Investigation of the Correlation between Graves’ Ophthalmopathy and CTLA4 Gene Polymorphism
Abstract
:1. Introduction
2. Experimental Section
2.1. Study Subjects
2.2. DNA Extraction
2.3. PCR Amplification
2.4. Purifying and Sequencing
2.5. Statistical Analysis
3. Results
4. Discussion
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Primer | GC Content | Tm (°C) | Base Pair |
---|---|---|---|
promotor and exon1 | |||
F: 5′ GGC AAC AGA GAC CCC ACC GTT 3′ R: 5′ GAG GAC CTT CCT TAA ATC TGG AGA G 3′ | 21/13 (62%) 25/12 (48%) | 65.3 65.8 | 1234 |
F: 5′ CTC TCC AGA TTT AAG GAA GGT CCT C 3′ R: 5′ GGA ATA CAG AGC CAG CCA AGC C 3′ | 25/12 (48%) | 65.8 | 1170 |
22/13 (59%) | 65.8 | ||
Exon2 and exon3 | |||
F: 5′ CAT GAG TTC ACT GAG TTC CC 3′ R: 5′ TAC CAC TGT CCT TCC TCT TC 3′ | 20/10 (50%) | 58.4 °C | 1034 |
20/10 (50%) | 58.4 °C | ||
Exon4 | |||
F: 5′ CTA GGG ACC CAA TAT GTG TTG 3′ R: 5′ AGA AAC ATC CCA GCT CTG TC 3 | 21/10 (48%) | 59.5 | 360 |
20/10 (50%) | 58.4 | ||
3′UTR | |||
F1: 5′ CAG CTA GGG ACC CAA TAT GTG TTG AG 3′ R1: 5′ GTC AAG TCA ACT CAG ATA CCA CCA GC 3′ F2: 5′ GCT TGG AAA CTG GAT GAG GTC ATA GC 3′ R2: 5′ AGA GGA AGA GAC ACA GAC AGA GTT GC 3′ | 26/13 (50%) | 59.5 | 1088 |
26/13 (50%) | 59.5 | ||
26/13 (50%) | 59.5 | 1255 | |
26/13 (50%) | 59.5 |
Total, No. (%) | |
---|---|
Median age of the patients | 46.2 ± 16.5 |
Sex of the patients | |
Male | 8 (36.4) |
Female | 14 (63.6) |
Graves’ ophthalmopathy | |
Mild | 7 (31.8) |
Moderate | 14 (63.6) |
Severe | 1 (4.6) |
SNP | Position | Allele | Minor Allele Frequency | HWE p Value | Odds Ratio | χ2 p Value | |
---|---|---|---|---|---|---|---|
Patient | Control | (95% CI) | |||||
rs11571315 | 203866178 | C/T | 0.181 | 0.275 | 0.237 | 1.707 (0.607–4.799) | 0.308 |
rs733618 | 203866221 | T/C | 0.409 | 0.500 | 0.670 | 1.444 (0.609–3.425) | 0.403 |
rs4553808 | 203866282 | A/G | 0.068 | 0.175 | 0.638 | 2.899 (0.695–12.091) | 0.182 |
rs11571316 | 203866366 | A/G | 0.114 | 0.100 | 0.884 | 1.154 (0.287–4.635) | 1 |
rs62182595 | 203866465 | A/G | 0.068 | 0.175 | 0.638 | 2.899 (0.695–12.091) | 0.182 |
rs16840252 | 203866796 | C/T | 0.068 | 0.200 | 0.535 | 3.417 (0.838–13.927) | 0.074 |
rs5742909 | 203867624 | C/T | 0.068 | 0.175 | 0.638 | 2.899 (0.695–12.091) | 0.182 |
rs231775 | 203867991 | A/G | 0.182 | 0.275 | 0.237 | 1.707 (0.607–4.799) | 0.308 |
rs3087243 | 203874196 | A/G | 0.114 | 0.100 | 0.884 | 1.154 (0.287–4.635) | 1 |
SNP | Genotype | Genotype Frequency | Odds Ratio (95 % CI) | p Value | |
---|---|---|---|---|---|
Patient (n) | Control (n) | ||||
rs11571315 | CC | 0 | 0 | NA | NA |
CT | 8 | 11 | 0.468 (0.136–1.611) | p = 0.226 | |
TT | 14 | 9 | 2.139 (0.621–7.370) | p = 0.226 | |
rs733618 | CC | 4 | 4 | 0.889 (0.190–4.150) | p = 1 |
CT | 18 | 12 | 3.000 (0.736–12.227) | p = 0.118 | |
TT | 0 | 4 | 0.421 (0.290–0.611) | p = 0.043 ** | |
rs4553808 | AA | 19 | 13 | 3.410 (0.742–15.677) | p = 0.152 |
AG | 3 | 7 | 0.293 (0.064–1.348) | p = 0.152 | |
GG | 0 | 0 | NA | NA | |
rs11571316 | AA | 0 | 0 | NA | NA |
AG | 5 | 4 | 1.176 (0.267–5.176) | p = 1 | |
GG | 17 | 16 | 0.850 (0.193–3.739) | p =1 | |
rs62182595 | AA | 0 | 0 | NA | NA |
AG | 3 | 7 | 0.293 (0.064–1.348) | p = 0.152 | |
GG | 19 | 13 | 3.410 (0.742–15.677) | p = 0.152 | |
rs16840252 | CC | 19 | 12 | 1.22 (0.932–19.131) | p = 0.052 * |
CT | 3 | 8 | 0.237 (0.052–1.073) | p = 0.052 * | |
TT | 0 | 0 | NA | NA | |
rs5742909 | CC | 19 | 13 | 3.410 (0.742–15.677) | p = 0.152 |
CT | 3 | 7 | 0.293 (0.064–1.348) | p = 0.152 | |
TT | 0 | 0 | NA | NA | |
rs231775 | AA | 0 | 0 | NA | NA |
AG | 8 | 11 | 0.468 (0.136–1.611) | p = 0.226 | |
GG | 14 | 9 | 2.139 (0.621–7.370) | p = 0.226 | |
rs3087243 | AA | 0 | 0 | NA | NA |
AG | 5 | 4 | 1.250 (0.283–5.525) | p = 1 | |
GG | 17 | 16 | 0.800 (0.181–3.536) | p = 1 |
CTLA4 Haplotypes | Patient(n) | Control (n) | OR (95%CI) | p Value |
---|---|---|---|---|
Crs733618Crs16840252 | 22 | 16 | 2.375 (1.636–3.448) | 0.043 ** |
Crs733618Trs16840252 | 3 | 5 | 0.474 (0.097–2.307) | 0.445 |
Trs733618Crs16840252 | 18 | 16 | 1.125 (0.241–5.252) | 1 |
Trs733618Trs16840252 | 3 | 7 | 0.293 (0.064–1.348) | 0.152 |
SNP | Disease | Subjects and Results | Ref. |
---|---|---|---|
rs733618 | Systemic lupus | Asian: | [23] |
erythematosus | C allele was strongly associated with SLE and also CC genotype was significantly associated with the risk of SLE, p = 0.000). | ||
Breast cancer | Chinese: | [27] | |
CC genotype and C allele showed an increased risk of breast cancer (p = 0.030, odds ratio (OR) = 1.457, 95% confidence internal (CI) 1.036–2.051; p = 0.024, OR = 1.214, 95% CI 1.026–1.436, respectively). | |||
Polycystic ovary syndrome | Chinese Han population: | [28] | |
significantly different between case and control groups in either genotypic or allelic distribution, p = 0.01 and 0.009, respectively. | |||
Survival in patients with sepsis | Adult Caucasian patients with sepsis: | [29] | |
lower 90-day mortality was observed for Trs733618 Ars231775 Ars3087243 haplotype-negative patients than for patients carrying the TAA haplotype, p = 0.0265. | |||
Survival in patients with multiple myeloma receiving bortezomib-based regimens | Unrelated Chinese Han population: GG genotype reduced the progression-free survival and the overall survival of patients with multiple myeloma who received bortezomib-based therapy, p = 0.002. | [30] | |
Non-small-cell lung cancer | Chinese: | [31] | |
(NSCLC) | T > C polymorphism was associated with the development of NSCLC in ≥60 years and even drinking subgroups. | ||
Myasthenia gravis (MG) | Chinese Han population: | [32] | |
C allele were more frequent in MG patients, p = 0.042. | |||
Urinary schistosomiasis | Gabonese children: | [33] | |
T allele and TT genotype were significantly overrepresented in the patient group, p = 0.001. | |||
Lymphatic filariasis (LF) | Sarawak, Malaysia: | [34] | |
CT genotype (p = 0.02) and those with combined minor allele C carriers (CT + CC; p = 0.01) exhibited a significantly decreased risk for LF. | |||
rs16840252 | Colorectal cancer | Chinese: | [35] |
polymorphism was associated with an increased risk of colon cancer in homozygote model p = 0.040 and recessive model p = 0.037. | |||
Recurrent schizophrenia | Chinese Han population: | [36] | |
A significant association with schizophrenia, p (allele) = 0.0081, p (genotype) = 0.0117. |
SNP | Subjects | Results | Ref. |
---|---|---|---|
rs733617 | Han population of Taiwan (family-based) | C allele over-transmitted to affected individuals (χ2 = 6.714, nominal p = 0.0096). | [17] |
rs5742909 | Polish Caucasian | genotype and allele were differentially distributed (p = 0.0002; p = 4.07 × 10−5), and lack of the rare T allele increased GD in patients with familial autoimmune thyroid incidence (p = 0.00005). | [37] |
Chinese | genotype frequencies of CT and allele frequencies of T were much higher in GD patients with ophthalmopathy than that in the group without ophthalmopathy (p = 0.020, p = 0.019). | [39] | |
Chinese | variant allele carriers might have decreased risks of GD when compared with the homozygote carriers TT + TC vs. CC: OR = 0.78, 95% CI = 0.62–0.97. | [44] | |
rs231775 | Han population of Taiwan (family-based) | CTLA4_+49_G/A (p = 0.0219), with its minor allele (G allele) over-transmitted to affected individuals (χ2 = 5.252, nominal p = 0.0219). | [17] |
Taiwanese | significant differences in the frequencies of the genotypes and alleles, p < 0.05. | [18] | |
Polish populations | a significantly lower frequency of the AA genotype in the group of patients with clinically evident GO (p = 0.02, OR = 2.6). | [38] | |
Chinese | genotype GG and allele frequencies of G in patients with Graves’ disease were significantly increased as compared with control group (p = 0.008, p = 0.007). | [39] | |
Han population of Chinese (unrelated) | allele G was significantly associated with GD in adults (p < 0.001) and children (p = 0.002)). | [40] | |
Chinese children < 16 years old (unrelated) | genotype GG (p = 0.005) and allele G (p = 0.03) were more prevalent in GD. | [41] | |
Chinese children | genotype and allele frequencies of children with GD differed significantly from those of the controls (p = 0.0023 and p = 0.022, respectively). | [42] | |
Saudi Arabian | G allele was more frequent in patients with GD than in the control group, p = 0.003. | [45] | |
Iranian | G allele was significantly higher in patients with Graves’ disease than in the control group (27.1% vs. 15.1%, OR = 2.096, 95%CI = 1.350–3.253 and p < 0.01). | [47] | |
Iranian | a significant increase of GG genotype and G allele was observed in patients (p = 0.012 and p = 0.025, respectively). | [48] | |
Italian | G allele frequency was significantly higher compared to control subjects (p = 0.04). | [49] | |
Caucasian and Asian | G allele vs. A allele, p < 0.00001; genotype: GG vs. AG + AA, P < 0.00001; GG + AG vs. AA, p < 0.00001; GG vs. AA, p < 0.00001; AG vs. AA, p < 0.00001. | [50] | |
rs3087243 | Taiwanese children | genotype GG was significantly associated with GD (OR = 1.71, 95% CI 1.20–2.44, p = 0.006); Allele G was significantly more frequent (OR = 1.61, 95% CI 1.18–2.19, p = 0.0049). | [19] |
Taiwanese | G allele is associated with susceptibility to Graves’ disease (p = 0.011). | [18] | |
Han population of Chinese (unrelated) | allele G was significantly associated with GD in adults (p < 0.001) and children (p < 0.001). | [40] | |
Chinese children < 16 years old (unrelated) | G allele was more prevalent in GD p = 0.02. | [41] | |
Southern China | G allele was significantly associated with an increased risk of GD development, p < 0.001. | [43] | |
Chinese | G > A allele frequencies between the patient and control groups, p = 0.014. | [44] | |
Russian | A allele and the AA genotypes were significantly increased in patients with GD. | [45] | |
Saudi Arabian | G allele was higher in GD patients than those in controls, p = 0.004. | [46] | |
Italian | allelic frequency of the G allele was also significantly higher in patients with GD (p = 0.02). | [49] | |
Japanese | for the TBII-positive GD, G allele carriers in patients had significant association with GD, OR = 2.97, 95%CI = 1.29–6.87, p = 0.008. | [51] | |
Russian | significantly higher frequencies of A allele and AA genotype and a lower proportion of G allele and GG genotype. | [52] |
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Chen, D.-P.; Chu, Y.-C.; Wen, Y.-H.; Lin, W.-T.; Hour, A.-L.; Wang, W.-T. Investigation of the Correlation between Graves’ Ophthalmopathy and CTLA4 Gene Polymorphism. J. Clin. Med. 2019, 8, 1842. https://doi.org/10.3390/jcm8111842
Chen D-P, Chu Y-C, Wen Y-H, Lin W-T, Hour A-L, Wang W-T. Investigation of the Correlation between Graves’ Ophthalmopathy and CTLA4 Gene Polymorphism. Journal of Clinical Medicine. 2019; 8(11):1842. https://doi.org/10.3390/jcm8111842
Chicago/Turabian StyleChen, Ding-Ping, Yen-Chang Chu, Ying-Hao Wen, Wei-Tzu Lin, Ai-Ling Hour, and Wei-Ting Wang. 2019. "Investigation of the Correlation between Graves’ Ophthalmopathy and CTLA4 Gene Polymorphism" Journal of Clinical Medicine 8, no. 11: 1842. https://doi.org/10.3390/jcm8111842