Disease Association of the CD103 Polymorphisms in Taiwan Chinese Graves' Ophthalmopathy Patients
Yu-Huei Liu PhD1, 2, Rong-Hsing Chen MD3, Wen-Chi Chen MD, PhD4, Yuhsin Tsai PhD2, Lei Wan PhD1, 2, 5 and Fuu-Jen Tsai MD, PhD1, 2, 3
Abstract Objective
To evaluate whether variations in the CD103 gene could be associated with Graves' ophthalmopathy (GO) in patients with Graves' disease.
Design
Case-control study. Participants
A total of 484 Chinese patients with Graves' disease in Taiwan, including 203 patients with GO and 281 patients without GO, were enrolled.
Methods
Five single nucleotide polymorphisms (SNPs) in CD103 were genotyped using an assay-on-demand allelic discrimination assay and detection system according to the manufacturer's instructions.
Main Outcome Measures
Association of SNPs in CD103 with the development of GO. Results
The CD103 SNP rs11652878 was associated with GO, which may decrease the risk of GO by 1.57-fold (P = 0.029). The Ht5-GCGCG haplotype, composed of 5 SNPs in the CD103 gene (rs1716, rs3744679, rs11652878, rs16953477, and rs9905739), were protective haplotypes (P = 0.010). Moreover, the heterozygous genotype (Ht5/non-Ht5) was correlated with a reduced risk of GO and high grades of goiter as compared with the non-Ht5/non-Ht5 genotype (P = 0.006 and P = 0.048, respectively). Logistic analysis confirmed the contribution of CD103 rs11652878 to the protection of GO.
These data suggest that patients with Graves' disease in the presence of the G allele of SNP rs11652878, especially Ht5-GCGCG, in CD103 are less susceptible toward the development of GO.
Keywords: Ozone; Spatial distribution; Passive sampler; Air quality monitoring station; Northern Taiwan
Disease Association of the CD103 Polymorphisms in Taiwan Chinese Graves' Ophthalmopathy Patients Yu-Huei Liu PhD1, 2 , Rong-Hsing Chen MD3 , Wen-Chi Chen MD, PhD4 , Yuhsin Tsai PhD2 , Lei Wan PhD1, 2, 5
and Fuu-Jen Tsai MD, PhD1, 2, 3, ,
1
Genetic Center, China Medical University Hospital, Taichung, Taiwan
2
School of Chinese Medicine, China Medical University, Taichung, Taiwan
3
School of Post Baccalaureate Chinese Medicine; China Medical University, Taichung, Taiwan
4
Graduate Institute of Integrated Medicine China Medical University, Taichung, Taiwan
5
Department of Biotechnology, Asia University, Taichung, Taiwan
Received 2 July 2009; revised 16 December 2009; accepted 21 December 2009. Available online: April 24, 2010.. Available online 24 April 2010.
Objective
To evaluate whether variations in the CD103 gene could be associated with Graves' ophthalmopathy (GO) in patients with Graves' disease.
Design
Case-control study.
Participants
A total of 484 Chinese patients with Graves' disease in Taiwan, including 203 patients with GO and 281 patients without GO, were enrolled.
Methods
Five single nucleotide polymorphisms (SNPs) in CD103 were genotyped using an assay-on-demand allelic discrimination assay and detection system according to the manufacturer's instructions.
Main Outcome Measures
Association of SNPs in CD103 with the development of GO.
Results
The CD103 SNP rs11652878 was associated with GO, which may decrease the risk of GO by
1.57-fold (P = 0.029). The Ht5-GCGCG haplotype, composed of 5 SNPs in the CD103 gene (rs1716, rs3744679, rs11652878, rs16953477, and rs9905739), were protective haplotypes (P =
of GO and high grades of goiter as compared with the non-Ht5/non-Ht5 genotype (P = 0.006 and
P = 0.048, respectively). Logistic analysis confirmed the contribution of CD103 rs11652878 to the protection of GO.
Conclusions
These data suggest that patients with Graves' disease in the presence of the G allele of SNP rs11652878, especially Ht5-GCGCG, in CD103 are less susceptible toward the development of GO.
Financial Disclosure(s)
The author(s) have no proprietary or commercial interest in any materials discussed in this article.
Article Outline
Patients and MethodsPatients
Single Nucleotide Polymorphism Selection Genomic DNA Extraction and Genotyping Statistical Analysis
Results
Basic Characteristics and Their Correlations between Patients with Graves' Disease Allele and Genotype Frequencies of CD103 Polymorphisms
Frequencies of CD103 Haplotypes
CD103 Polymorphisms and Clinical Features of Graves' Disease
Discussion References
Inflammatory response plays an important role in the innate immune system.1
Changes in the inflammatory response lead to chronic inflammation, chronic infection, and autoimmune disease, which result in cellular damage.[1], [2], [3] and [4]
Damage causes the release of several inflammatory cytokines in the damaged microenvironment. Interaction between cells of the immune system and damaged cells leads to extraocular muscle damage and inflammation of the connective tissue.[4] and
[5]
Links between chronic inflammation and autoimmune diseases may play an important role in Graves' disease. However, the underlying mechanisms are not well understood.[4], [6] and [7]
Graves' disease is an autoimmune disease that is characterized by hyperthyroidism, diffuse goiter, thyroid-specific autoantibodies with or without Graves' ophthalmopathy (GO), and dermopathy resulting from circulating autoantibodies.8
Among them, GO is the most common extrathyroidal manifestation; it affects 25% to 50% of patients with Graves' disease.[7], [9], [10] and [11]
Clinical symptoms and signs of GO consist of ocular irritation, lid retraction, periorbital swelling, and exophthalmos.[12] and [13]
Approximately 28% of patients with GO seek treatment with severe cases, with restriction in motility, diplopia, keratopathy, and optic neuropathy.[12] and [13]
Despite ongoing basic and clinical research,[14] and [15]
the role of genetic factors in the development of GO remains controversial.[14], [16], [17], [18], [19], [20], [21], [22] and [23]
Therefore, the underlying mechanisms for the development of GO need to be elucidated.
The CD103 region on chromosome 17p13 contains many important autoimmune response
genes.[24], [25] and [26]
CD103 (integrin αE, also known as human mucosal lymphocyte antigen 1) has been found to be expressed by subsets of CD4+
and CD8+
T cells and dendritic cells.27
Although CD103 is not a homing receptor, the ability of CD103 to bind to E-cadherin–expressing
epithelial cells is thought to retain lymphocytes at the epithelial surface, thus playing a role in the homing of T cells to the gut.28
In addition, CD103 prevents virus infection of the lungs,29
confines leukemia relapse to the gut of patients with T-cell acute lymphoblastic leukemia switched
clonally related acute myeloid leukemia,30
promotes tumor cell lysis,31
and destroys the intestinal epithelium of the host in a graft-versus-host disease model.32
Cutaneous inflammatory disease develops in CD103-deficient mice.33
Moreover, recent studies suggest that CD103 may play a role in mediating autoimmune diseases such as celiac disease and type I diabetes mellitus.[34], [35], [36]
and [37]
Although previous reports suggest a positive correlation between CD103 expression and
autoimmune diseases, it remains unknown whether CD103 plays a role in GO. The present study investigated single nucleotide polymorphisms (SNPs) in CD103 that may be associated with significant protection against GO in Taiwanese patients with Graves' disease.
Patients and Methods
Patients
A total of 484 patients with a confirmed diagnosis of Graves' disease at China Medical University Hospital in Taiwan were enrolled and actively followed up. All patients in this study provided informed consent as approved by the Ethics Committee of China Medical University Hospital. Diagnosis of Graves' disease was based on the typical clinical features of hyperthyroidism, diffuse enlargement of the thyroid gland, increased free thyroxine or triiodothyronine levels, suppressed thyroid-stimulating hormone levels, positive thyrotrophin-receptor autoantibodies, and presence or absence of antimicrosomal or antithyroglobulin antibodies. Information
regarding gender, age at onset of Graves' disease, treatment of hyperthyroidism, personal history of cigarette smoking, systemic diseases, and family history of autoimmune thyroid disease was obtained. The inclusion criteria were: fulfillment of the diagnostic criteria of Graves' disease at the time of examination, willingness to participate and capability of giving informed consent, self-reported nonaboriginal Taiwanese with none of the parents or grandparents having an
aboriginal background. The exclusion criteria were: inability to understand or give informed consent and pregnant or given birth within 1 year to exclude patients with postpartum thyroiditis. Graves' ophthalmopathy was identified according to the following criteria: normal upper eyelid position 1.5 mm below the superior limbus and normal lower eyelid position at the level of the inferior limbus in primary gaze. Proptosis was measured by the Hertel exophthalmometer and was defined as the anteroposterior protrusion of the globe more than 19 mm from the lateral orbital rim in either eye or any discrepancy in the degree of protrusion of the 2 eyes by more than 1 mm. All individuals classified as affected were interviewed and examined by experienced clinicians. Full medical record abstraction was conducted to obtain demographics (age and gender), history of tobacco use, treatment, and clinical features. All samples from individuals were collected by venipuncture for subsequent genomic DNA isolation.
Single Nucleotide Polymorphism Selection
CD103 SNP genotype information was downloaded in December 2008 from the HapMap HCB +
JPT population. HapMap genotypes were analyzed within Haploview, and tag SNPs were selected using the Tagger function by applying the following additional criteria: (1) a threshold minor allele frequency (MAF) in the HapMap HCB + JPT population of 0.10 for tag SNP and (2) probe or primers that pass the qualification as recommended by the manufacturer (Applied Biosystems Inc., Foster City, CA) to ensure a high genotyping success rate. Five polymorphisms met the criteria and were selected, including SNP rs1716 (G/A) in exon 24, SNP rs3744679 (C/G) in exon 22, SNP rs11652878 (A/G) in exon 15, and SNP rs16953477 (C/G) and SNP rs9905739 (C/G) in the 3′ region of the gene.
Genomic DNA Extraction and Genotyping
Genomic DNA was extracted from peripheral blood leukocytes using a genomic DNA kit (Qiagen GmbH, Hilden, Germany) in accordance with the manufacturer's instructions.
Genotyping was achieved using an assay-on-demand allelic discrimination assay and detection system according to the manufacturer's instructions (Applied Biosystems). The reaction mixture for the polymerase chain reaction contained 10 ng genomic DNA, 10 μl TaqMan master mix, and 0.125 μl 40× assay mix. Polymerase chain reaction analysis was performed in 96-well plates on a thermal cycler (ABI 9700; Applied Biosystems). Reaction conditions were 50° C for 2 minutes and 95° C for 10 minutes, followed by 40 cycles at 95° C for 15 seconds and 60° C for 1 minute.
Statistical Analysis
Haplotypes were inferred from unphased genotype data using the Phase 2.1 program based on the Bayesian algorithm.38
SPSS software version 14.0 (SPSS Inc., Chicago, IL) was used to analyze the data. The demographics, genotype frequency, allelic frequency, and haplotype frequency distributions of the polymorphisms in patients with Graves' disease with or without GO were analyzed by the chi-square method or by nonparametric Mann–Whitney U test analysis. A P
value less than 0.05 was considered to be statistically significant. The odds ratio (OR) was calculated from genotype frequencies and allelic frequencies with a 95% confidence interval (CI).
Results
Patients with Graves' Disease
The demographics and clinical information of the participants are summarized in Table 1. The age, gender, smoking status, recurrence, treatment, and clinical features of each variable were compared. As demonstrated in Table 2, the chi-square test and the Mann–Whitney U test revealed that the gender, smoking status, recurrence or progression, and radioiodine therapy were associated significantly with GO in patients with Graves' disease.
Table 1.
Demographic and Clinical Characteristics of 484 Patients with Graves' Disease
Mean age at diagnosis (standard deviation), yrs 39.41 (12.42) Gender
Male 100 (20.7%)
Female 384 (79.3%)
Cigarette smoking status
Never 372 (76.9%)
Former 24 (5.0%)
Current 86 (17.8%)
Ever (former/current unknown) 2 (0.4%) Recurrence
Yes 228 (47.1%)
No 256 (52.9%)
Treatment Radioiodine
Yes 21 (4.3%)
No 463 (95.7%)
Thyroid gland surgery
Yes 48 (9.9%) No 436 (90.1%) Clinical features Goiter Grade 1 32 (6.6%) Grade 2 26 (5.4%) Grade 3 54 (11.2%) Grade 4 309 (63.8%) Grade 5 63 (13.0) Nodular hyperplasia Yes 50 (10.3%) No 434 (89.7%) Ophthalmopathy Yes 203 (41.9%) No 281 (58.1%) Myxedema Yes 6 (1.2%) No 478 (98.8%) Vitiligo Yes 4 (0.8%) No 480 (99.2%)
Table 2.
Factors Associated with Graves' Ophthalmopathy in 484 Patients with Graves' Disease
Patient Characteristics
Graves' Disease with Graves' Ophthalmopathy (n = 203),
No. (%)
Graves' Disease without Graves' Ophthalmopathy (n = 281), No. (%) P Value Age at diagnosis (yrs) 0.000 Mean (standard deviation) 36.8±11.1 41.3±13.0 Range 17–72 13–84 Gender 0.039† Male 51 (25.1) 49 (17.4) Female 152 (74.9) 232 (82.6) Smoking status‡ 0.029† Smoking 57 (28.1) 55 (19.6) Nonsmoking 146 (71.9) 226 (80.4) Recurrence NS† Yes 99 (48.8) 129 (45.9) No 104 (51.2) 152 (54.1) Treatment 0.005† Radioiodine Yes 15 (7.4) 6 (2.1) No 188 (92.6) 275 (97.9) Thyroid gland surgery NS †
Patient Characteristics
Graves' Disease with Graves' Ophthalmopathy (n = 203),
No. (%)
Graves' Disease without Graves' Ophthalmopathy (n = 281), No. (%) P Value Yes 25 (12.3) 23 (8.2) No 178 (87.7) 258 (91.8) Clinical features Goiter NS§ Grade 1 14 (6.9) 18 (6.4) Grade 2 5 (2.5) 21 (7.5) Grade 3 22 (10.8) 32 (11.4) Grade 4 132 (65.0) 177 (63.0) Grade 5 30 (14.8) 33 (11.7) Nodular hyperplasia NS † Yes 23 (11.3) 27 (9.6) No 180 (88.7) 254 (90.4) Myxedema 0.039 Yes 5 (2.5) 1 (0.4) No 198 (97.5) 280 (99.6) Vitiligo NS† Yes 2 (1.0) 2 (0.7) No 201 (99.0) 279 (99.3) NS = not significant.
Age and myxedema were determined by Mann–Whitney U test.
†
All characteristics except age, goiter, and myxedema were determined by chi-square test using 2×2 contingency tables.
‡
Smoking category includes former, current, and ever categories indicated in Table 1.
§
Goiter was determined by chi-square test using 2×5 contingency tables.
Allele and Genotype Frequencies of CD103
Polymorphisms
To identify SNPs that are associated with GO, a total of 5 SNPs within CD103 were genotyped. The genotype distribution of these 5 polymorphisms was not statistically different between GO and controls individually (Table 3). However, the allele frequency distribution of SNP
rs11652878 in the exon region of CD103 was statistically different in patients with Graves' disease with GO compared with those without GO (P = 0.029). The frequency of the G allele of SNP rs11652878 was significantly lower in patients with GO than in those without GO,
indicating that the G allele of SNP rs11652878 may decrease the risk of GO by 1.57 fold (P = 0.029; OR [allele G/allele A], 1.57; 95% CI, 1.04–2.36). These results showed that the patients with the G allele of SNP rs11652878 have a lower risk of Graves' disease with GO as compared with those without GO, implying that this polymorphism may play a protective role in the development of GO.
Table 3.
Allele and Genotype Frequencies of CD103 in 484 Patients with Graves' Disease
Single Nucleotide Polymorphisms Graves' Disease with Graves' Ophthalmopathy, No. (%) Graves' Disease without Graves' Ophthalmopathy, No. (%) P Value Odds Ratio (95% Confidence Interval)†
Single Nucleotide Polymorphisms Graves' Disease with Graves' Ophthalmopathy, No. (%) Graves' Disease without Graves' Ophthalmopathy, No. (%) P Value Odds Ratio (95% Confidence Interval)† rs1716 A/A 21 (10.3) 22 (7.8) 0.069 1 A/G 77 (37.9) 136 (48.4) 1.12 (0.58–2.15) G/G 105 (51.7) 123 (43.8) 0.66 (0.45–0.97) A allele 119 (29.3) 180 (32.0) 0.366 1 G allele 287 (70.7) 382 (68.0) 0.82 (0.60–1.12) rs3744679 C/C 185 (91.1) 251 (89.3) 0.600 1 C/G 18 (8.9) 29 (10.3) 1.19×109 (0.00–) G/G 0 (0) 1 (0.4) 1.00×109 (0.00–) C allele 388 (95.6) 531 (94.5) 0.448 1 G allele 18 (4.4) 31 (5.5) 1.26 (0.68–2.32) rs11652878 A/A 159 (78.3) 198 (70.5) 0.064 1 A/G 43 (21.2) 76 (27.0) 5.62 (0.68–46.16) G/G 1 (0.5) 7 (2.5) 3.96 (0.47–33.27) A allele 361 (88.9) 472 (84.0) 0.029 1 G allele 45 (11.1) 90 (16.0) 1.57 (1.04–2.36) rs16953477 C/C 203 (100.0) 279 (99.3) 0.228 1 C/G 0 (0.0) 2 (0.7) 1.18×109 (0.00–)
Single Nucleotide Polymorphisms Graves' Disease with Graves' Ophthalmopathy, No. (%) Graves' Disease without Graves' Ophthalmopathy, No. (%) P Value Odds Ratio (95% Confidence Interval)† G/G 0 (0.0) 0 (0.0) C allele 406 (100.0) 560 (99.6) 0.229 1 G allele 0 (0.0) 2 (0.4) 8.59×108 (0.00–) rs9905739 C/C 7 (3.4) 5 (1.8) 0.244 1 C/G 196 (96.6) 276 (98.2) 1.97 (0.62–6.30) G/G 0 (0.0) 0 (0.0) C allele 210 (51.7) 286 (50.9) 0.798 1 G allele 196 (48.3) 276 (49.1) 0.99 (0.73–1.34)
CI = confidence interval; SNP = single nucleotide polymorphism.
P values less than 0.05 were considered significant.
Genotype frequencies except SNP rs9905739 were determined by chi-square test using 2×3 contingency tables. SNP rs9905739 and allele frequencies were determined by chi-square test using 2×2 contingency tables.
†
Odds ratios and 95% CIs per genotype and allele were estimated by applying unconditional logistic regression.
Frequencies of CD103 Haplotypes
Haplotype frequencies were estimated according to the 5 polymorphisms with an allele frequency of more than 5%. Fifteen haplotypes were observed. The 5 haplotypes that matched the criteria are listed in Table 4. The frequency of the most common haplotype, Ht1-GCACC, in patients
without GO was 32.7%, compared with 32.3% in patients with GO. The haplotype-specific analysis showed that the Ht5-GCGCG haplotype may reduce the risk of GO by 1.94 fold (P =
0.010; OR, 1.94; 95% CI, 1.02–3.68). These observations suggested that Ht5-GCGCG may play a protective role in the development of GO because patients with Ht5-GCGCG are less
susceptible to the development of GO.
Table 4.
Haplotype Frequencies of CD103 in 484 Patients with Graves' Disease
Haplo type† rs1 716 rs374 4679 rs1165 2878 rs1695 3477 rs990 5739 Graves Disease with Graves' Ophthalm opathy (n = 406), No. (%) Graves Disease without Graves' Ophthalm opathy (n = 562), No. (%) P Val ue‡ Odds Ratio (95% Confiden ce Interval) § Ht1 G C A C C 131 (32.3) 184 (32.7) 0.8 77 1.11 (0.62 –2.00) Ht2 G C A C G 89 (21.9) 111 (19.8) 0.4 11 1.01 (0.5 6–1.82) Ht3 A C A C C 60 (14.8) 80 (14.2) 0.8 12 1.17 (0.6 9–2.00) Ht4 A C A C G 65 (16.0) 79 (14.1) 0.3 99 1.04 (0.6 0–1.82) Ht5 G C G C G 31 (7.6) 72 (12.8) 0.0 10 1.94 (1.0 2–3.68)
CI = confidence interval; GO = Graves' ophthalmopathy; Ht = haplotype.
The percentages of Graves patients with GO with Ht1 to Ht5 were compared with the percentages of Graves patients without GO without Ht1 to Ht5. Percentages may not add to
100% because of the presence of rare haplotypes (below 5%) not presented in this table. The P values less than 0.05 were considered significant.
†
Order of SNPs comprising the CD103 haplotypes: rs1716 (G/A), rs3744679 (G/C),
rs11652878 (A/G), rs16953477 (C/G), and rs9905739 (C/G). The haplotypes were identified by the Bayesian statistical method available in the program Phase 2.1.
‡
Individual haplotype frequency toward GO development was determined by the chi-square test using 2×2 contingency tables.
§
Odds ratios and 95% CIs per genotype and allele were estimated by applying unconditional logistic regression.
CD103 Polymorphisms and Clinical Features of Graves'
Disease
The association between clinical features and genotypes of CD103 was analyzed. The results are summarized in Table 5. Patients who were homozygous for Ht5 among the 484 participants were not found. A total of 381 patients represented the non-Ht5/non-Ht5 homozygous genotype. In that, the heterozygous genotype (Ht5/non-Ht5) may decrease the risk of GO by 1.96-fold as compared with the homozygous non-Ht5/non-Ht5 (P = 0.006; OR, 1.96; 95% CI, 1.22–3.16). In addition, this heterozygous genotype may reduce the risk of high grades of goiter (P = 0.048). These results imply that the Ht5/non-Ht5 heterozygous genotype may reduce the risk of GO and high grades of goiter.
Table 5.
Clinical Significance of CD103 Genotype Ht5/Ht5, Ht5/non-Ht5, and non-Ht5/non-Ht5 in Patients with Graves' Disease
Ht5/Non-Ht5 (n = 103), No. (%) Non-Ht5/Non-Ht5 (n = 381), No. (%) P Value Odds Ratio (95% Confidence Interval) Mean age at diagnosis (SD) 40.7 (12.6) 39.1 (12.4) NS — Range 18–74 13–84 Gender (n) NS — Male 21 (20.4) 79 (20.7) Female 82 (79.6) 302 (79.3) Smoking status NS — Smoking 21 (20.4) 91 (23.9) Nonsmoking 82 (79.6) 290 (76.1) Recurrence NS — Yes 47 (45.6) 181 (47.5) No 56 (54.4) 200 (52.5) Treatment Radioiodine NS — Yes 6 (5.8) 15 (3.9) No 97 (94.2) 366 (96.1) Thyroid gland surgery NS — Yes 7 (6.8) 41 (10.8) No 96 (93.2) 340 (89.2) Clinical features Goiter 0.048†
Clinical Features Genotype (n = 484) Ht5/Non-Ht5 (n = 103), No. (%) Non-Ht5/Non-Ht5 (n = 381), No. (%) P Value Odds Ratio (95% Confidence Interval) Grade 1 11 (10.7) 21 (5.5) 1 Grade 2 4 (3.9) 22 (5.8) 4.98 (1.62–15.30) Grade 3 11 (10.7) 43 (11.3) 1.46 (0.37–5.72) Grade 4 71 (68.9) 238 (62.5) 2.35 (0.80–6.90) Grade 5 6 (5.8) 57 (15.0) 2.78 (1.15–6.75) Nodular hyperplasia NS Yes 12 (11.7) 38 (10.0) No 91 (88.3) 343 (90.0) Ophthalmopathy 0.006‡ Yes 31 (30.1) 172 (45.1) 1 No 72 (69.9) 209 (54.9) 1.96 (1.22–3.16) Myxedema NS — Yes 2 (2.0) 4 (1.0) No 101 (98.0) 377 (99.0) Vitiligo NS — Yes 1 (1.0) 3 (8.0) No 102 (99.0) 378 (99.2)
CI = confidence interval; Ht = haplotype; NS = not significant; SD = standard deviation.
The percentages of Graves' patients with Ht5/non-Ht5 were compared with the
percentages of Graves patients with non-Ht5/non-Ht5. No Ht5/Ht5 was found in the current patients.
†
The chi-square test (5×2 table) was performed to obtain the P value.
‡
The chi-square test (2×2 table) was performed to obtain the P value.
Discussion
The polymorphisms of several candidate genes such as cytotoxic T lymphocyte-associated 4
(CTLA-4), CD40, human leukocyte antigen (HLA), interleukin 23 receptor (IL23R), protein
tyrosine phosphatase, nonreceptor-type, 22 (PTPN22), thyroglobulin, and thyroid-stimulating hormone receptor (TSHR) have been reported to contribute to Graves' disease.[39], [40] and [41]
However, the link between gene polymorphisms and the development of GO remains controversial.[14], [16], [17],
[18], [19], [20], [21], [22] and [23]
The present study investigated 5 SNPs (SNP rs1716, rs3744679, rs11652878, rs16953477, and rs9905739) from the CD103 gene and the association with GO risk. The SNP rs11652878 may decrease the risk of GO by 1.57 fold. In addition, the Ht5-GCGCG haplotype may reduce the risk of GO by 1.94 fold. To confirm these results, the most strongly associated haplotype, Ht5-GCGCG, was examined further regarding its association with GO. The results did not demonstrate that any patient with Graves' disease was homozygous for Ht5. The
heterozygous genotype (Ht5/non-Ht5) decreased the risk of GO by 1.96 fold as compared with
the non-Ht5/non-Ht5 genotype. Furthermore, this heterozygous genotype also shows statistical
association toward lower grades of goiter. The study provided evidence for the role of polymorphisms in CD103 in the development of GO. This is the first demonstration that the representation of the G allele of SNP rs11652878, especially the Ht5-GCGCG haplotype and heterozygous genotype Ht5/non-Ht5 of CD103, may be associated with protection against the development of GO in patients with Graves' disease.
Initial activation of T cells in GO is thought to be mediated by several thyroid-related factors such as the thyrotropin receptor antigen. CD103, not only in T cells, may play a crucial role in this eye disease by activating E-cadherin in dermal fibroblasts. Indeed, CD103 plays diverse roles in the prevention of inflammatory diseases.[17], [18], [19], [20], [21] and [22]
CD103 may be pivotal in mediating autoimmune diseases.[23], [24], [25] and [26]
However, the polymorphisms of CD103 have been discussed rarely. This study focused on the 5 polymorphisms of CD103 aforementioned. Although a single genotype did not show clinical relevance individually, the allele polymorphisms did show a statistical association with the development of GO. The G allele at SNP rs11652878 results in a silent residue change (N619N) in the coding region of exon 15, which seems to be expressed more selectively in patients with Graves' disease with GO than in those without GO (11.1% and 16.0%, respectively). Although there was an attempt to identify whether the G allele at SNP rs11652878, the Ht5 haplotype, and Ht5/non-Ht5 genotype of CD103 protect both genders equally from GO, it was found that the presentation of the Ht5 haplotype and Ht5/non-Ht5
genotype protects only females with Graves' disease from GO (P = 0.002 and P = 0.008,
respectively). This may be because the sample size of the male patients with Graves' disease was not large enough. In addition to the polymorphism in exon 15, 2 of these polymorphisms within exon 24 (rs1716) and exon 22 (rs3744679) of CD103 represent changes in residues in the coding region (R950W and Q892H, respectively). However, the results did not show any statistical significance for these 2 polymorphisms in the development of GO. Furthermore, 2 other polymorphisms within the untranslated 3′ region of CD103, SNP rs16953477 and SNP
rs9905739, did not show statistical significance. Confirmation of these results in larger samples is warranted.
In addition to the genetic analysis, the relationship between GO and nongenetic factors, including age, gender, smoking status, recurrence, treatment, and the clinical features in 484 patients with Graves' disease, were explored. These results demonstrated that the development of GO may be
associated with age, gender, smoking status, radioiodine treatment, and myxedema. Most of the results are consistent with those of previous reports and provide additional evidence that supports the risks for GO.[42], [43] and [44]
Further studies will address whether the nongenetic factors have an effect on the development of GO.
In summary, this study provides evidence for the association of multiple genetic and nongenetic factors toward the development of GO. The results suggest that the presence of the G allele at rs11652878 in CD103, especially Ht5-GCGCG, may protect against the development of GO. This report provides evidence that SNPs of the CD103 gene provide insight into the risk of GO development in patients with Graves' disease.
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Manuscript no. 2009-891.
Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article.
Supported by the National Science Council (grant nos.: 96-2628-B-039-002-MY3 and
98-2320-B-039-008-MY3), Taipei, Taiwan; and the China Medical University Hospital (grant nos.: DMR-97-001, DMR-97-002, and DMR-97-124), Taichung, Taiwan.
*Lei Wan and Fuu-Jen Tsai contributed equally to this study.
Correspondence: Fuu-Jen Tsai, MD, PhD, Genetic Center, China Medical University Hospital, No. 2 Yuh-Der Road, 404 Taichung, Taiwan
