July 2011
Volume 52, Issue 8
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Genetics  |   July 2011
Association of TCF4 Gene Polymorphisms with Fuchs' Corneal Dystrophy in the Chinese
Author Affiliations & Notes
  • Anbupalam Thalamuthu
    From the Genome Institute of Singapore, Singapore;
  • Chiea Chuen Khor
    Infectious Diseases, Genome Institute of Singapore, A*STAR, Singapore;
    NUS-GIS Center for Molecular Epidemiology, Singapore;
  • Divya Venkataraman
    Singapore Eye Research Institute, Singapore;
  • Li Wei Koh
    Singapore Eye Research Institute, Singapore;
  • Donald T. H. Tan
    Singapore Eye Research Institute, Singapore;
    Singapore National Eye Centre, Singapore;
    Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; and
  • Tin Aung
    Singapore Eye Research Institute, Singapore;
    Singapore National Eye Centre, Singapore;
    Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; and
  • Jodhbir S. Mehta
    Singapore Eye Research Institute, Singapore;
    Singapore National Eye Centre, Singapore;
    Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; and
    Department of Clinical Sciences, Duke-NUS Graduate Medical School, Singapore.
  • Eranga N. Vithana
    Singapore Eye Research Institute, Singapore;
    Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; and
  • Corresponding author: Eranga N. Vithana, Singapore Eye Research Institute, 11 Third Hospital Avenue, Singapore 168751; eranga.n.v@seri.com.sg
  • Footnotes
    2  These authors contributed equally and are joint first authors.
Investigative Ophthalmology & Visual Science July 2011, Vol.52, 5573-5578. doi:10.1167/iovs.11-7568
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      Anbupalam Thalamuthu, Chiea Chuen Khor, Divya Venkataraman, Li Wei Koh, Donald T. H. Tan, Tin Aung, Jodhbir S. Mehta, Eranga N. Vithana; Association of TCF4 Gene Polymorphisms with Fuchs' Corneal Dystrophy in the Chinese. Invest. Ophthalmol. Vis. Sci. 2011;52(8):5573-5578. doi: 10.1167/iovs.11-7568.

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Abstract

Purpose.: To test the association between TCF4, a gene recently found to confer susceptibility to Fuchs' corneal dystrophy (FCD) in Caucasian populations, and Chinese patients with FCD.

Methods.: Fifty-seven Chinese subjects with clinically diagnosed FCD and 121 normal control subjects were recruited. Genomic DNA was extracted and the 18 single nucleotide polymorphisms (SNPs) within TCF4 were genotyped (Sequenom MassArray primer extension system; Sequenom, Inc., San Diego, CA). Statistical association between individual SNPs and FCD was evaluated using 1 df additive genetic models, and verified with 2 df unguided genotype tests of association. P < 0.002 was considered statistically significant after accounting for the 18 SNPs.

Results.: The affected individuals ranged in age from 48 to 87 years, with an average age of 67 years. There was no statistical difference in the demographic information between the FCD and the control group (mean age of 65.1 years; range, 39–85, P = 0.12). Two SNPs within TCF4 (rs17089887 and rs17089925) were significant experiment-wide (P = 7.34 × 10-5 and P = 0.00045 respectively) with an increase in disease risk of >2.3-fold per copy of the risk allele compared with individuals who were wild type. However, the most significantly associated SNP from the original report (rs613872) was not found to be present in Chinese FCD subjects.

Conclusions.: Polymorphisms within TCF4, a gene which has been implicated in FCD susceptibility among Europeans, was also found to be strongly associated with FCD in Chinese.

Fuchs' corneal dystrophy (FCD) (MIM 136800) is a bilateral, often asymmetric, progressive disorder affecting the corneal endothelium 1 that afflicts approximately 4% of the population over the age of 40 years. 2 FCD is characterized by the development of guttae, excrescences of the Descemet membrane that typically appear in the fourth or the fifth decade of life and increase in number over time. From the time of onset, there is typically slow progression, caused by impaired endothelial dysfunction, eventually leading to stromal edema and impaired vision. 3  
Few studies have examined the prevalence of FCD on a large scale. Cross-sectional studies however suggest a relatively higher prevalence of the disease in European countries relative to other parts of the world including Asia. A population based study conducted in Reykjavik, Iceland revealed 11% of females and 7% of males with guttae. 4 Corneal guttae and FCD are rare in the Japanese population. 5 An examination of 107 patients with cataract in Japan revealed four (3.8%) with ‘primary cornea guttata,’ described as early signs of FCD. 6 However, FCD appears to be more common in Chinese compared with Japanese. A study that compared the prevalence of cornea guttata between Japan and Singapore found a significantly increased prevalence of disease in Singapore (5.5% vs. 8.5%). This was associated with a lower mean endothelial cell count among the affected individuals in Singapore compare with the Japanese. 7 A Singaporean study also found 7.1% of the penetrating keratoplasty (PK) transplants to be secondary to FCD, further indicating that FCD is not as uncommon as previously thought among Chinese people. 8  
FCD is likely to be complex in etiology, with genetic as well as environmental factors playing a role in its causation. Although it has often been described in the literature as an autosomal dominant inherited condition, 9 11 the precise mode of inheritance for most typical cases remain unknown. FCD may be classified into an early-onset variant (familial FCD) or a late-onset (classic) variant, the latter may be further subclassified into late-onset familial FCD or the more common late-onset sporadic FCD. 12 The much rarer early onset variant has been found to be caused by mutations in the COL8A2 gene. 13,14 This gene encodes the α2 subtype of collagen VIII which is a major component of Descemet's membrane, and has recently been shown to strongly associate with central corneal thickness. 15 Linkage studies have identified several chromosomal loci associated with common late-onset familial FCD, including chromosomes 5q33.1–q35.2, 9p22.1–9p24.1, 13ptel–13q12.13, and 18q21.2–q21.32. 16 19 In addition, rare missense mutations in genes SLC4A11 and TCF8, associated with congenital hereditary endothelial dystrophy and posterior polymorphous corneal dystrophy, respectively, have also been identified in late onset FCD cases. 19 21  
Very recently, a genome-wide association study conducted in 130 European FCD cases and 260 matched control subjects found that common alleles at TCF4 contribute substantively to the risk of FCD. 22 Here, we conducted an independent validation study reassessing the role of TCF4 in 57 unrelated patients with late-onset FCD of Chinese ethnicity in Singapore and show that at least 2 variants in TCF4 are independently associated with FCD at an experiment-wide significance level. The single nucleotide polymorphism (SNP) rs613872, most highly associated with FCD in Caucasians, was found to be nonpolymorphic in the Chinese. 
Methods
Ascertainment of Cases and Control Subjects
The study protocol had the approval of the institutional review board of Singapore National Eye Centre and was in compliance with the tenets of the Declaration of Helsinki. All patients underwent complete ophthalmic examination including funduscopy and slit lamp examination and confocal specular microscopy. The diagnosis of FCD was based on the presence of greater than 5 mm of confluent central corneal endothelial guttae in each eye (Krachmer grade 4 or higher) 2 or histopathologically confirmed FCD after performing corneal transplantation. A detailed history was recorded for all subjects, including any family history and duration of onset of symptoms. After the nature and possible consequences of study enrollment were explained to each patient, written informed consent to participate in the research was obtained from each study participant. Chinese subjects with no corneal guttae (Krachmer grade 0) on slit lamp examination and confocal specular microscopy were recruited as control subjects. We excluded individuals in whom the corneal endothelium could not be evaluated. 
Genotyping
Genomic DNA was extracted from leukocytes of the peripheral blood (Nucleon Blood Extraction Kit, Amersham, Biosciences, Buckinghamshire, UK). We genotyped 18 single nucleotide polymorphisms (SNPs) across TCF4, selected based on Chinese Hapmap data (Sequenom MassArray iPLEX primer extension system; www.sequenom.com; Sequenom, Inc., San Diego, CA). In SNP selection, we also considered the TCF4 gene regions from which the original association signals were observed in the European population, 22 and chose SNPs appropriate for a Chinese population (Table 1).T1 
Table 1.
 
Characteristics of Genotyped SNPs within TCF4
Table 1.
 
Characteristics of Genotyped SNPs within TCF4
SNP ID Position† Position Allele Freq* OR‡ P
Cases Controls
rs7235583 53747212 Upstream A/C 0.07018 0.08678 0.808 0.6131
rs1945737 53744545 Upstream C/T 0.4035 0.3967 0.982 0.9369
rs17806802 53718138 Upstream A/G§ NA NA NA NA
rs2286812 53717464 Upstream C/T 0.1404 0.125 1.136 0.6964
rs1477440 53696010 Upstream A/G 0.5263 0.4298 1.423 0.1468
rs17089925 53400834 Upstream C/T 0.6228 0.4174 2.381 0.0004
rs2123392 53214865 Intron 3 C/T 0.2719 0.4000 0.469 0.0047
rs613872 53210302 Intron 3 G/T§ NA NA NA NA
rs17089887 53208256 Intron 3 C/T 0.6491 0.4504 2.567 0.0003
rs1319637 53207325 Intron 3 A/G 0.0351 0.0785 0.420 0.1439
rs1452787 53207207 Intron 3 A/G 0.2719 0.3926 0.479 0.006
rs2123389 53201972 Intron 3 A/G 0.0351 0.0703 0.575 0.336
rs7233312 53143573 Intron 3 C/T 0.3333 0.4008 0.692 0.127
rs17089826 53126993 Intron 5 C/T 0.0088 0.00413 4.763 0.2836
rs2919450 53084545 Intron 5 A/C 0.6228 0.4959 0.630 0.03985
rs17594358 53050489 Intron 6 A/G§ NA NA NA NA
rs1348047 53050058 Intron 6 G/T 0.6140 0.4339 1.993 0.0046
rs17594301 53048885 Intron 6 C/T§ NA NA NA NA
Statistical Analysis
Logistic regression (1 df) trend and unguided (2 df) genotype tests were used to model statistical associations of all the SNPs with FCD, adjusted for age and sex. Conditional analysis using logistic regression was also done to examine the independent effect of an SNP conditional on another SNP. Hardy-Weinberg equilibrium of the genotypic frequencies among cases and separately among the controls was also examined. Haplotype association tests for the joint effect of all the haplotypes and haplotype-specific effects were performed. All the afore-mentioned analyses were performed using the package PLINK. 23 Haploview 24 was used to compute the linkage disequilibrium (LD) statistics and the LD plot. Single SNP P value <0.002 was considered statistically significant after correcting for 18 independent tests. 
To understand the discriminatory power of the SNPs within the gene TCF4, we used logistic regression as the model for classification. Area under the receiver operating characteristic curve (AUC), sensitivity, and specificity were used to identify the best subset of SNPs for classification. The R 25 package Epi 26 was used to perform the classification analysis based on logistic regression. 
Results
Demographics of Subjects
Fifty-seven unrelated patients with a diagnosis of late onset FCD and 121 normal control subjects were enrolled into the study. The affected probands ranged in age from 48 to 87 years, with an average age of 67 years. There was no statistical difference in the demographic information between the FCD and the control group (mean age of 65.1 years; range, 39–85; P = 0.12). There were 45 females and 12 males among the FCD cases. There were 70 females and 51 males within the control group. All the patients and control subjects were Chinese. Twelve of the FCD patients had a family history of FCD and the remaining 45 cases were ‘late-onset’ sporadic FCD. 
Single Nucleotide Polymorphism (SNP) Association Analysis
Characteristics of the entire set of SNPs genotyped in this study are shown in Table 1. The allelic and genotype frequencies of the most significant SNPs within TCF4 investigated in Chinese patients with FCD are shown in Table 2. The genotype frequencies of the controls and cases are in keeping with Hardy-Weinberg equilibrium. Single-locus analysis conducted on the 18 SNPs within TCF4 revealed four of them to be nonpolymorphic in Chinese. This included the most significantly associated SNP from the original report (rs613872). 22 After accounting for the testing of 18 SNPs, only association signals at rs17089887 and rs17089925 remained significant experiment-wide (genotype P = 7.34 × 10-5 and P = 0.00045, respectively; Table 2). Each copy of the C allele of rs17089887 and the T allele of rs17089925 conferred a 2.57- (95% CI, 1.54–4.29) and 2.38-fold (95% CI, 1.47–3.85) increased risk of FCD, respectively. 
Table 2.
 
Most Significant SNPs within TCF4 Investigated in Chinese Patients with Fuchs' Corneal Dystrophy
Table 2.
 
Most Significant SNPs within TCF4 Investigated in Chinese Patients with Fuchs' Corneal Dystrophy
SNP ID Allele Distribution (%) Trend Test (P) Per Allele Odds Ratio (95% CI) Genotype Distribution (%) Unguided 2 df Genotype P
Cases Controls Cases Controls
rs1348047 G 70 (0.614) 105 (0.434) 0.0046 1.99 (1.24–3.21) GG* 23 (0.403) 24 (0.198) 0.01408
T 44 (0.386) 137 (0.566) GT 24 (0.421) 57 (0.471)
TT 10 (0.175) 40 (0.331)
rs1452787 G 31 (0.272) 95 (0.393) 0.006 0.48 (0.28–0.81) GG† 8 (0.140) 20 (0.165) 0.0042
A 83 (0.728) 147 (0.607) GA 15 (0.263) 55 (0.454)
AA 34 (0.596) 46 (0.380)
rs17089887 C 74 (0.649) 109 (0.450) 0.0003 2.57 (1.54–4.29) CC* 28 (0.491) 22 (0.182) 7.34E-05
T 40 (0.351) 133 (0.550) TC 18 (0.316) 65 (0.537)
TT 11 (0.193) 34 (0.281)
rs17089925 T 71 (0.623) 101 (0.417) 0.0004 2.38 (1.47–3.85) TT* 26 (0.456) 22 (0.182) 0.00045
C 43 (0.377) 141 (0.583) TC 19 (0.333) 57 (0.471)
CC 12 (0.210) 42 (0.347)
rs2123392 C 31 (0.272) 96 (0.400) 0.0047 0.47 (0.28–0.79) CC† 8 (0.140) 20 (0.167) 0.00316
T 83 (0.728) 144 (0.600) CT 15 (0.263) 56 (0.467)
TT 34 (0.596) 44 (0.367)
Linkage Disequilibrium and Haplotype Association Analysis
The LD plot (Fig. 1) shows three blocks within TCF4 based on the 14 typed SNPs; block 1 (rs1348047 and rs2919450), block 2 (rs2123389 to rs17089925), and block3 (rs2286812 to rs7235583). The association signals arose from blocks 1 and 2 only. Baratz et al. 22 also showed extensive LD between individual SNPs across the entire TCF4 gene for Caucasian samples, using imputed genotypes for 720 SNPs across the chromosome 18 locus. According to the position and identity of SNPs within LD blocks, blocks 1 and 2 here may correspond with blocks 7 to 8 and 17 of the Caucasian study, respectively. However, as the set of SNPs used for LD plots in these two studies is different, any comparison of LD patterns between Caucasians and Chinese need to be interpreted with caution. To examine the joint association of SNPs within these blocks, haplotype association tests were performed. The P values for global tests of haplotype associations for block 1, 2, and 3, respectively, are 0.0041, 0.0030, and 0.67. These associations are of similar magnitude to the association signals from blocks 7 to 8 and block 17 reported in the Caucasian study. 22 Of note, the upstream haplotype block associations described in Baratz et al. 22 (in blocks 31 and 34), were not statistically significant (P > 0.05) in our study. We are mindful that the haplotype-based association tests did not show evidence of association exceeding that observed by single SNP analysis, suggesting that single SNP analysis is sufficiently informative to account for the association signals observed in our study. In addition, no evidence for increased risk for any specific haplotype was observed based on haplotype specific association tests within these blocks (results not shown). 
Figure 1.
 
Plot of pairwise linkage disequilibrium (D prime) across 14 TCF4 SNPs in the Chinese control subjects.
Figure 1.
 
Plot of pairwise linkage disequilibrium (D prime) across 14 TCF4 SNPs in the Chinese control subjects.
Conditional Analysis
Among the four associated SNPs, pairwise conditional logistic regression analysis was performed to identify the marginal independence of the association signals (Table 3). The SNP rs1348047 and rs2123392 are associated independently of the SNPs rs17089887 and rs17089925. The rs17089887 and rs17089925 are highly correlated (r 2 = 0.736) and hence these two SNPs are not independently associated with the FCD. 
Table 3.
 
Association between TCF4 Variants and Fuchs' Corneal Dytrophy
Table 3.
 
Association between TCF4 Variants and Fuchs' Corneal Dytrophy
SNP Conditional on
rs1348047 rs17089887 rs17089925 rs2123392
P OR (95% CI) P OR (95% CI) P OR (95% CI) P OR (95% CI)
rs1348047 NA NA 0.008 1.93 (1.19–3.13) 0.012 1.82 (1.14–2.91) 0.0163 1.78 (1.11–2.86)
rs17089887 0.008 1.93 (1.19–3.13) NA NA 0.391 1.47 (0.61–3.52) 0.0136 2.70 (1.23–5.88)
rs17089925 0.012 1.82 (1.14–2.91) 0.391 1.47 (0.61–3.52) NA NA 0.014 2.14 (1.17–3.95)
rs2123392 0.0163 1.78 (1.11–2.86) 0.0136 0.37 (0.17–0.81) 0.014 2.14 (1.17–3.95) NA NA
Classification Analysis
The associated SNPs rs1348047 from block 1 and the SNPs rs17089887, rs2123392, and rs17089925 from block 2 were examined for their ability to classify FCD subjects from control samples. All possible subsets using these four SNPs were examined for the classification performance using sensitivity, specificity, and the AUC metrics. The best result was obtained for the combination of SNPs rs1348047 and SNPs rs17089887 which are from the two independent blocks within TCF4. The receiver operating characteristic (ROC) curve and the corresponding AUC values for the model with and without the covariate sex are given in Figure 2. The risk model distinguished between case and control subjects with 71% accuracy when sex was included in the model. Due to limited sample size, the analysis was restricted to the complete samples and no test sets were used to evaluate classification accuracy. 
Figure 2.
 
Plot of ROC curves for classification models based on two independent TCF4 SNPs. The ROC curves with and without the covariate sex are shown in black and red respectively. Beta coefficients of the two logistic regression models used for classification are shown.
Figure 2.
 
Plot of ROC curves for classification models based on two independent TCF4 SNPs. The ROC curves with and without the covariate sex are shown in black and red respectively. Beta coefficients of the two logistic regression models used for classification are shown.
Discussion
The TCF4 gene located on chromosome 18q21.1 is a large gene that spans across 366,861 bases of genomic DNA. It consists of 20 exons and encodes a 667-amino acid protein. We observed strong evidence of association between two TCF4 SNPs and susceptibility to FCD in Singaporean Chinese. The index SNP reported in Europeans (rs613872) was found to not be present in individuals of Chinese descent, and instead, a SNP located just 2000 base pairs away (rs17089887) and another correlated SNP (rs17089925) showed strong association in Chinese. This is in keeping with the phenomenon that SNPs tagging a given functional causal variant may differ from one population to another, often attributed to differences in patterns of linkage disequilibrium. However in this case the tagging SNP rs613872 was simply not polymorphic in the Chinese and the association signal, in all likelihood arising from the same functional locus as in the Europeans, was detected via SNPs adjacent to rs613872. Similar to the original report, our study also indicated at least two regions of the TCF4 locus, to be associated independently with FCD. A larger sample cohort may be required to give adequate power to improve the association with some of the independent SNPs that showed marginal association with FCD (Table 2). The odds ratios observed here in Chinese (>2.3 per copy of the risk allele) are consistent with that observed in Europeans (>4 per copy of the risk allele). 22 These findings clearly highlight the importance of TCF4 as a genetic determinant of FCD susceptibility with global significance. 
The magnitude of association observed both here and in the European studies are noteworthy and of substantial effect sizes (per allele OR >2-fold increase), reminiscent of that conferred by Complement Factor H polymorphisms and age-related macular degeneration. 27 29 In comparison, the vast majority of robustly replicated loci for other complex diseases only confer per allele ORs of <1.50. 30,31 These observations suggest TCF4 to be a major susceptibility gene for FCD. The protein encoded by TCF4, referred to as E2-2, is a member of the ubiquitously expressed class 1 basic helix-loop-helix (bHLH) transcription factors that are involved in cellular growth and differentiation. 32 TCF4 is expressed predominantly in pre-B-cells but expression has also been shown in adult heart, brain, placenta, skeletal muscle, and lung. TCF4 expression has also been shown in the developing corneal endothelium of the mouse. 22 In man, haploinsufficiency of TCF4 is a cause of Pitt-Hopkins syndrome (PHTS; MIM 610,954). 33 PHTS is a rare, autosomal dominant, syndromic encephalopathy characterized by severe psychomotor delay, epilepsy, daily bouts of diurnal hyperventilation starting in infancy, mild postnatal growth retardation, postnatal microcephaly, and distinctive facial features. It is unusual to have the same gene being associated with two such divergent phenotypes as PHTS and late onset FCD. However, several plausible hypotheses have been put forth for the molecular mechanisms underlying FCD associated with TCF4 risk variants. 22 It has been suggested that the risk variants of TCF4 may alter the expression of TCF8. TCF4 is known to up regulate the expression of TCF8, missense variations of which are associated with late-onset FCD cases. The TCF8 gene encodes a transcription factor that plays a critical role in embryonic development. Of particular significance are previous reports of TCF8 gene playing a role in the regulation of type I collagen expression and in the repression of the epithelial phenotype, which is critical in the maintenance of an endothelial phenotype. 34,35  
Our results, observed here in individuals of Chinese descent, strongly support data reported from previous European studies which show strong association between TCF4 variants and FCD. Further study should now focus on the functional disease mutations responsible for the strong association signal to dissect the molecular mechanisms underlying FCD pathogenesis. 
Footnotes
 Supported by a grant from the Singapore Eye Research Institute.
Footnotes
 Disclosure: A. Thalamuthu, None; C.C. Khor, None; D. Venkataraman, None; L.W. Koh, None; D.T.H. Tan, None; T. Aung, None; J.S. Mehta, None; E.N. Vithana, None
The authors thank the patients for participating in the study. 
References
Adamis AP Filatov V Tripathi BJ Tripathi RC . Fuchs' endothelial dystrophy of the cornea. Surv Ophthalmol. 1993;38:149–168. [CrossRef] [PubMed]
Krachmer JH Purcell JJJr Young CW Bucher KD . Corneal endothelial dystrophy. A Study of 64 families. Arch Ophthalmol. 1978;96:2036–2039. [CrossRef] [PubMed]
Waring GO Bourne WM Edelhauser HF Kenyon KR . The corneal endothelium. Normal and pathologic structure and function. Ophthlamology. 1982;89:531–590. [CrossRef]
Zoega GM Fujisawa A Sasaki H . Prevalence and risk factors for cornea guttata in the Reykjavik Eye Study. Ophthalmology. 2006;113:565–569. [CrossRef] [PubMed]
Hogan MJ Wood I Fine M . Fuch's endothelial dystrophy of the cornea: 29th Sanford Gifford Memorial Lecture. Am J Ophthlamol. 1974;78:363–383. [CrossRef]
Nagaki Y Hayasaka S Kitagawa K Yamamoto S . Primary cornea guttata in Japanese patients with cataract: specular microscopic observations. Jpn J Ophthalmol. 1996;40:520–525. [PubMed]
Kitagawa K Kojima M Sasaki H . Prevalence of primary cornea guttata and morphology of corneal endothelium in aging Japanese and Singaporean subjects. Ophthalmic Res. 2002;34:135–138. [CrossRef] [PubMed]
Tan DT Janardhanan P Zhou H . Penetrating keratoplasty in Asian eyes: the Singapore Corneal Transplant Study. Ophthalmology. 2008;115:975–982. [CrossRef] [PubMed]
Cross HE Maumenee AE Cantolino SJ . Inheritance of Fuchs' endothelial dystrophy. Arch Ophthalmol. 1971;85:268–272. [CrossRef] [PubMed]
Rosenblum P Stark WJ Maumenee IH Hirst LW Maumenee AE . Hereditary Fuchs' dystrophy. Am J Ophthalmol. 1980;90:455–462. [CrossRef] [PubMed]
Magovern M Beauchamp GR Mc Tigue JW . Inheritance of Fuchs' combined dystrophy. Ophthalmology. 1979;86:1897–1923. [CrossRef] [PubMed]
Aldave AJ Rayner SA Salem AK . No pathogenic mutations identified in the COL8A1 and COL8A2 genes in familial Fuchs corneal dystrophy. Invest Ophthalmol Vis Sci. 2006;47:3787–3790. [CrossRef] [PubMed]
Gottsch JD Sundin OH Liu SH . Inheritance of a novel COL8A2 mutation defines a distinct early-onset subtype of fuchs corneal dystrophy. Invest Ophthalmol Vis Sci. 2005;46:1934–1939. [CrossRef] [PubMed]
Biswas S Munier FL Yardley J . Missense mutations in COL8A2, the gene encoding the alpha2 chain of type VIII collagen, cause two forms of corneal endothelial dystrophy. Hum Mol Genet. 2001;10:2415–2423. [CrossRef] [PubMed]
Vithana EN Aung T Khor CC . Collagen-related genes influence the glaucoma risk factor, central corneal thickness. Hum Mol Genet. 2011;20:649–658. [CrossRef] [PubMed]
Sundin OH Jun AS Broman KW . Linkage of late-onset Fuchs corneal dystrophy to a novel locus at 13pTel-13q12.13. Invest Ophthalmol Vis Sci. 2006;47:140–145. [CrossRef] [PubMed]
Sundin OH Broman KW Chang HH . A common locus for late-onset Fuchs corneal dystrophy maps to 18q21.2-q21.32. Invest Ophthalmol Vis Sci. 2006;47:3919–3926. [CrossRef] [PubMed]
Riazuddin SA Eghrari AO Al Saif A . Linkage of a mild late-onset phenotype of Fuchs corneal dystrophy to a novel locus at 5q33.1-q35.2. Invest Ophthalmol Vis Sci. 2009;50:5667–5671. [CrossRef] [PubMed]
Riazuddin SA Zaghloul NA Al-Saif A . Missense mutations in TCF8 cause late-onset Fuchs corneal dystrophy and interact with FCD4 on chromosome 9p. Am J Hum Genet. 2010;86:45–53. [CrossRef] [PubMed]
Vithana EN Morgan PE Ramprasad V . SLC4A11 mutations in Fuchs endothelial corneal dystrophy. Hum Mol Genet. 2008;17:656–666. [CrossRef] [PubMed]
Riazuddin SA Vithana EN Seet LF . Missense mutations in the sodium borate cotransporter SLC4A11 cause late-onset Fuchs corneal dystrophy. Hum Mutat. 2010 Nov;31:1261–1268. [CrossRef] [PubMed]
Baratz KH Tosakulwong N Ryu E . E2–2 protein and Fuchs's corneal dystrophy. N Engl J Med. 2010;363:1016–1024. [CrossRef] [PubMed]
Purcell S Neale B Todd-Brown K . PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81:559–575. [CrossRef] [PubMed]
Barrett JC Fry B Maller J Daly MJ . Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics. 2005;21:263–265. [CrossRef] [PubMed]
R Development Core Team. R: A Language and Environment for Statistical Computing. Vienna, Austria: R Foundation for Statistical Computing; 2008.
Carstensen B Plummer M Laara E . Epi: a package for statistical analysis in epidemiology. R package version 1.0.8. Available at: http://www.pubhealth.ku.dk/∼bxc/Epi/ . Accessed January 31, 2011.
Klein RJ Zeiss C Chew EY . Complement factor H polymorphism in age-related macular degeneration. Science. 2005;308:385–389. [CrossRef] [PubMed]
Haines JL Hauser MA Schmidt S . Complement factor H variant increases the risk of age-related macular degeneration. Science. 2005;308:419–421. [CrossRef] [PubMed]
Edwards AO Ritter R Abel KJ . Complement factor H polymorphism and age-related macular degeneration. Science. 2005;308:421–424. [CrossRef] [PubMed]
Thomas G Jacobs KB Kraft P . A multistage genome-wide association study in breast cancer identifies two new risk alleles at 1p11.2 and 14q24.1 (RAD51L1). Nat Genet. 2009;41:579–584. [CrossRef] [PubMed]
Purdue MP Johansson M Zelenika D . Genome-wide association study of renal cell carcinoma identifies two susceptibility loci on 2p21 and 11q13.3. Nat Genet. 2011;43:60–65. [CrossRef] [PubMed]
Murre C Bain G van Dijk MA . Structure and function of helix-loop-helix proteins. Biochim Biophys Acta. 1994;1218:129–135. [CrossRef] [PubMed]
Amiel J Rio M de Pontual L . Mutations in TCF4, encoding a class I basic helix-loop-helix transcription factor, are responsible for Pitt-Hopkins syndrome, a severe epileptic encephalopathy associated with autonomic dysfunction. Am J Hum Genet. 2007;80:988–993. [CrossRef] [PubMed]
Terraz C Toman D Delauche M Ronco P Rossert J . Delta Ef1 binds to a far upstream sequence of the mouse pro-alpha 1(I) collagen gene and represses its expression in osteoblasts. J Biol Chem. 2001;276:37011–37019. [CrossRef] [PubMed]
Frisch SM . E1a induces the expression of epithelial characteristics. J Cell Biol. 1994;127:1085–1096. [CrossRef] [PubMed]
Figure 1.
 
Plot of pairwise linkage disequilibrium (D prime) across 14 TCF4 SNPs in the Chinese control subjects.
Figure 1.
 
Plot of pairwise linkage disequilibrium (D prime) across 14 TCF4 SNPs in the Chinese control subjects.
Figure 2.
 
Plot of ROC curves for classification models based on two independent TCF4 SNPs. The ROC curves with and without the covariate sex are shown in black and red respectively. Beta coefficients of the two logistic regression models used for classification are shown.
Figure 2.
 
Plot of ROC curves for classification models based on two independent TCF4 SNPs. The ROC curves with and without the covariate sex are shown in black and red respectively. Beta coefficients of the two logistic regression models used for classification are shown.
Table 1.
 
Characteristics of Genotyped SNPs within TCF4
Table 1.
 
Characteristics of Genotyped SNPs within TCF4
SNP ID Position† Position Allele Freq* OR‡ P
Cases Controls
rs7235583 53747212 Upstream A/C 0.07018 0.08678 0.808 0.6131
rs1945737 53744545 Upstream C/T 0.4035 0.3967 0.982 0.9369
rs17806802 53718138 Upstream A/G§ NA NA NA NA
rs2286812 53717464 Upstream C/T 0.1404 0.125 1.136 0.6964
rs1477440 53696010 Upstream A/G 0.5263 0.4298 1.423 0.1468
rs17089925 53400834 Upstream C/T 0.6228 0.4174 2.381 0.0004
rs2123392 53214865 Intron 3 C/T 0.2719 0.4000 0.469 0.0047
rs613872 53210302 Intron 3 G/T§ NA NA NA NA
rs17089887 53208256 Intron 3 C/T 0.6491 0.4504 2.567 0.0003
rs1319637 53207325 Intron 3 A/G 0.0351 0.0785 0.420 0.1439
rs1452787 53207207 Intron 3 A/G 0.2719 0.3926 0.479 0.006
rs2123389 53201972 Intron 3 A/G 0.0351 0.0703 0.575 0.336
rs7233312 53143573 Intron 3 C/T 0.3333 0.4008 0.692 0.127
rs17089826 53126993 Intron 5 C/T 0.0088 0.00413 4.763 0.2836
rs2919450 53084545 Intron 5 A/C 0.6228 0.4959 0.630 0.03985
rs17594358 53050489 Intron 6 A/G§ NA NA NA NA
rs1348047 53050058 Intron 6 G/T 0.6140 0.4339 1.993 0.0046
rs17594301 53048885 Intron 6 C/T§ NA NA NA NA
Table 2.
 
Most Significant SNPs within TCF4 Investigated in Chinese Patients with Fuchs' Corneal Dystrophy
Table 2.
 
Most Significant SNPs within TCF4 Investigated in Chinese Patients with Fuchs' Corneal Dystrophy
SNP ID Allele Distribution (%) Trend Test (P) Per Allele Odds Ratio (95% CI) Genotype Distribution (%) Unguided 2 df Genotype P
Cases Controls Cases Controls
rs1348047 G 70 (0.614) 105 (0.434) 0.0046 1.99 (1.24–3.21) GG* 23 (0.403) 24 (0.198) 0.01408
T 44 (0.386) 137 (0.566) GT 24 (0.421) 57 (0.471)
TT 10 (0.175) 40 (0.331)
rs1452787 G 31 (0.272) 95 (0.393) 0.006 0.48 (0.28–0.81) GG† 8 (0.140) 20 (0.165) 0.0042
A 83 (0.728) 147 (0.607) GA 15 (0.263) 55 (0.454)
AA 34 (0.596) 46 (0.380)
rs17089887 C 74 (0.649) 109 (0.450) 0.0003 2.57 (1.54–4.29) CC* 28 (0.491) 22 (0.182) 7.34E-05
T 40 (0.351) 133 (0.550) TC 18 (0.316) 65 (0.537)
TT 11 (0.193) 34 (0.281)
rs17089925 T 71 (0.623) 101 (0.417) 0.0004 2.38 (1.47–3.85) TT* 26 (0.456) 22 (0.182) 0.00045
C 43 (0.377) 141 (0.583) TC 19 (0.333) 57 (0.471)
CC 12 (0.210) 42 (0.347)
rs2123392 C 31 (0.272) 96 (0.400) 0.0047 0.47 (0.28–0.79) CC† 8 (0.140) 20 (0.167) 0.00316
T 83 (0.728) 144 (0.600) CT 15 (0.263) 56 (0.467)
TT 34 (0.596) 44 (0.367)
Table 3.
 
Association between TCF4 Variants and Fuchs' Corneal Dytrophy
Table 3.
 
Association between TCF4 Variants and Fuchs' Corneal Dytrophy
SNP Conditional on
rs1348047 rs17089887 rs17089925 rs2123392
P OR (95% CI) P OR (95% CI) P OR (95% CI) P OR (95% CI)
rs1348047 NA NA 0.008 1.93 (1.19–3.13) 0.012 1.82 (1.14–2.91) 0.0163 1.78 (1.11–2.86)
rs17089887 0.008 1.93 (1.19–3.13) NA NA 0.391 1.47 (0.61–3.52) 0.0136 2.70 (1.23–5.88)
rs17089925 0.012 1.82 (1.14–2.91) 0.391 1.47 (0.61–3.52) NA NA 0.014 2.14 (1.17–3.95)
rs2123392 0.0163 1.78 (1.11–2.86) 0.0136 0.37 (0.17–0.81) 0.014 2.14 (1.17–3.95) NA NA
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