CTLA-4 and not CD28 is a susceptibility gene for thyroid autoantibody production

One of the hallmarks of the human autoimmune thyroid diseases (AITDs) is the production of high titers of autoantibodies against thyroglobulin and thyroid peroxidase that often precedes the development of clinical disease. A high percentage of family members of patients with AITDs have significant titers of thyroid antibodies (TAbs), suggesting a genetic predisposition for their development, and segregation analyses have favored a dominant mode of inheritance. The aim of the present study was to identify the susceptibility genes for TAb production. We completed a genome-wide scan in 56 multiplex families (323 individuals) in which all family members with AITDs and/or detectable TAbs were considered affected. The highest 2-point logarithm of odds (LOD) score of 3.6 was obtained for marker D2S325 on chromosome 2q33 at 210.9 centimorgans. This locus showed no evidence for linkage to Graves' disease or Hashimoto's thyroiditis (2-point LOD scores, 0.42 for Graves' disease and -0.60 for Hashimoto's thyroiditis), demonstrating that the gene in this region conferred susceptibility to TAbs, but that clinical disease development required additional genetic and/or environmental factors. We then fine-mapped the region linked with TAbs using 11 densely spaced microsatellite markers. Multipoint linkage analysis using these markers showed a maximum LOD score of 4.2 obtained for marker D2S155 at 209.8 centimorgans (with heterogeneity, alpha = 0.41). As the linked region contained the CTLA-4 and CD28 genes, we then tested whether they were the susceptibility genes for TAbs on chromosome 2q33. The CD28 gene was sequenced in 15 individuals, and a new C/T single nucleotide polymorphism (SNP) was identified in intron 3. Analysis of this SNP revealed no association with TAbs in the probands of the linked families (families that were linked with D2S155) compared with controls. The CTLA-4 gene was analyzed using the known A/G(49) SNP, and the results showed a significantly increased frequency of the G allele in the probands of the linked families compared with the probands of the unlinked families or with controls (P = 0.02). We concluded that 1) a major gene for thyroid autoantibody production was located on chromosome 2q33; 2) the TAb gene on chromosome 2q33 was most likely the CTLA-4 gene and not the CD28 gene; and 3) CTLA-4 contributed to the genetic susceptibility to TAb production, but there was no evidence that it contributed specifically to Graves' or Hashimoto's diseases.     

The development of Graves' disease and the CTLA-4 gene on chromosome 2q33.

Case-control studies suggest that the CTLA-4 gene may be a susceptibility locus for Graves' disease. The previously reported A/G polymorphism at position 49 in exon 1 of the CTLA-4 gene was, therefore, investigated in a case-control (n = 743) and family-based (n = 179) dataset of white Caucasian subjects with Graves' disease. The relationship between CTLA-4 genotype and severity of thyroid dysfunction at diagnosis was also investigated. An increase in frequency of the G (alanine) allele was seen in Graves' patients compared with control subjects (42% vs. 31.5%, respectively; corrected P<0.0002; odds ratio = 1.58), and a significant difference in the distribution of GG, GA, and AA genotypes was observed between the groups (chi2 = 21.7; corrected P<0.00003). Increased transmission of the G allele was seen from heterozygous parents to affected offspring compared to unaffected offspring (chi2 = 5.7; P = 0.025). Circulating free T4 concentrations at diagnosis were significantly associated with CTLA-4 genotype (F = 3.26; P = 0.04). These results support the hypothesis that CTLA-4 may play a role in regulating self-tolerance by the immune system and in the pathogenesis of autoimmune disorders such as Graves' disease.     

Polymorphism in the promoter and exon 1 of the cytotoxic T lymphocyte antigen-4 gene associated with autoimmune thyroid disease in Koreans.

The objective of this study was to examine the polymorphism in the cytotoxic T lymphocyte antigen-4 (CTLA-4) gene and its relationship with autoimmune thyroid disease in Koreans. Polymorphism in the promoter and exon 1 of CTLA-4, clinical symptoms of disease and thyrotropin receptor antibody (TSHRAb) characteristics were analyzed. Polymorphism was detected using restriction fragment length polymorphism and polymerase chain reaction amplification of genomic DNA. All subjects were Korean (97 Graves' disease, 110 Hashimoto's thyroiditis, and 199 normal controls). Graves' patients had significantly more G allele in exon 1 and C allele in the promoter than controls. When the exon 1 genotype was GG, the frequency of CC genotype in the promoter was higher. Allele frequencies in CTLA-4 did not differ from controls in patients with Hashimoto's thyroiditis. In Graves' patients, there were significant differences between genotypic groups in serum triiodothyronine (T3) levels and the presence of ophthalmopathy. However, TSHRAbs and other clinical characteristics were not significantly different. In conclusion, the CTLA-4 G allele in exon 1 and C allele in the promoter may confer genetic susceptibility to Graves' disease in Koreans. These two polymorphisms are additional and dependent genetic risk markers that help to characterize risk alleles within CTLA-4 gene.     

Remission of Graves' hyperthyroidism and A/G polymorphism at position 49 in exon 1 of cytotoxic T lymphocyte-associated molecule-4 gene

We studied whether a patient with Graves' disease will go into remission during antithyroid drug (ATD) treatment. Remission of Graves' hyperthyroidism is predicted by a smooth decrease in TSH receptor antibody (TRAb) during ATD treatment. Cytotoxic T cell lymphocyte-associated molecule-4 (CTLA-4) may play an important role in the development of Graves' hyperthyroidism and in its remission. We studied A/G polymorphism at position 49 in exon 1 of the CTLA-4 gene in 144 Japanese Graves' patients. We intended to reveal the possible association of CTLA-4 gene polymorphism with the remission of Graves' hyperthyroidism. All patients with Graves' disease were treated with ATD. Thyroid-stimulating antibody and TSH binding inhibitory Ig were measured as TRAb. We analyzed CTLA-4 genotypes and alleles with PCR. We calculated the frequencies of CTLA-4 genotypes and alleles. A significant increase in the frequency of the G allele was seen in Graves' patients compared with controls (P = 0.0095). Graves' patients were divided into three groups (A, B, and C) according to time of TRAb disappearance after the start of ATD treatment. In group A patients TRAb had disappeared within 1 yr after the start of ATD treatment, in group B TRAb had disappeared between the beginning of the second year and the end of the fifth year of treatment, and in group C TRAb continued to be positive after 5 yr of ATD treatment. The frequencies of the GG genotype and the G allele were significantly higher in group C patients with persistently positive TRAb over 5 yr of ATD treatment than in the other groups (P < 0.0001). Group C patients did not have the AA genotype. The periods of time until remission were significantly shorter in the AA genotype. Graves' patients with the G allele need to continue ATD treatment for longer periods.     

血清甲状腺自身抗体、碘摄入量与Graves病发病及临床转归的关系

目的探讨血清甲状腺刺激性抗体（TSAb）、甲状腺刺激阻断性抗体（TSBAb）等甲状腺自身抗体、碘摄入量与Graves病（GD）甲状腺功能亢进症（甲亢）发病和转归的关系。方法测定3个不同碘摄入量地区63例临床甲亢患者的血清TSAb、TSBAb、促甲状腺激素结合抑制免疫球蛋白（TBⅡ）、甲状腺过氧化物酶抗体（TPOAb）和甲状腺球蛋白抗体（TGAb）,2年后随访。TSAb和TSBAb采用转染了重组人促甲状腺素受体的中国仓鼠卵巢细胞（rhTSHR—CHO细胞）生物法测定。结果初访GD甲亢患者TSAb、TBⅡ和TSBAb的阳性率分别为80．9％、61．7％和6．4％,TSAb和TBⅡ任-抗体阳性率为91．5％,显著高于对照组。TSAb和TBⅡ的一致率为59．6％。GD甲亢患者TSAb与TBⅡ（r=0．407）、甲状腺球蛋白（r=0、301）、甲状腺体积（r=0．317）正相关。初访碘过量地区GD甲亢患者TSAb阳性率（91．7％）显著高于轻度碘缺乏地区（66．7％）,3个地区GD患者TBⅡ、TPOAb、TGAb阳性率、活性和甲状腺体积无统计学差异。随访时患者分为甲状腺功能恢复组（G1）和未恢复组（G2）。G1组TSAb活性和甲状腺体积显著下降。当TPOAb滴度显著增高,且随访时继续保持高滴度时,甲状腺功能不易恢复。此时TSAb对甲状腺功能的影响降为次要因素。结论TSAb对GD甲亢的诊断和判断临床转归的意义大于TBⅡ,联合应用二者能提高GD甲亢患者促甲状腺激素受体抗体的检出率;GD甲亢的转归与TSAb、TPOAb浓度和甲状腺体积有关。     

CTLA-4 gene polymorphism in Japanese patients with rheumatoid arthritis

OBJECTIVE: To examine whether CTLA-4 gene confers susceptibility to rheumatoid arthritis (RA) in Japanese. METHODS: We investigated the distribution of a CTLA-4 gene polymorphism in 85 Japanese patients with RA and 200 controls. An A/G transition at position 49 of exon 1 was analyzed by the polymerase chain reaction (PCR)-restriction fragment length polymorphism method. The patients were also analyzed with respect to HLA-DR status. HLA-DR typing was performed by PCR sequence-specific oligonucleotide typing. RESULTS: The distribution of genotype frequencies differed between RA and controls (chi-squared 8.63, 2 df, p = 0.013). The CTLA-4 AG genotype occurred more frequently in patients with RA (59 vs 44%), and the presence of at least one G allele (GG or AG) conferred an odds ratio of 2.53 (95% CI 1.74-3.32). When the patients were analyzed with respect to HLA-DR status, this association was restricted to patients carrying the susceptible HLA allele (HLA-DRB1*0405). CONCLUSION: The CTLA-4 gene is associated with Japanese patients with RA carrying the susceptible HLA allele.     

Cytotoxic T lymphocyte antigen-4 (CTLA-4) gene polymorphisms and susceptibility to type 1 autoimmune hepatitis

Genetic susceptibility to type 1 autoimmune hepatitis is indicated by a preponderance of female subjects and strong associations with human leukocyte antigens (HLA) DRB1*0301 and DRB1*0401. The gene encoding cytotoxic T-lymphocyte antigen-4 (CTLA-4) on chromosome 2q33 may also influence autoimmunity. To determine the frequency and significance of the exon 1 adenine (A)-guanine (G) base-exchange polymorphism for CTLA-4 in patients with type 1 autoimmune hepatitis, 155 northern European Caucasoid patients and 102 ethnically-matched control subjects were tested by polymerase chain reaction. The genotype distribution was significantly different in patients compared to controls (AA = 50/155 patients vs. 51/102 controls; AG = 84/155 patients vs. 38/102 controls; GG = 21/155 patients vs. 13/102 controls, chi(2) = 8.94, P =.011). This difference was caused by a significant over-representation of the G allele in patients compared to controls (105/155 patients vs. 51/102 controls, chi(2) = 8.34, P =.004, odds ratio = 2.12). The GG genotype was associated with a significantly higher mean serum aspartate transaminase level (P =. 03), greater frequency of antibodies to thyroid microsomal antigens (P =.004) and was found more commonly in patients with HLA DRB1*0301 (P =.02). Treatment outcomes, however, were not affected by the genotype. The CTLA-4 G allele is more common in patients with type 1 autoimmune hepatitis and may represent a second susceptibility allele. Furthermore, there may be synergy between the HLA-DRB1*0301 and the GG genotype in terms of disease risk.     

Association between the Polymorphism A/G at Position 49 of Exon 1 of the CTLA-4 Gene and Antithyroid Antibody Production in Children with Hashimoto's Thyroiditis

CTLA-4 gene is considered to be one of the strongest factors determining the predisposition to antithyroid antibody (Ab) production. The aim of the study was to evaluate the association of the polymorphism A/G of exon 1 of CTLA-4 gene and antithyroid Ab level in children with Hashimoto's thyroiditis (HT). Material and Methods: 45 children with HT (aged 14.9 ± 2, range 8.1-7.9) and 55 healthy controls (aged 14.8 ± 2.34, range 8.0-17.4) were enrolled. Controls were euthyroid and free from any autoimmune disease. CTLA-4 gene (+49)A/G polymorphism was evaluated by a single-strand conformation polymorphism method and restriction fragment-length polymorphism. Results: The frequency of GG genotype in HT children was significantly higher than in controls: 31 vs. 14.5% respectively (p < 0.04, OR = 2.65, CI = 0.99-7.06). Anti-Tg Ab titers were higher in patients homozygous for G allele than with AA genotype. The GG genotype seemed to be protective from hypothyroidism at the moment of HT diagnosis, but this observation was not statistically confirmed. Conclusions: Our study provides the evidence supporting the association between CTLA-4 gene (+49)A/G polymorphism and the susceptibility to HT in Polish children and confirms the existence of a link between (+49)A/G polymorphism and anti-Tg Ab level.     

CT60 single nucleotide polymorphisms of the cytotoxic T-lymphocyte-associated antigen-4 gene region is associated with Graves' disease in an Italian population.

Graves' disease (GD) is an autoimmune and polygenic disorder. Several studies have shown that human leukocyte antigen (HLA) class II and the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) gene are involved in the genetic susceptibility. We performed a case control study on 150 patients with GD and 301 controls, matched for age and gender, to verify the association of three polymorphisms located in CTLA-4 region (A49G, [AT](n)-3'UTR, and CT60) and of HLA-DRB1 and DQB1 loci with the disease in an Italian population. The prevalence of patients with GD carrying the G allele of CT60 was significantly higher compared to control subjects (p = 0.02, odds ratio [OR] = 1.82). The allelic frequency of the G allele of CT60 was also significantly higher in patients with GD (p = 0.02). The G allele frequency of A49G in patients was significantly higher compared to control subjects (p = 0.04). The 280 allele phenotype frequency of (AT)(n)-3'UTR was also significantly higher in patients (p = 0.04). The G allele of A49G, the G allele of CT60, and the 280 allele of (AT)(n)-3'UTR microsatellite were significantly increased in patients with GD with thyroid-associated ophthalmopathy (TAO) compared to controls (p = 0.04, p = 0.03, and p = 0.02, respectively), however, we did not find any significant difference between TAO and non-TAO patients. We also found the HLA-DRB1*03 allele to be associated with GD; interestingly, the association of the CTLA-4 markers was independent from the HLA DRB1*03 status. These results highlight the role of the CTLA-4 locus, in addition to HLA, in the susceptibility to GD. Inside the CTLA-4 region, CT60 appears to be the most associated polymorphism to GD, however, further studies are needed to identify the etiologic variant.     

A CTLA-4 gene polymorphism is associated with both Graves' disease and autoimmune hypothyroidism

OBJECTIVEThe autoimmune thyroid diseases, Graves' disease and autoimmune hypothyroidism, result from a complex interaction between genetic, environmental and endogenous factors. The genetic loci conferring susceptibility remain unclear. A recent report has demonstrated an association between a microsatellite polymorphism of the CTLA-4 gene (allele 106) on chromosome 2q33 and Graves' disease in Caucasian patients in the USA. The aim of the present study was to confirm this association in UK patients and to determine whether this polymorphism is also associated with autoimmune hypothyroidism.
DESIGNAnalysis of Caucasian patients with autoimmune thyroid disease from a single clinic, compared to local Caucasian controls.
PATIENTSWe studied 112 patients with Graves' disease, 44 with autoimmune hypothyroidism and 91 controls.
MEASUREMENTSCTLA-4 microsatellite gene polymorphisms were determined by polymerase chain reaction amplification of genomic DNA and resolution of the products on sequencing gels.
RESULTSAs in previous studies, 21 alleles of the CTLA-4 microsatellite region were detected. Allele 106 was significantly increased in patients with Graves' disease ( P =0.006) and in those with autoimmune hypothyroidism ( P =0.02) when compared to controls. There was no significant difference between the groups in the distribution of the other alleles and no association between allele 106 and sex, HLA-DR or -DQ specificities or the presence of ophthalmopathy in the Graves' patients.
CONCLUSIONSThese results confirm that the CTLA-4 gene, or one closely associated with it, confers susceptibility to Grave's disease but is not specific as the CTLA-4 106 allele is also associated with autoimmune hypothyroidism. This association seems to be with autoimmune thyroid disease in general.     

The combination of absent thyroid peroxidase antibodies and high thyroid-stimulating immunoglobulin levels in Graves' disease identifies a group at markedly increased risk of ophthalmopathy.

Among Graves' Disease (GD) patients, we have observed an unexpectedly high prevalence of antithyroperoxidase antibody (TPOAb) and antithyroglobulin antibody (TgAb) negativity in those with severe ophthalmopathy. To study the possible role of thyroid autoantibodies in the pathogenesis of Graves' ophthalmopathy (GO), TPOAb, TgAb, thyroid-stimulating immunoglobulin (TSI), and thyrotropin-binding inhibitory immunoglobulin (TBII) levels were measured, and the presence or absence of GO was assessed by a single observer in 100 consecutive patients with newly diagnosed, untreated GD who were nonsmokers. Ophthalmopathy was present in 43 patients. TSI levels (p = 0.001), and the prevalence of TPOAb-negativity (p = 0.002) were significantly higher in patients with ophthalmopathy compared to those without. Logistic regression analysis showed that TSI levels (p = 0.005) and the absence of TPOAb (p = 0.0025) were independent predictors of GO. No correlation between TBII or TgAb and eye disease was found. The prevalence of GO increased with each quartile of TSI levels. The prevalence was 20%, 36%, 52%, and 64% in the first, second, third and fourth quartiles of TSI, respectively. The odds ratio of GO (with 95% confidence intervals) when TSI levels were above the median level (1640%) was 3.6 (1.5-8.0), when TPOAb was negative it was 5.0 (1.7-14.4), and with both risk factors it was 36.6 (4.3-313.5). The prevalence of ophthalmopathy in this last group was 92.9%. The combination of negative TPOAb and high TSI levels appears to be associated with a markedly increased risk of clinically evident ophthalmopathy.     

A C/T polymorphism in the 5'-untranslated region of the CD40 gene is associated with Graves' disease in Koreans.

The genetic loci conferring susceptibility to Graves' disease remain unclear. The aim of the present study was to examine a C/T polymorphism in the 5'-untranslated region of the CD40 gene and its relationship with autoimmune thyroid diseases in Koreans. The C/T polymorphism in the 5'-untranslated region of CD40 gene, clinical characteristics, and thyroid antibodies were analyzed in a series of Korean patients (132 with Graves' disease, 118 with Hashimoto's thyroiditis, and 164 normal controls). The CC genotype was significantly associated with Graves' disease (odds ratio, 1.93; 95% confidence interval, 1.21-3.09; corrected p = 0.019). On the other hand, the frequency of the TT genotype was significantly lower in Graves' patients than in controls (8% vs. 18%; odds ratio, 0.38; 95% confidence interval, 0.18-0.82; corrected p = 0.044). Allele frequencies in CD40 did not differ from controls in patients with Hashimoto's thyroiditis. In patients with Graves' disease, there were significant differences between genotypic groups in the activity of stimulating thyrotropin (TSH) receptor antibody. However, clinical characteristics and other thyroid antibodies were not significantly different. In conclusion, the C allele in the 5'-untranslated region of the CD40 gene may confer genetic susceptibility to Graves' disease in Koreans.     

Why measure thyroglobulin autoantibodies rather than thyroid peroxidase autoantibodies?

Autoantibodies to thyroglobulin (TgAb) and thyroid peroxidase (TPOAb) are of immunoglobulin G (IgG) class and have high affinities for their respective autoantigens. Both autoantibodies are markers of thyroid autoimmunity and they can be measured by a variety of assays. From the clinical perspective, TgAb are less prevalent than TPOAb and less useful than TPOAb for prediction of thyroid dysfunction. Moreover, TgAb interfere with Tg measurements to monitor metastases in thyroid cancer. However, increasing evidence suggests that these TgAb provide a surrogate for Tg. In terms of disease pathogenesis, Tg has been suggested to play a role in Graves' ophthalmopathy. Pending further studies, TgAb epitopes could distinguish between individuals who are euthyroid or who have clinical disease. A final, intriguing reason for measuring and characterizing TgAb is the interest these autoantibodies have rekindled in their autoantigen. It is conceivable that Tg polymorphisms, combined with the explosive mix of iodine, TPO and H2O2 necessary for thyroid hormone synthesis, inadvertently provide the trigger for the autoimmune thyroid response.     

Appearance of anti TSH-receptor antibodies and clinical Graves' disease after radioiodine therapy for hyperfunctioning thyroid adenoma

Radioiodine treatment use is frequent in patients with benign hyperfunctioning thyroid diseases and the side-effects are rare. In this paper we described the appearance of TSH-receptor antibodies and the concomitant development of persistent hyperthyroidism in a patient with hyperfunctioning thyroid adenoma after 131I treatment. A 70-year-old man presented a hyperfunctioning thyroid adenoma with suppressed uptake in the adjacent normal gland. Antibodies against the thyroglobulin (TgAb), thyroid peroxidase (TPOAb) and TSH-receptor (TRAb) were absent. One year after remission by radioiodine therapy the patient developed severe and persistent hyperthyroidism associated with diffuse 131I uptake in the gland. TgAb and TPOAb remained absent, but TRAb were present. Although spontaneous development of Graves' disease cannot be excluded, the time sequence and the negative familial and personal history for autoimmune diseases suggest a possible connection between the two phenomena. The release of TSH-receptor antigen from follicular cells damaged by 131I may have triggered the autoimmune response turning a toxic nodular goiter patient into a Graves' disease patient.     

Differential evolution of thyroid peroxidase and thyrotropin receptor antibodies in graves' disease: thyroid peroxidase antibody activity reverts to pretreatment level after carbimazole withdrawal.

In this study, we compared the evolution of thyroid peroxidase antibody (TPOAb) and thyroid-stimulating antibody (TSAb) activities before, during, and after treatment of Graves' disease (GD) with carbimazole. TPOAb and TSAb were measured in sera from 75 patients with GD, during an 18-month block-replace regimen and after drug withdrawal (12, 24, and 36 months). At diagnosis, TPOAb were present in 85% of the patients versus 99% for TSAb. During the treatment, TPOAb values and prevalence significantly decreased, as observed with TSAb. After drug withdrawal, TPOAb levels increased once again to reach the pretreatment values, whereas TSAb remained unchanged. TPOAb values and prevalence at drug withdrawal were not significantly different between patients who remained euthyroid and those who had a relapse of hyperthyroidism. In contrast, TSAb values and prevalence were higher at drug withdrawal in relapse patients. In conclusion, TPOAb and TSAb changes are similar during GD treatment by carbimazole but diverge after drug withdrawal. TPOAb might reflect autoimmune perturbations independently of the clinical status and of the thyroid-stimulating activity.     

'Linkage analysis of thyroid antibody production: evidence for shared susceptibility to clinical autoimmune thyroid disease

Context: Epidemiological data suggest a genetic susceptibility to thyroid antibody (TAb) production. Objective: The objective of the study was to identify genetic loci that are linked with TAb production. Design: The design of the study was a whole genome linkage study in families with clustering of thyroid autoimmunity. Settings: The study took place at an academic medical center. Participants: Participants included 102 multigenerational families (540 individuals) multiplex for autoimmune thyroid disease (AITD) and TAb production. Main Outcome Measures: We computed two-point logarithm of odds (LOD) scores and multipoint heterogeneity LOD scores for 400 microsatellite markers spanning the entire human genome at an average distance of 10 cm ( approximately 10 Mb). Results: Three loci showed evidence for linkage with TAb production: 1) 2q locus, which gave a maximum multipoint heterogeneity LOD score (HLOD) of 2.8 and contained the CTLA-4 gene, previously reported to be linked and associated with clinical AITD; (2) 6p locus (HLOD 2.5), which was the same AITD-1 locus found to be linked with clinical AITD; and (3) 8q locus (HLOD 2.2), which contained the thyroglobulin gene, also previously reported to be linked and associated with AITD. All loci that were linked to TAb were also linked to AITD, suggesting that TAb and AITD share the same genetic predisposition. Conclusions: We conclude that: 1) some of the genes/loci predisposing to TAb and AITD are shared, whereas distinct genes/loci also exist; (2) the presence of TAb in relatives of AITD patients may be associated with increased risk for the development of clinical AITD; and (3) further studies are needed to determine the predictive value of TAb levels for the development of clinical AITD in relatives of patients with familial AITD.     

酒精性肝硬化患者血CTLA-4和PNPLA3基因多态性及其临床意义分析*

目的 探讨细胞毒性T淋巴细胞相关抗原4(CTLA-4)和Patatin样磷脂酶3(PNPLA3)基因多态性与酒精性肝硬化发病的关系。方法 2017年1月～2019年1月我院治疗的酒精性肝硬化患者110例和同期健康人100例,采用聚合酶链反应-限制性片段长度多态性检测血CTLA-4基因rs4675369位点和PNPLA3基因rs738409位点多态性。结果 肝硬化患者CTLA-4基因rs4675369位点为AA型、AG型和GG型比率分别为26.4%、49.1%和24.6%,与健康人的26.0%、50.0%和24.0%比,无显著性差异(P>0.05),等位基因A和G比率分别为50.9%和49.1%,与健康人的51.0%和49.0%比,也无显著性差异(P>0.05);肝硬化患者PNPLA3基因rs738409位点GG基因型和等位基因G比率分别为17.2%和38.2%,显著高于健康人的4.0%和24.0%(P<0.05);血CTLA-4基因rs4675369位点AA型、AG型和GG型和PNPLA3基因rs738409位点CC型、CG型和GG型肝硬化患者血清丙氨酸氨基转移酶、天门冬氨酸氨基转移酶、谷氨酰转肽酶和碱性磷酸酶水平之间比,差异均无统计学意义(P>0.05)。结论 本研究结果未提示CTLA-4基因多态性与酒精性肝硬化发病存在相关关系,而PNPLA3基因多态性与酒精性肝硬化发病的关系也需要进一步研究明确。     

Graves' hyperthyroidism showing transient hypothyroidism during interferon therapy for chronic hepatitis type C

We report a patient with Graves' disease in whom thyroid function was changed from initial hyperthyroidism to transient hypothyroidism and back to hyperthyroidism during interferon (IFN) therapy. A 43-year-old man was admitted to our hospital to receive IFN treatment for chronic active hepatitis (type C) in June 1998. His thyroid function was normal and testing for thyroid gland antibodies (TSH binding inhibitor immunoglobulins; TBII, anti-thyroglobulin antibodies; TgAb and anti-thyroid peroxidase antibodies; TPOAb) was negative before IFN therapy. The patient had neither history of thyroid disease nor any particular family history. He developed hyperthyroidism four months after its initiation of IFN therapy. When he was hyperthyroid, TBII, the activity of thyroid-stimulating antibodies (TSAb) and thyroid stimulation-blocking antibodies (TSBAb) were 40.2% (normal range, -15 approximately +15.0%), 1201% (normal range, 相似文献   

Differences between changes in serum thyrotropin-binding inhibitory antibodies and thyroid-stimulating antibodies in the course of antithyroid drug therapy for Graves' disease.

There has recently been controversy regarding whether the measurement of thyrotropin-binding inhibitory antibodies (TBIAb) is useful in the management of Graves' disease. Another method of assessing Graves' disease by measuring adenylate cyclase activity in thyroid cells, known as thyroid-stimulating antibodies (TSAb), differs from TBIAb not only in terms of assay but also in immunoglobulin type according to recent studies. In this study, the concentrations of TBIAb and TSAb were compared in serial serum samples collected from 29 patients with Graves' hyperthyroidism during 12 months of antithyroid drug therapy. Before therapy, there was a correlation between TBIAb and TSAb (r = 0.59). The radioactive iodine uptake (RAIU) was not significantly correlated with either TBIAb or TSAb (r = 0.20 and r = 0.29, respectively), and the serum free thyroxine (FT4) concentration was also not significantly correlated with either TBIAb or TSAb (r = 0.06 and r = 0.22, respectively). In patients with Graves' ophthalmopathy, TSAb levels were higher than in patients without ophthalmopathy (1015%+/-851% vs. 456%+/-323%, p<0.01), but the TBIAb levels were not significantly different. After antithyroid treatment, TBIAb did not decrease significantly (from 42.1%+/-20.8% to 20.5%+/-19.5%, p = 0.29). On the other hand, TSAb was significantly decreased after 12 months of treatment (from 649%+/-611% to 294%+/-205%, p< 0.05). These findings indicate that TBIAb and TSAb are not identical, and that TSAb has a closer relationship to thyroid function than TBIAb. In the clinical setting, determination of the serum TSAb level may provide a more accurate index of the thyroid status in Graves' disease patients receiving antithyroid therapy.     

Association of cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) gene polymorphism and non-genetic factors with Graves' ophthalmopathy in European and Japanese populations

OBJECTIVE: The development and severity of Graves' ophthalmopathy (GO) may result from a complex interplay of genetic and environmental factors. The aim of this study was to investigate the association of cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) gene polymorphism and non-genetic factors (age, sex, cigarette smoking) with GO in two different populations, Polish-Caucasians and Japanese. DESIGN: We investigated the distribution of CTLA-4 A49G polymorphism in 264 Caucasian patients with Graves' disease (GD), of which 95 had clinically evident GO (NOSPECS class >or=3) and 319 Japanese patients with GD, of which 99 had ophthalmopathy. The control groups consisted of healthy Polish adults (n=194), Polish centenarians (n=51) and Japanese adults (n=112). RESULTS: Allele G and G/G genotype were significantly increased in Caucasian patients with GD (48% and 25% respectively) and in Japanese patients with GD (69% and 47% respectively) compared with control groups. There were no significant differences in the G allele and G/G genotype frequencies in GO patients compared with GD patients without ophthalmopathy. Multiple logistic regression analysis demonstrated that cigarette smoking (P=0.03, odds ratio (OR)=1.7) and age of onset of GD over 42 Years (P=0.08; OR=1.6) were contributing factors associated with susceptibility to GO in Polish patients. In Japanese patients, a younger age of onset of GD had an effect on the development of GO (P=0.02, OR=1.8). CONCLUSIONS: (i) Allele G and G/G genotype confer genetic susceptibility to GD; (ii) CTLA-4 A49G polymorphism is not associated with the development of GO; (iii) different non-genetic factors may contribute to GO in different populations.