0015 0.0017 0.65 (0.49–0.85)
BDA DR3/DR4-DQB1*0302− 15 rs3024613 G Major 163:125 0.5660 0.0249 0.0396 0.77 (0.61–0.97)
BDA No stratification 15 rs3024613 G Major 304:253 0.5458 0.0306 0.0614 0.83 (0.70–0.98)
DAN DR3/DR4-DQB1*0302− 15 rs3024613 A Minor 43:29 0.5972 0.0979 0.0483 1.48 (0.42–1.08)
AP DR3/DR4-DQB1*0302− 17 rs3024622 G Minor 64:43 0.5981 0.0417 0.0189 1.49 (1.01–2.19)
EUR DR3/DR4-DQB1*0302+ 17 rs3024622 C Major 131:101 0.5647 0.0486 0.1021 0.77 (0.60–1.00)
AP No stratification 18 rs4787423 T Major 64:37 0.6337 0.0069 0.0977 0.58 (0.39–0.87)
DAN DR3/DR4-DQB1*0302− 20 rs2234897 T Major 4:0 1.0000 0.0185 0.0578 0.11 (0.01–2.08)
AP DR3/DR4-DQB1*0302− 21 rs1805011 C Minor 30:16 0.6522 0.0375 0.0587 1.88 (1.02–3.44)
HBDI DR3/DR4-DQB1*0302− 21 rs1805011 A Major 111:76 0.5936 0.0103 0.0153 0.68 (0.51–0.92)
HBDI No stratification 21 rs1805011 A Major 184:132 0.5823 0.0034 0.0071 0.72 (0.57–0.90)
HBDI DR3/DR4-DQB1*0302− 22 rs1805012 T Major 112:79 0.5864 0.0167 0.0208 0.70 (0.53–0.94)
HBDI No stratification 22 rs1805012 T Major 183:133 0.5791 0.0048 0.0094 0.72 (0.58–0.91)
AP DR3/DR4-DQB1*0302− 23 rs1801275 G Minor 47:27 0.6351 0.0193 0.0239 1.74 (1.08–2.79)
DAN DR3/DR4-DQB1*0302+ 23 rs1801275 G Minor 38:22 0.6333 0.0377 0.0104 1.73 (1.02–2.92)
HBDI DR3/DR4-DQB1*0302− 23 rs1801275 A Major 169:133 0.5596 0.0381 0.0309 0.79 (0.63–0.99)
HBDI No stratification 23 rs1801275 A Major 287:238 0.5467 0.0323 0.0338 0.83 (0.7–0.98)
AP DR3/DR4-DQB1*0302− 24 rs1805016 A Major 8:4 0.6667 0.2437 0.0285 0.50 (0.15–1.67)
DAN DR3/DR4-DQB1*0302+ 24 rs1805016 C Minor 15:6 0.7143 0.0459 0.0311 2.50 (0.97–6.44)
DAN No stratification 24 rs1805016 C Minor 28:16 0.6364 0.0687 0.0222 1.75 (0.95–3.23)
JOS DR3/DR4-DQB1*0302− 24 rs1805016 C Minor 3:0 1.0000 0.0414 0.1573 7.00 (0.36–135.52)
DAN DR3/DR4-DQB1*0302− 25 rs2074570 A Major 8:2 0.8000 0.0496 0.1167 0.25 (0.05–1.18)
UK DR3/DR4-DQB1*0302+ 25 rs2074570 A Major 14:4 0.7778 0.0153 0.0222 0.29 (0.09–0.87)
UK No stratification 25 rs2074570 A Major 22:9 0.7097 0.0177 0.0097 0.41 (0.19–0.88)
UK DR3/DR4-DQB1*0302+ 27 rs3024685 G Minor 60:40 0.6000 0.0448 0.1365 1.50 (1.01–2.24)
DAN DR3/DR4-DQB1*0302+ 28 rs12102586 T Minor 27:11 0.7105 0.0084 0.0040 2.45 (1.22–4.95)
SAR DR3/DR4-DQB1*0302− 28 rs12102586 T Minor 6:1 0.8571 0.0465 0.2059 6.00 (0.72–49.84)
UK No stratification 28 rs12102586 C Major 41:23 0.6406 0.0235 0.0378 0.56 (0.34–0.93)
EUR DR3/DR4-DQB1*0302+ 29 rs4787956 T Major 117:86 0.5764 0.0293 0.0617 0.74 (0.56–0.97)
EUR No stratification 29 rs4787956 T Major 280:237 0.5416 0.0585 0.0465 0.85 (0.71–1.01)
UK DR3/DR4-DQB1*0302+ 29 rs4787956 C Minor 57:34 0.6264 0.0153 0.0489 1.68 (0.39–0.91)
UK DR3/DR4-DQB1*0302+ 30 rs16976728 A Minor 55:36 0.6044 0.0456 0.1181 1.53 (0.43–1.00)
EUR DR3/DR4-DQB1*0302+ 31 rs4787426 T Major 61:40 0.6040 0.0360 0.2243 0.66 (0.44–0.98)
EUR No stratification 31 rs4787426 T Major 147:112 0.5676 0.0294 0.0868 0.76 (0.60–0.97)
DAN DR3/DR4-DQB1*0302− 32 rs12445135 C Major 6:0 1.0000 0.0039 0.0348 0.08 (0.004–1.37)
JOS No stratification 32 rs12445135 T Minor 6:1 0.8571 0.0465 0.0833 6.00 (0.72–49.84)
UK DR3/DR4-DQB1*0302− 33 rs4787427 G Minor 32:17 0.6531 0.0308 0.0469 1.88 (1.05–3.39)
UK DR3/DR4-DQB1*0302− 34 rs7191188 C Major 38:22 0.6333 0.0377 0.0652 0.58 (0.34–0.98)
EUR DR3/DR4-DQB1*0302− 35 rs6498015 C Major 100:65 0.6061 0.0062 0.2798 0.65 (0.48–0.88)
EUR No stratification 35 rs6498015 C Major 148:107 0.5804 0.0101 0.2535 0.72 (0.56–0.93)
UK DR3/DR4-DQB1*0302− 35 rs6498015 T Minor 27:14 0.6585 0.0406 0.0478 1.93 (1.01–3.68)
UK No stratification 35 rs6498015 T Minor 51:32 0.6145 0.0362 0.0637 1.59 (1.02–2.48)
EUR DR3/DR4-DQB1*0302− 36 rs6498016 A Minor 127:96 0.5695 0.0376 0.0148 1.32 (0.58–0.99)
EUR No stratification 36 rs6498016 A Minor 201:150 0.5726 0.0064 0.0070 1.34 (0.60–0.92)
SAR DR3/DR4-DQB1*0302− 36 rs6498016 G Major 17:7 0.7083 0.0382 0.0643 0.41 (0.17–0.99)
UK DR3/DR4-DQB1*0302− 36 rs6498016 G Major 34:18 0.6538 0.0253 0.0388 0.53 (0.30–0.93)
HBDI No stratification 37 rs2382722 A Major 386:345 0.5280 0.1293 0.0492 0.89 (0.78–1.03)
UK DR3/DR4-DQB1*0302− 37 rs2382722 G Minor 38:21 0.6441 0.0258 0.0182 1.81 (1.06–3.08)
AP DR3/DR4-DQB1*0302+ 38 rs9944340 T Major 56:29 0.6588 0.0031 0.0172 0.52 (0.33–0.81)
EUR DR3/DR4-DQB1*0302+ 38 rs9944340 T Major 109:77 0.5860 0.0187 0.0074 0.70 (0.53–0.94)
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Abbreviations: CI, confidence interval; PDT, parental-disequilibrium test; RR, relative risk; SNP, single-nucleotide polymorphism; TDT, transmission-disequilibrium test.

Significant P-values are shown in bold.

A pattern of association consistent with the initial reports of T1D association was observed, however, in the HBDI cohort (Table 4).19,20 The variant alleles for IL4R SNP rs1805011 (400A), rs1805012 (431R), and rs1801275 (576R) (a series of three linked non-synonymous SNPs) are associated with a reduced risk for T1D in the HBDI families, both in the absence of stratification and in those families with no DR3/DR4-DQB1*0302-affected siblings (Table 4). SNP rs1805011 (E400A) shows the strongest effect with a relative risk (RR) of 0.72 (95% CI = 0.57–0.9, P = 0.0034) in all HBDI families and an RR = 0.68 (0.51–0.92, P = 0.010) in the subset of families with no DR3-DR4-DQB1*0302-affected sibs.

Table 4.

RR in IL4R SNPs with significant TDT or PDT P-values in the HBDI families

Cohort Stratification Marker
number		 SNP Over-
transmitted
allele		 IS TU % Trans TDT
P-value		 PDT
P-value		 RR
minor		 CI_minor
HBDI DR3/DR4-DQB1*0302− 7 rs3024537 G Major 134:103 0.5654 0.0437 0.0274 0.77 (0.60–0.99)
HBDI No stratification 7 rs3024537 G Major 239:188 0.5597 0.0135 0.0088 0.79 (0.65–0.95)
HBDI DR3/DR4-DQB1*0302− 21 rs1805011 A Major 111:76 0.5936 0.0103 0.0153 0.68 (0.51–0.92)
HBDI No stratification 21 rs1805011 A Major 184:132 0.5823 0.0034 0.0071 0.72 (0.57–0.90)
HBDI DR3/DR4-DQB1*0302− 22 rs1805012 T Major 112:79 0.5864 0.0167 0.0208 0.70 (0.53–0.94)
HBDI No stratification 22 rs1805012 T Major 183:133 0.5791 0.0048 0.0094 0.72 (0.58–0.91)
HBDI DR3/DR4-DQB1*0302− 23 rs1801275 A Major 169:133 0.5596 0.0381 0.0309 0.79 (0.63–0.99)
HBDI No stratification 23 rs1801275 A Major 287:238 0.5467 0.0323 0.0338 0.83 (0.70–0.98)
HBDI No stratification 37 rs2382722 A Major 386:345 0.5280 0.1293 0.0492 0.89 (0.78–1.03)
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Abbreviations: CI, confidence interval; PDT, parental-disequilibrium test; RR, relative risk; SNP, single-nucleotide polymorphism; TDT, transmission-disequilibrium test.

Significant P-values are shown in bold.

The results of the analysis of three-marker haplotypes are provided in Table 5. A three-marker haplotype (consisting of the variant allele at rs1805011, rs1805012, and rs1801275) has a transmission of 41%, with an RR of 0.71, an OR of 0.54 (0.39–0.74), and a marginally significant TDT (P = 0.043) for this haplotype. The transmissions to each affected child in these multiplex families were all analyzed, so that the dataset is equivalent to 540 trio families with a DR3/DR4-DQB1*0302 and 342 trio families without a DR3/DR4-DQB1*0302-affected child. This is in contrast to the initial study of 242 HBDI families in which transmission only to the proband was evaluated.19 In addition, SNP rs3024537 also exhibited a modest protective effect in all HBDI families (RR = 0.79; 0.65–0.95) as well as in those without DR3/DR4-DQB1*0302 (RR = 0.77; CI 0.60–0.99) (Table 4). This SNP also was nominally protective in the North American and Asia-Pacific cohorts, but seemed to be positively associated with T1D in the Joslin cohort, although the sample size for this latter cohort was very small.

Table 5.

Significant three-locus haplotypes in the HBDI families

Marker
numbers		 SNP 1 SNP 2 SNP 3 Stratification TDT
P-value		 Haplotype Number
transmitted		 Number not
transmitted		 %
Transmitted		 RR OR OR CI
3-4-5 rs6498012 rs1110470 rs4787948 DR3/DR4-DQB1*0302+ 0.039 C-T-A 120 94 56.07 1.23 1 1–1
rs6498012 rs1110470 rs4787948 0.039 G-C-G 92 88 51.11 1.19 0.82 0.55–1.22
rs6498012 rs1110470 rs4787948 0.039 C-C-A 60 71 45.79 1.00 0.66 0.43–1.02
rs6498012 rs1110470 rs4787948 0.039 G-C-A 25 42 37.32 0.65 0.47 0.27–0.82
rs6498012 rs1110470 rs4787948 0.039 C-T-G 0 2 0.00 2.00E-08 0 0–0
7–8–9 rs3024537 rs1805010 rs3024560 None 0.014 G-G-G 251 232 51.96 1.73 0.95 0.74–1.22
rs3024537 rs1805010 rs3024560 0.014 G-A-T 290 255 53.21 1.72 1 1–1
rs3024537 rs1805010 rs3024560 0.014 A-G-T 91 98 48.15 1.57 0.82 0.59–1.14
rs3024537 rs1805010 rs3024560 0.014 G-G-T 18 21 46.15 1.42 0.75 0.39–1.45
rs3024537 rs1805010 rs3024560 0.014 A-G-G 55 99 35.72 1.00 0.49 0.34–0.71
7-8-9 rs3024537 rs1805010 rs3024560 DR3/DR4-DQB1*0302− 0.019 A-G-T 52 48 52.01 2.07 0.99 0.63–1.55
rs3024537 rs1805010 rs3024560 0.019 G-G-G 149 130 53.40 2.01 1.05 0.76–1.45
rs3024537 rs1805010 rs3024560 0.019 G-A-T 161 147 52.27 1.91 1 1–1
rs3024537 rs1805010 rs3024560 0.019 G-G-T 9 12 42.86 1.41 0.68 0.28–1.67
rs3024537 rs1805010 rs3024560 0.019 A-G-G 31 65 32.29 1.00 0.44 0.27–0.71
19-20-21 rs3024668 rs2234897 rs1805011 None 0.021 C-T-A 203 142 58.84 1.11 1 1–1
rs3024668 rs2234897 rs1805011 0.021 C-C-A 24 26 48.00 1.00 0.65 0.36–1.17
rs3024668 rs2234897 rs1805011 0.021 T-T-C 56 70 44.44 0.88 0.56 0.37–0.84
rs3024668 rs2234897 rs1805011 0.021 C-T-C 77 117 39.69 0.74 0.46 0.32–0.66
rs3024668 rs2234897 rs1805011 0.021 T-T-A 4 9 30.77 0.51 0.31 0.09–1.03
20-21-22 rs2234897 rs1805011 rs1805012 None 0.008 T-A-T 193 135 58.84 1.16 1 1–1
rs2234897 rs1805011 rs1805012 0.008 C-A-T 23 26 46.94 1.00 0.62 0.34–1.13
rs2234897 rs1805011 rs1805012 0.008 T-C-C 118 168 41.26 0.83 0.49 0.36–0.68
rs2234897 rs1805011 rs1805012 0.008 T-C-T 2 7 22.22 0.29 0.20 0.04–0.98
20-21-22 rs2234897 rs1805011 rs1805012 DR3/DR4-DQB1*0302− 0.019 T-A-T 116 75 60.73 1.30 1 1–1
rs2234897 rs1805011 rs1805012 0.019 C-A-T 13 16 44.83 1.00 0.53 0.24–1.15
rs2234897 rs1805011 rs1805012 0.019 T-C-C 68 101 40.24 0.88 0.44 0.29–0.66
rs2234897 rs1805011 rs1805012 0.019 T-C-T 2 7 22.22 0.32 0.18 0.04–0.91
21-22-23 rs1805011 rs1805012 rs1801275 None 0.043 A-T-A 231 181 56.07 1.00 1 1–1
rs1805011 rs1805012 rs1801275 0.043 A-T-G 94 97 49.21 0.97 0.76 0.54–1.07
rs1805011 rs1805012 rs1801275 0.043 C-C-G 103 149 40.87 0.71 0.54 0.39–0.74
rs1805011 rs1805012 rs1801275 0.043 C-T-G 2 3 40.00 0.54 0.52 0.09–3.16
23–24–25 rs1801275 rs1805016 rs2074570 None 0.049 G-C-G 2 0 100.00 77740 Inf 0–infinity
rs1801275 rs1805016 rs2074570 0.049 A-A-A 237 190 55.50 1.00 1 1–1
rs1801275 rs1805016 rs2074570 0.049 G-C-A 65 65 50.00 0.98 0.80 0.54–1.19
rs1801275 rs1805016 rs2074570 0.049 G-A-G 34 36 48.57 0.98 0.76 0.46–1.26
rs1801275 rs1805016 rs2074570 0.049 G-A-A 114 161 41.45 0.74 0.57 0.42–0.77
25-26-27 rs2074570 rs8832 rs3024685 DR3/DR4-DQB1*0302− 0.032 A-G-G 6 4 59.99 2.89 1.19 0.33–4.31
rs2074570 rs8832 rs3024685 0.032 G-A-G 2 2 50.00 2.12 0.80 0.11–5.72
rs2074570 rs8832 rs3024685 0.032 A-G-A 191 152 55.68 2.12 1 1–1
rs2074570 rs8832 rs3024685 0.032 A-A-G 152 159 48.88 1.88 0.76 0.56–1.04
rs2074570 rs8832 rs3024685 0.032 G-G-A 21 25 45.65 1.64 0.67 0.36–1.24
rs2074570 rs8832 rs3024685 0.032 A-A-A 27 57 32.14 1.00 0.38 0.23–0.62
26-27-28 rs8832 rs3024685 rs12102586 None 0.027 G-G-C 13 8 61.91 2.57 1.42 0.58–3.47
rs8832 rs3024685 rs12102586 0.027 A-G-T 56 43 56.57 1.99 1.14 0.74–1.74
rs8832 rs3024685 rs12102586 0.027 G-A-C 327 285 53.43 1.62 1 1–1
rs8832 rs3024685 rs12102586 0.027 A-G-C 257 273 48.49 1.48 0.82 0.65–1.04
rs8832 rs3024685 rs12102586 0.027 G-A-T 45 55 45.00 1.25 0.71 0.47–1.09
rs8832 rs3024685 rs12102586 0.027 A-A-C 55 89 38.19 1.00 0.54 0.37–0.78
26-27-28 rs8832 rs3024685 rs12102586 DR3/DR4-DQB1*0302− 0.020 G-G-C 6 4 60.00 2.87 1.15 0.32–4.15
rs8832 rs3024685 rs12102586 0.020 A-G-T 33 25 56.90 2.40 1.01 0.58–1.78
rs8832 rs3024685 rs12102586 0.020 G-A-C 188 144 56.63 2.08 1 1–1
rs8832 rs3024685 rs12102586 0.020 A-G-C 143 164 46.59 1.74 0.67 0.49–0.91
rs8832 rs3024685 rs12102586 0.020 G-A-T 25 32 43.86 1.42 0.60 0.34–1.05
rs8832 rs3024685 rs12102586 0.020 A-A-C 26 52 33.34 1.00 0.38 0.23–0.64
28-29-30 rs12102586 rs4787956 rs16976728 DR3/DR4-DQB1*0302+ 0.041 C-C-A 121 87 58.17 1.00 1.49 1.04–2.14
rs12102586 rs4787956 rs16976728 0.041 C-T-G 135 145 48.21 0.78 1 1–1
rs12102586 rs4787956 rs16976728 0.041 T-T-A 7 8 46.66 0.71 0.94 0.33–2.66
rs12102586 rs4787956 rs16976728 0.041 T-T-G 31 37 45.59 0.68 0.90 0.53–1.53
rs12102586 rs4787956 rs16976728 0.041 C-T-A 37 42 46.84 0.67 0.95 0.57–1.56
rs12102586 rs4787956 rs16976728 0.041 C-C-G 6 18 25.00 0.25 0.36 0.14–0.93
34-35-36 rs7191188 rs6498015 rs6498016 DR3/DR4-DQB1*0302+ 0.004 C-C-A 12 5 70.59 1.00 2.87 0.98–8.37
rs7191188 rs6498015 rs6498016 0.004 C-T-G 63 48 56.75 0.62 1.57 1–2.45
rs7191188 rs6498015 rs6498016 0.004 T-C-A 79 70 53.02 0.53 1.35 0.9–2.02
rs7191188 rs6498015 rs6498016 0.004 T-C-G 29 28 50.88 0.50 1.24 0.7–2.2
rs7191188 rs6498015 rs6498016 0.004 C-C-G 118 141 45.56 0.45 1 1–1
rs7191188 rs6498015 rs6498016 0.004 T-T-G 0 9 0.00 5.16E-10 0 0–0
36-37-38 rs6498016 rs2382722 rs9944340 DR3/DR4-DQB1*0302+ 0.041 G-G-C 2 0 1.00 1.33E+09 Inf 0–infinity
rs6498016 rs2382722 rs9944340 0.041 G-A-T 48 37 56.48 1.04 1.59 0.96–2.62
rs6498016 rs2382722 rs9944340 0.041 A-A-T 84 65 56.37 1.00 1.58 1.04–2.4
rs6498016 rs2382722 rs9944340 0.041 G-A-C 90 96 48.38 0.79 1.15 0.78–1.69
rs6498016 rs2382722 rs9944340 0.041 G-G-T 103 126 44.98 0.74 1 1–1
rs6498016 rs2382722 rs9944340 0.041 A-G-T 0 3 0.00 2.05E-08 0 0–0
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Abbreviations: OR, odds ratio; RR, relative risk; SNP, single-nucleotide polymorphism; TDT, transmission-disequilibrium test.

The strength of significance for the association of three-SNP haplotypes with T1D in the individual cohorts as well as the overall dataset is shown in Figure 2a–c. In the HBDI families, all three-SNP haplotypes containing the rs1805011 400A variant are associated with T1D in the unstratified analysis (Figure 2a); the haplotype with 400A as the middle SNP is also associated in the families without DR3/DR4-DQB1*0302 (Figure 2c). In the total data, haplotypes including the first three SNPs (rs2057768, rs2107356, and rs6498012) were associated in the unstratified data and in families with DR3/DR4-DQB1*0302. In these data, haplotypes with rs1805010 (I75V), rs2239347, rs3116578, and rs3024613 (all intronic) and rs4787426 and rs6498015 were associated in the unstratified data. Haplotypes with SNP rs4787426, rs12445135, rs4787427, rs7191188, and rs6498016 were also associated in the families with DR3/DR-DQB1*0302.

Figure 2.

Figure 2

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TDT significance in IL4R three-SNP haplotypes: (a) TDT significance in three locus haplotypes, no stratification; (b) TDT significance in three locus haplotypes with DR3/DR4-DQB1*0302; and (c) TDT significance in three locus haplotypes without DR3/DR4-DQB1*0302.

Discussion

Many published association studies of candidate gene polymorphisms examine only a few SNPs per gene and have relatively small sample sizes, resulting in limited statistical power to identify disease-associated alleles. Consequently, reports of association for candidate genes with T1D are often discordant. The extensive set of multiplex families, collected by the T1DGC, has enabled replication analyses of a variety of reported associations (the T1DGC Rapid Response Project). Although the association of three linked SNPs in IL4R observed in this large set of HBDI families was nominally significant and consistent with the initial reports in a subset of HBDI families and a small case/control study among Filipinos, no evidence for association of any individual SNPs was seen in the overall dataset.

The simplest interpretation of the lack of association of any of the individual IL4R SNPs in the overall data is that the earlier reported associations,19,20 as well as the nominally significant observations within the HBDI cohort, are spurious and simply reflect false positive results (type I error). It may be premature, however, to definitively exclude IL4R as a T1D candidate gene. The HBDI families represent the largest individual cohort in the T1DGC dataset and the protective association of the three linked non-synonymous SNPs observed, after stratification, in the families without DR3/DR4-DQB1*0302 replicate earlier findings.19 The set of HBDI families in the T1DGC collection include those studied in the initial report;19 however, two meiotic transmissions, rather than one transmission per family, were analyzed in this larger T1DGC HBDI family collection. As a result, the association of IL4R SNPs with T1D became more significant with this expanded dataset. The question remains why IL4R SNPs seem to be associated in the HBDI cohort, but not in the overall dataset. It is conceivable that heterogeneity among these cohorts, in terms of environmental triggers or interacting genetic effects or linkage disequilibrium patterns, could account for these differences. Some three-SNP haplotypes show nominally significant association in the overall dataset, although, unlike rs180511 and flanking SNPs, there is no prior hypothesis associated with them. In conclusion, this large study of IL4R SNPs provides no clear and consistent evidence of T1D association, but the complex pattern of data suggests that some SNPs should not be definitively excluded as T1D-associated polymorphisms.

Materials and methods

Study population

The T1DGC has created a resource base of well-characterized families from multiple ethnic groups to characterization of T1D susceptibility genes (http://www.t1dgc.org). Genotyping for the Rapid Response project was performed on 2295 families in nine cohorts. The families selected for these analyses consisted mainly of nuclear families with an affected sib pair. This study reports the results for the IL4R gene in 9251 individuals, including 5580 children (4445 (80%) affected, 840 (15%) unaffected, and 295 (5%) unknown status) and 3671 parents (157 (4%) affected, 2576 (70%) unaffected, and 938 (26%) unknown status). The majority of the subjects were Caucasian (81%) with 18% unknown ethnicity and 1% other (Asian, African American, and Pacific Islander).

Genotyping

SNP genotyping was performed by the Broad Institute Center for Genotyping and Analysis (http://www.broad.mit.edu/gen_analysis/genotyping/). Aliquots of the T1DGC source 96-well plates were adjusted to 5–10 ng ml−1 in water in new 96-well plates. The iPLEX Gold chemistry of Sequenom’s MassARRAY platform (San Diego, CA, USA) was used for genotyping of all SNPs as part of the larger set of T1DGC Rapid Response Project. Sequenom’s SpectroDesigner software was used for SNP assay design, and SpectroTyper 4.0 was used to call genotypes automatically, followed by manual review.

Statistical genetic analysis

A TDT26 was performed on each of the markers as implemented in Haploview software (version 4.1).27 The transmission proportions were used to compute ORs and 95% CIs as described.28 The PDT method, as implemented in Haploview 4.1, was also used as a family based test of genetic association.29 This method incorporates parental phenotypes and, specifically, the parental genotype–phenotype correlation terms. The model is based on the between-within-sibship-association model using a liability-threshold-model approach. The incorporation of parental phenotypes can considerably increase power, as compared with the standard TDT and equivalent quantitative tests, whereas providing both significant protection against stratification and a means of evaluating the contribution of stratification to positive results. This methodology enables the extraction of more information from existing family based collections that are currently being genotyped and analyzed by use of standard approaches.

For pedigrees, full DRB1-DQB1 typing was available.4 T1D patients were stratified into those carrying DR3/DR4, defined here as carrying one DRB1*0301-DQB1*0201 haplotype and one DRB1*0401/02/04/05/08-DQB1*0302/04 or DQB1*0201 haplotype. All other participants were categorized as non-DR3/DR4.

Acknowledgements

We are grateful to the family members who contributed samples and to all the participating T1DGC investigators and sites listed at www.t1dgc.org. This research uses resources provided by the Type I Diabetes Genetics Consortium, a collaborative clinical study sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Allergy and Infectious Diseases (NIAID), National Human Genome Research Institute (NHGRI), National Institute of Child Health and Human Development (NICHD), and Juvenile Diabetes Research Foundation International (JDRF) and supported by U01 DK062418. Genotyping was performed at the Broad Institute Center for Genotyping and Analysis is supported by grant U54 RR020278 from the National Center for Research Resources.

Footnotes

Conflict of interest

The authors declare no conflict of interest.

References

  • 1.Risch N. Assessing the role of HLA-linked and unlinked determinants of disease. Am J Hum Genet. 1987;40:1–14. [PMC free article] [PubMed] [Google Scholar]
  • 2.Concannon P, Erlich HA, Julier C, Morahan G, Nerup J, Pociot F, et al. Type 1 diabetes: evidence for susceptibility loci from four genome-wide linkage scans in 1,435 multiplex families. Diabetes. 2005;54:2995–3001. doi: 10.2337/diabetes.54.10.2995. [DOI] [PubMed] [Google Scholar]
  • 3.Noble JA, Valdes AM, Cook M, Klitz W, Thomson G, Erlich HA. The role of HLA class II genes in insulin-dependent diabetes mellitus: molecular analysis of 180 Caucasian, multiplex families. Am J Hum Genet. 1996;59:1134–1148. [PMC free article] [PubMed] [Google Scholar]
  • 4.Erlich H, Valdes AM, Noble J, Carlson JA, Varney M, Concannon P, et al. HLA DR-DQ haplotypes and genotypes and type 1 diabetes risk: analysis of the type 1 diabetes genetics consortium families. Diabetes. 2008;57:1084–1092. doi: 10.2337/db07-1331. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Nejentsev S, Howson JM, Walker NM, Szeszko J, Field SF, Stevens HE, et al. Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A. Nature. 2007;450:887–892. doi: 10.1038/nature06406. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Noble JA, Valdes AM, Bugawan TL, Apple RJ, Thomson G, Erlich HA. The HLA class I A locus affects susceptibility to type 1 diabetes. Hum Immunol. 2002;63:657–664. doi: 10.1016/s0198-8859(02)00421-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Noble JA, Valdes AM, Thomson G, Erlich HA. The HLA class II locus DPB1 can influence susceptibility to type 1 diabetes. Diabetes. 2000;49:121–125. doi: 10.2337/diabetes.49.1.121. [DOI] [PubMed] [Google Scholar]
  • 8.Valdes AM, Erlich HA, Noble JA. Human leukocyte antigen class I B and C loci contribute to type 1 diabetes (T1D) susceptibility and age at T1D onset. Hum Immunol. 2005;66:301–313. doi: 10.1016/j.humimm.2004.12.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Cucca F, Dudbridge F, Loddo M, Mulargia AP, Lampis R, Angius E, et al. The HLA-DPB1-associated component of the IDDM1 and its relationship to the major loci HLA-DQB1, -DQA1, and -DRB1. Diabetes. 2001;50:1200–1205. doi: 10.2337/diabetes.50.5.1200. [DOI] [PubMed] [Google Scholar]
  • 10.Erlich HA, Rotter JI, Chang JD, Shaw SJ, Raffel LJ, Klitz W, et al. Association of HLA-DPB1*0301 with IDDM in Mexican-Americans. Diabetes. 1996;45:610–614. doi: 10.2337/diab.45.5.610. [DOI] [PubMed] [Google Scholar]
  • 11.Lie BA, Todd JA, Pociot F, Nerup J, Akselsen HE, Joner G, et al. The predisposition to type 1 diabetes linked to the human leukocyte antigen complex includes at least one non-class II gene. Am J Hum Genet. 1999;64:793–800. doi: 10.1086/302283. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Nejentsev S, Gombos Z, Laine AP, Veijola R, Knip M, Simell O, et al. Non-class II HLA gene associated with type 1 diabetes maps to the 240-kb region near HLA-B. Diabetes. 2000;49:2217–2221. doi: 10.2337/diabetes.49.12.2217. [DOI] [PubMed] [Google Scholar]
  • 13.Bottini N, Gloria-Bottini F, Borgiani P, Antonacci E, Lucarelli P, Bottini E. Type 2 diabetes and the genetics of signal transduction: a study of interaction between adenosine deaminase and acid phosphatase locus 1 polymorphisms. Metabolism. 2004;53:995–1001. doi: 10.1016/j.metabol.2004.03.006. [DOI] [PubMed] [Google Scholar]
  • 14.Marron MP, Raffel LJ, Garchon HJ, Jacob CO, Serrano-Rios M, Martinez Larrad MT, et al. Insulin-dependent diabetes mellitus (IDDM) is associated with CTLA4 polymorphisms in multiple ethnic groups. Hum Mol Genet. 1997;6:1275–1282. doi: 10.1093/hmg/6.8.1275. [DOI] [PubMed] [Google Scholar]
  • 15.Smyth DJ, Cooper JD, Bailey R, Field S, Burren O, Smink LJ, et al. A genome-wide association study of nonsynonymous SNPs identifies a type 1 diabetes locus in the interferon-induced helicase (IFIH1) region. Nat Genet. 2006;38:617–619. doi: 10.1038/ng1800. [DOI] [PubMed] [Google Scholar]
  • 16.Rich SS, Concannon P, Erlich H, Julier C, Morahan G, Nerup J, et al. The Type 1 Diabetes Genetics Consortium. Ann N Y Acad Sci. 2006;1079:1–8. doi: 10.1196/annals.1375.001. [DOI] [PubMed] [Google Scholar]
  • 17.Chatila TA. Interleukin-4 receptor signaling pathways in asthma pathogenesis. Trends Mol Med. 2004;10:493–499. doi: 10.1016/j.molmed.2004.08.004. [DOI] [PubMed] [Google Scholar]
  • 18.Ivansson EL, Gustavsson IM, Magnusson JJ, Steiner LL, Magnusson PK, Erlich HA, et al. Variants of chemokine receptor 2 and interleukin 4 receptor, but not interleukin 10 or Fas ligand, increase risk of cervical cancer. Int J Cancer. 2007;121:2451–2457. doi: 10.1002/ijc.22989. [DOI] [PubMed] [Google Scholar]
  • 19.Mirel DB, Valdes AM, Lazzeroni LC, Reynolds RL, Erlich HA, Noble JA. Association of IL4R haplotypes with type 1 diabetes. Diabetes. 2002;51:3336–3341. doi: 10.2337/diabetes.51.11.3336. [DOI] [PubMed] [Google Scholar]
  • 20.Bugawan TL, Klitz W, Alejandrino M, Ching J, Panelo A, Solfelix CM, et al. The association of specific HLA class I and II alleles with type 1 diabetes among Filipinos. Tissue Antigens. 2002;59:452–469. doi: 10.1034/j.1399-0039.2002.590602.x. [DOI] [PubMed] [Google Scholar]
  • 21.Kruse S, Japha T, Tedner M, Sparholt SH, Forster J, Kuehr J, et al. The polymorphisms S503P and Q576R in the interleukin-4 receptor alpha gene are associated with atopy and influence the signal transduction. Immunology. 1999;96:365–371. doi: 10.1046/j.1365-2567.1999.00705.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Reimsnider SK, Eckenrode SE, Marron MP, Muir A, She JX. IL4 and IL4Ralpha genes are not linked or associated with type 1 diabetes. Pediatr Res. 2000;47:246–249. doi: 10.1203/00006450-200002000-00016. [DOI] [PubMed] [Google Scholar]
  • 23.Maier LM, Twells RC, Howson JM, Lam AC, Clayton DG, Smyth DJ, et al. Testing the possible negative association of type 1 diabetes and atopic disease by analysis of the interleukin 4 receptor gene. Genes Immun. 2003;4:469–475. doi: 10.1038/sj.gene.6364007. [DOI] [PubMed] [Google Scholar]
  • 24.Maier LM, Chapman J, Howson JM, Clayton DG, Pask R, Strachan DP, et al. No evidence of association or interaction between, the IL4RA, IL4, and IL13 genes in type 1 diabetes. Am J Hum Genet. 2005;76:517–521. doi: 10.1086/428387. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Howson JMM, Walker NM, Smyth DJ, Todd JA the Type I Diabetes Genetics Consortium. Analysis of 19 genes for association with type I diabetes in the Type I Diabetes Genetics Consortium families. Genes Immun. 2009;10 Suppl 1:S74–S84. doi: 10.1038/gene.2009.96. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Spielman RS, McGinnis RE, Ewens WJ. Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM) Am J Hum Genet. 1993;52:506–516. [PMC free article] [PubMed] [Google Scholar]
  • 27.Barrett JC, Fry B, Maller J, Daly MJ. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics. 2005;21:263–265. doi: 10.1093/bioinformatics/bth457. [DOI] [PubMed] [Google Scholar]
  • 28.Kazeem GR, Farrall M. Integrating case-control and TDT studies. Ann Hum Genet. 2005;69(Pt 3):329–335. doi: 10.1046/j.1529-8817.2005.00156.x. [DOI] [PubMed] [Google Scholar]
  • 29.Purcell S, Sham P, Daly MJ. Parental phenotypes in family-based association analysis. Am J Hum Genet. 2005;76:249–259. doi: 10.1086/427886. [DOI] [PMC free article] [PubMed] [Google Scholar]

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