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. Author manuscript; available in PMC: 2010 Jan 11.
Published in final edited form as: Genes Immun. 2009 Dec;10(Suppl 1):S54–S59. doi: 10.1038/gene.2009.92

Evidence for association of the TCF7 locus with type I diabetes

HA Erlich 1,5, AM Valdes 2, C Julier 3, D Mirel 4, JA Noble 5; the Type I Diabetes Genetics Consortium
PMCID: PMC2804262  NIHMSID: NIHMS163338  PMID: 19956102

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 been genotyped for the HLA class I and class II loci and, recently, for a genome-wide panel of single-nucleotide polymorphisms (SNPs). In addition, multiple SNPs in specific candidate genes have been genotyped in these families in an attempt to evaluate previously reported T1D associations, including the C883A (Pro–Thr) polymorphism in exon 2 of TCF7, a T-cell transcription factor. The TCF7 883A allele was associated with T1D in subjects with T1D not carrying the high-risk HLA genotype DR3/DR4. A panel of 11 SNPs in TCF7 was genotyped in 2092 families from 9 cohorts of the T1DGC. SNPs at two positions in TCF7 were associated with T1D. One associated SNP, C883A (rs5742913), was reported earlier to have a T1D association. A second SNP, rs17653687, represents a novel T1D susceptibility allele in TCF7. After stratification on the high T1D risk DR3/DR4 genotype, the variant (A) allele of C883A was significantly associated with T1D among non-DR3/DR4 cases (transmission =55.8%, P =0.004; OR =1.26) but was not significantly associated in the DR3/DR4 patient subgroup, replicating the earlier report. The reference A allele of intronic SNP rs17653687 was modestly associated with T1D in both DR3/DR4 strata (transmission =54.4% in DR3/DR4; P =0.03; transmission =52.9% in non-DR3/DR4; P =0.03). These results support the previously reported association of the non-synonymous Pro–Thr SNP in TCF7 with T1D, and suggest that other alleles at this locus may also confer risk.

Keywords: polymorphism, transcription factor, Th1, type I diabetes

Introduction

Type I diabetes (T1D) is an autoimmune disease involving destruction of the insulin-producing cells of the pancreas, resulting in dysfunctional glucose homeostasis and the requirement for exogenous insulin. The genetic component of T1D is significant (λs =15) with, by far, the strongest contribution (40–50%) coming from the HLA region.1,2 Although the HLA-DR and HLA-DQ-encoding loci are the major determinants of genetic risk for T1D, association studies have revealed that multiple genes within the HLA region contribute to T1D risk.3–9 In addition, linkage and association studies have identified many T1D susceptibility regions and genes outside the HLA region.10–12 Of the genes identified by association, some have been detected by genome-wide approaches13 whereas others have been identified in candidate gene studies, based on biological plausibility of the gene and/or of the specific polymorphism. Unlike the genome-wide association scans, many of the candidate gene studies investigated a limited of number of single-nucleotide polymorphisms (SNPs) and samples and, consequently, had modest statistical power. In some cases, the reports of T1D association were discordant.

To address the issue of limited statistical power in many of the published candidate gene association studies, the Type I Diabetes Genetics Consortium (T1DGC), an international collaboration that has collected thousands of T1D families (multiplex and simplex),14 undertook genotyping and analysis of multiple SNPs per gene in a variety of candidate genes reported to be associated with T1D. This project involved SNPs in 21 different genes (the T1DGC Rapid Response Project). One of the candidate studied in the Rapid Response Project was the HMG box transcription factor family member TCF7.15 Expression of TCF7 is limited to T cells and NK cells16 in which the gene product binds β-catenin and promotes mRNA expression of Th1-specific loci, including IL12-Rβ2.17 The initial association study for variants in TCF7 with T1D risk reported the association of a single SNP, referred to at the time as C883A, by Transmission Disequilibrium Test (TDT) analysis of genotyping data from 283 Caucasian, multiplex families from the Human Biological Data Interchange (HBDI) repository. The TCF7 C883A SNP is located at the position indicated by rs5742913; however, the polymorphism is reported as a C–T change (dbSNP). The C–A polymorphism at this position has the alternate designation ss93257904; however, throughout this manuscript, the C–A SNP will be referred to as rs5742913.

The data were stratified on the genotype HLA–DR3/DR4, with rationale that the expected modest effect of this TCF7 polymorphism might be more difficult to discern in the presence of the high-risk HLA genotype than in its absence. The minor (A) allele of the nonconservative polymorphism Pro–Thr (C883A) was associated with T1D in the subset of T1D cases who do not have the heterozygous DR3/DR4-DQB1*0302 genotype (referred to hereafter as simply DR3/DR4), which is known to confer very high T1D risk. No T1D association was seen in patients who were already high risk because of the presence of the DR3/DR4 genotype. The variant (A) allele showed overtransmission overall (54.8%), greater overtransmission (57.4%) to the non-DR3/4 cases, and significant overtransmission from fathers to affected children (64.1%, P< 0.007). Significant over-transmission was also observed to male affected children, and the presence of at least one copy of the A allele was significantly associated with young age of T1D onset (P =0.036). The previous report also included data for one additional TCF7 SNP (A383T, rs244656) as well as five SNPs within 5 Mb of C883A in the 5q31 region (CSF2 I117T, rs25882; IL13 C4045T, intron 13, rs1295686; IL13 R111Q, rs20541; IL4 C582T, -590, rs2243250; IL9 T113M, rs2969885).15

In the T1DGC Rapid Response project, 11 SNPs within TCF7 were genotyped using the Sequenom iPlex technology on the T1DGC collection of T1D trios (Table 1). For rs5742913, original data analysis showed no copies of the T allele and suggested that the SNP was monomorphic in the tested sample set. Re-analysis of the data for the presence of the A allele at the rs5742913 position, however, revealed a T1D association for the A allele, thus replicating the previous finding. The data presented here also reveal an apparent T1D association for a TCF7 intronic SNP (rs17653687) that has not been reported earlier.

Table 1.

Cohorts used for the study

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.

Proportions of DR3/DR4 vs non-DR3/DR4 are shown, as well as average age of onset in each cohort.

Results

Genotyping in TCF7 was performed for 11 SNPs in 9 different cohorts using the Sequenom platform. The geographic origin and the number of the families in each cohort genotyped in this study are shown in Table 1. The names, positions, and variant allele frequencies for these 11 SNPs, as well as the proportion of genotype calls and the deviation from Hardy Weinberg equilibrium is provided in Table 2. One SNP, rs30500, showed a deviation from Hardy Weinberg equilibrium (P =0.03) based on comparing the observed and expected frequency of heterozygotes among parents, as well as the lowest proportion of genotype calls (96.2%). The other SNPs, including the two T1D-associated SNPs, all had genotype call rates of greater than 97.9% and did not deviate significantly from Hardy Weinberg equilibrium. The pattern of linkage disequilibrium (r2) for TCF7 is shown in Figure 1. Two haplotype blocks are revealed with strong LD within each block.

Table 2.

TCF7 SNPs studied

Marker Name Position HW P value founders % Call rate Number of trios MAF Alleles (major:minor)
1 rs30503 133465245 0.36 97.9 1541 12.7% C:G
2 rs30500 133467775 0.03 96.2 1492 18.4% C:T
3 rs30499 133469625 0.08 99.4 1584 23.5% A:G
4 rs244948 133472960 0.16 98.6 1554 13.6% G:A
5 rs5742913 (ss93257904) 133479582 0.72 98.6 1568 11.6% C:A
6 rs244692 133480434 0.16 98.5 1563 8.3% A:G
7 rs151822 133483860 0.08 99.3 1576 23.1% T:C
8 rs152404 133486613 0.13 98.8 1564 14.7% T:C
9 rs152406 133489485 1.00 99.6 1597 5.2% G:A
10 rs249611 133492556 0.88 99.6 1586 8.5% A:G
11 rs17653687 133495899 0.19 98.5 1555 16.2% A:G
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Abbreviations: MAF, minor allele frequency; SNP, single-nucleotide polymorphism.

Designations for the two single nucleotide polymorphisms that showed type I diabetes association are shown in bold.

Figure 1.

Figure 1

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Map of the 11 TCF7 SNPs genotyped for this study, with haplotype blocks and LD values shown.

A TDT analysis of these 11 SNPs indicated that two SNPs (rs 5742913 and rs17653687) had significant transmission deviations (P =0.022 and 0.020) in the total family data (Table 3). For rs5742913 (C883A), the variant A allele was overtransmitted, as reported earlier15 whereas for rs17653687, the variant G allele was under-transmitted. Parental Disequilibrium Test (PDT) analysis (Table 3) of these (unstratified) data also indicated significant association of these two SNPs (P =0.011 and 0.007, respectively). The data were stratified into two groups based on HLA genotype to replicate the previously published results. The strata of TDT analysis are based on cases carrying the high-risk DR3/DR4 genotype (Table 4) and those not carrying the high-risk genotype (non-DR3/DR4, Table 5). For the high-risk DR3/DR4 cases, the C883A SNP (rs5742913) is not significantly associated with T1D risk (transmission of the variant A allele =51.8%, P =0.440) whereas the rs17653687, in the same haplotype block, shows a marginally significant overtransmission (54.4%, P =0.048) of the reference (A allele (Table 4)). Similar results were obtained by PDT analysis for rs5742913 (P =0.277) and for rs17653687 (P =0.026).

Table 3.

Genetic association between TCF7 SNPs and T1D in all pedigrees regardless of MHC genotype

Marker Over transmitted allele is T:U Trans (%) χ2 TDT P value Odds ratio 95% CI PTDT P value
rs30503 C Major 675:623 52.0 2.083 0.1489 1.08 (0.97–1.20) 0.0774
rs30500 C Major 852:800 51.6 1.637 0.2008 1.07 (0.96–1.17) 0.1304
rs30499 A Major 1125:1062 51.4 1.815 0.1779 1.06 (0.97–1.15) 0.1266
rs244948 G Major 696:679 50.6 0.21 0.6466 1.03 (0.92–1.13) 0.6921
rs5742913 A Minor 728:643 53.1 5.27 0.0217 1.13 (1.01–1.25) 0.0112
rs244692 A Major 468:439 51.6 0.927 0.3356 1.07 (0.93–1.21) 0.4014
rs151822 T Major 1088:1064 50.6 0.268 0.6049 1.02 (0.93–1.11) 0.4978
rs152404 C Minor 762:750 50.4 0.095 0.7576 1.02 (0.91–1.12) 0.9597
rs152406 G Major 311:302 50.7 0.132 0.7162 1.03 (0.87–1.20) 0.7808
rs249611 G Minor 491:488 50.2 0.009 0.9236 1.01 (0.88–1.14) 0.8754
rs17653687 A Major 868:774 52.9 5.381 0.0204 1.12 (1.01–1.23) 0.0066
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Abbreviations: PTDT, parental TDT; SNP, single-nucleotide polymorphism; T1D, type I diabetes; TDT, Transmission Disequilibrium Test.

Designations for the two SNPs that showed T1D association are shown in bold. Data indicating significant association in the unstratified sample set are shown in bold.

Table 4.

Genetic association between TCF7 SNPs and T1D in trios where the affected offspring carried the HLA-DR3/DR4 genotype

Marker Over transmitted allele is T:U Trans (%) χ2 TDT P value Odds ratio 95% CI PTDT P value
rs30503 G Minor 229:224 50.6 0.055 0.8143 1.02 (0.85–1.22) 0.9265
rs30500 C Major 268:255 51.2 0.323 0.5697 1.05 (0.88–1.24) 0.5498
rs30499 G Minor 347:335 50.9 0.211 0.6459 1.04 (0.89–1.20) 0.7078
rs244948 G Major 223:214 51.0 0.185 0.6668 1.04 (0.86–1.25) 0.6388
rs5742913 A Minor 223:207 51.9 0.595 0.4404 1.08 (0.89–1.30) 0.2767
rs244692 A Major 149:139 51.7 0.347 0.5557 1.07 (0.85–1.35) 0.6051
rs151822 C Minor 343:316 52.0 1.106 0.2929 1.09 (0.93–1.26) 0.421
rs152404 C Minor 267:233 53.4 2.312 0.1284 1.15 (0.96–1.36) 0.2022
rs152406 A Minor 102:78 56.7 3.2 0.0736 1.31 (0.97–1.75) 0.0784
rs249611 G Minor 171:148 53.6 1.658 0.1978 1.16 (0.92–1.43) 0.2709
rs17653687 A Major 270:226 54.4 3.903 0.0482 1.19 (1.00–1.42) 0.0263
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Abbreviations: PTDT, parental TDT; SNP, single-nucleotide polymorphism; T1D, type I diabetes; TDT, Transmission Disequilibrium Test.

Designations for the two SNPs that showed T1D association are shown in bold. Data indicating significant association in the DR3/DR4 subset are shown in bold.

Table 5.

Genetic association between TCF7 SNPs and T1D in trios where the affected offspring did not carry the HLA-DR3/DR4 genotype

Marker Over transmitted allele is T:U Trans (%) χ2 TDT P value Odds ratio 95% CI PTDT P value
rs30503 C Major 336:283 54.3 4.538 0.0332 1.19 (1.01–1.39) 0.015
rs30500 C Major 403:377 51.7 0.867 0.3519 1.07 (0.92–1.23) 0.2787
rs30499 A Major 546:485 53.0 3.609 0.0575 1.13 (0.99–1.27) 0.051
rs244948 G Major 335:327 50.6 0.097 0.7559 1.02 (0.87–1.19) 0.8487
rs5742913 A Minor 345:273 55.8 8.388 0.0038 1.26 (1.07–1.48) 0.0075
rs244692 A Major 223:209 51.6 0.454 0.5006 1.07 (0.88–1.28) 0.6053
rs151822 T Major 534:475 52.9 3.45 0.0633 1.12 (0.99–1.27) 0.0442
rs152404 T Major 378:335 53.0 2.593 0.1073 1.13 (0.97–1.30) 0.0465
rs152406 G Major 146:133 52.3 0.606 0.4364 1.10 (0.86–1.38) 0.4429
rs249611 A Major 241:217 52.6 1.258 0.2621 1.11 (0.92–1.33) 0.13
rs17653687 A Major 399:355 52.9 2.568 0.1091 1.12 (0.97–1.29) 0.0307
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Abbreviations: PTDT, parental TDT; SNP, single-nucleotide polymorphism; T1D, type I diabetes; TDT, Transmission Disequilibrium Test.

Designations for the two SNPs that showed T1D association are shown in bold. Data indicating significant association in the non-DR3/DR4 subset are shown in bold.

For the non-DR3/DR4 cases, however, the result was reversed, with the variant (A) allele of the C883A SNP significantly overtransmitted (transmission =55.8%, P =0.004) and the reference (A) allele of rs17653687 not significantly overtransmitted (transmission =52.9%; P =0.109). TDT analysis of the non-DR3/DR4 cases identified an additional, marginally significant association of the reference (C) allele of rs30503 (transmission =52%; P =0.033). Analyses of the data by PDT also demonstrated the significant overtransmission of the variant 883A allele of rs5742913 (P =0.008) to non-DR3/DR4 cases. PDT analyses also revealed several nominally significant T1D associations, including rs30503 (P =0.015), consistent with the TDT analysis, but also several SNPs (rs30499, P =0.051; rs151822, P =0.044; rs 152404, P =0.047, and rs17653697, P =0.031) that were not significantly T1D associated based on TDT analyses (Table 5). For all these SNPs, the reference allele is overtransmitted, unlike the C883A SNP, in which the variant A allele is overtransmitted. Given the strong LD (Figure 1) among these SNPs, the overtransmission of the reference allele at these SNPs may reflect the protective effect of the variant allele at one of these SNPs, the strongest effect being the intronic rs17653687 SNP. The C883A SNP in exon 2 is the only TCF7 SNP, from the set tested here, in which the variant allele is over transmitted. This overtransmission is seen overall and in the non-DR3/DR4 patient subset but is not seen in the subset of cases with the high-risk DR3/DR4 genotype.

Discussion

Many published association studies of candidate gene polymorphisms are limited in statistical power and, consequently, the reports of T1D association are often discordant. The extensive T1DGC collection of families has enabled replication analyses of a variety of reported associations (T1DGC Rapid Response Project). TDT and PDT analyses of the large combined dataset indicate that two SNPs (rs5742913 and rs17653687) in TCF7, a gene encoding a T-cell transcription factor, are significantly associated with T1D (Table 3). After stratification on the T1D high-risk HLA-DR3/DR4 genotype, the variant A allele of C883A (Pro–Thr) (rs5742913) is associated with T1D only in the non-DR3/DR4 patients, consistent with the initial report of TCF7 association15 whereas the rs17653687, an intronic polymorphism, shows a modest overtransmission of the reference allele, A, in both DR3/DR4 and non-DR3/4 patients. The association with T1D of the A allele of the C883A polymorphism, previously reported15 and replicated in this study, illustrates the value of stratifying T1D association data on the high-risk genotype HLA-DR3/DR4. A recent study of a variety of T1D candidate genes18 concluded that TCF7 could not be excluded as a T1D candidate gene, reporting evidence of association of rs5742913/C883A in a large case/control cohort (P =0.0005) but no association in a family collection (P =0.3486). This report, however, did not find evidence for increased T1D association of the TCF7 SNP in individuals with low HLA risk.

The role of polymorphism in the HLA class I and class II genes in T1D risk is likely to reflect the specificity of peptide binding and presentation by the HLA proteins, whereas polymorphism in other T1D susceptibility genes, such as PTPN22, CTLA4, and TCF7, may involve the overall level of T-cell activation. TCF7 is a T-cell transcription factor that activates expression of IL-1217 and has multiple isoforms. Resting T cells preferentially express inhibitory TCF7 isoforms and T-cell activation changes the isoform balance in favor of stimulatory TCF7 isoforms.19 The Pro–Thr polymorphism (rs5742913) at nucleotide position 883 of exon 2 is a non-conservative change that could potentially affect TCF7 function. As TCF7 upregulates genes in the Th1 pathway and the A allele (Thr) is associated with a Th1 disease, T1D, one possible explanation for the T1D association would be that the Thr variant has increased activity and, consequently, tilts the Th1/Th2 balance toward the Th1 pathway of T-cell differentiation.

On the basis of the LD patterns and the observed disease association patterns (Table 5), the associated SNP rs5742913 is a plausible causal polymorphism for T1D susceptibility. For the intron SNP rs17653687, the variant allele G appears to be ‘protective’ (OR <1.0 and undertransmitted). The association of this SNP cannot be attributed to LD with the C883A SNP. Additional studies will be required to validate this association and to explore effects on isoform production and other potential functional mechanisms.

In summary, these data support the hypothesis that TCF7 is involved in genetic risk to T1D, although the associations observed for both the intronic SNP rs17653687 and the nonsynonymous change encoded by rs5742913 are relatively modest (odds ratios ≤1.26). This is in stark contrast with the very large effects seen with class II haplotypes in the HLA region.

Materials and methods

Subjects

The T1DGC assembled a collection of 2295 affected sib-pair families for genotyping in this evaluation of candidate genes published earlier as containing variants associated with T1D. The samples and description of the families are provided in the T1DGC web site (http://www.t1dgc.org) and contain samples from nine cohorts. Details of the sample, quality control, and other aspects of the data can be found in this volume (Brown et al.20). Age of onset data were also included in the cohort and study data but were not used in the current data analyses reported here.

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 TCF7 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, and followed by manual review. SNPs were also genotyped on the Illumina GoldenGate chemistry but not reported here.

Statistical analyses

A TDT21 was carried out on each of the markers as implemented by Haploview 4.1.22 The transmission proportions were used to compute odds ratios and 95% confidence intervals as described earlier.23 The parental TDT method, as implemented by Haploview 4.1, was also used as a family-based test of genetic association. The PDT incorporates parental phenotypes and, specifically, the parental genotype–phenotype correlation terms.24 This 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 transmission/disequilibrium test and equivalent quantitative tests, while 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.25 T1D patients were stratified into those carrying DR3/DR4, defined here as carrying one DRB1*0301-DQB1* 0201 haploytpe and one DRB1*0401/02/04/05/08-DQB1*0302/04 or DQB1*0201 haplotype. All other patients were categorized as non-DR3/DR4.

Acknowledgments

We are grateful to all the T1D patients and 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), the National Institute of Allergy and Infectious Diseases (NIAID), the National Human Genome Research Institute (NHGRI), the National Institute of Child Health and Human Development (NICHD), and the Juvenile Diabetes Research Foundation International (JDRF) and supported by U01 DK062418. We thank John Todd and Joanna Howson for careful reading of the manuscript and valuable discussion. 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.

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