Linkage of Graves’ disease to the human leucocyte antigen region in the Chinese‐Han population in Taiwan

Chen, Pei‐Lung; Fann, Cathy S.J.; Chang, Chien-Ching; Wu, I‐Lin; Chiu, Wei‐Yih; Lin, Chin-Yu; Yang, Wei‐Shiung; Chang, Tien–Chun

doi:10.1111/j.1365-2265.2007.02787.x

Cited by 9 publications

(15 citation statements)

References 48 publications

(142 reference statements)

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“…With the same collection of familial samples, we did not detect evidence of linkage at the CTLA4 region, 31 which could be explained by the effect size of CTLA4 and by the sample size of our collection. However, we were able to demonstrate significant linkage (NPL score ¼ 4.1, P ¼ 0.00002) at the human leukocyte antigen region.…”

Section: Discussionmentioning

confidence: 55%

“…However, we were able to demonstrate significant linkage (NPL score ¼ 4.1, P ¼ 0.00002) at the human leukocyte antigen region. 31 With an intention to reduce heterogeneity of our samples, we purposely enrolled individuals with only Han ethnic background, and collected GD-only pedigrees by excluding families with a history of hypothyroidism or Hashimoto's thyroiditis. With this strategy of sample collection, we successfully detected linkage signal of human leukocyte antigen and association signal of CTLA4.…”

Section: Discussionmentioning

confidence: 99%

“…31 Briefly, the diagnosis of GD was made based on the manifestations of biochemical hyperthyroidism with either ophthalmopathy or a diffuse goiter and a significant titer of auto-antibodies, including antimicrosomal, antithyroglobulin or anti-TSH receptor antibody as in previous reports. 31,32 To increase phenotypic homogeneity, pedigrees containing any member with possible Hashimoto's thyroiditis (HT [MIM603372], based either on medical records of HT or on self-stated history of symptoms/signs of hypothyroidism without previous treatment of thyroidectomy or radioactive iodine) were excluded. To reduce heterogeneous ethnic background, only subjects with four grandparents of Han origin were included.…”

Section: Methodsmentioning

confidence: 99%

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Family-based association study of cytotoxic T-lymphocyte antigen-4 with susceptibility to Graves' disease in Han population of Taiwan

Fann

et al. 2007

Genes Immun

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Graves' disease (GD) is a common organ-specific autoimmune disorder inherited as a complex trait. Although there has not been consensus regarding the genuine susceptibility alleles, many population-based genetic studies showed association of the cytotoxic T-lymphocyte antigen-4 (CTLA4) gene with GD. In contrast, evidence utilizing family-based studies came only from the Caucasian population. Here we performed a family-based association study in the Han population in Taiwan. We enrolled 374 affected individuals and 347 unaffected family members in 151 GD pedigrees. Four single-nucleotide polymorphisms (SNP) and a short tandem repeat polymorphism (STRP) at CTLA4 were genotyped. Association of GD with a novel risk SNP at the 5 0 upstream region, CTLA4_À1722_T/C (rs733618), was demonstrated (P ¼ 0.0096). We also replicated the association signal of a coding SNP, CTLA4_ þ 49_G/A (rs231775, P ¼ 0.0219). A common haplotype composed of CTLA4_À1722_T/C and CTLA4_(AT)n (an STRP marker: UniSTS:48500) showed protective effect (P ¼ 0.0004). Our results of family-based association study, taken together with those from the Caucasian population, provide evidence that CTLA4 confers susceptibility to GD across different ethnic backgrounds.

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Section: Discussionmentioning

confidence: 55%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Family-based association study of cytotoxic T-lymphocyte antigen-4 with susceptibility to Graves' disease in Han population of Taiwan

Fann

et al. 2007

Genes Immun

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“…Among all the methods for studying diseases pathophysiology, genetic approach has valuable capability as being both hypothesis-testing and hypothesis-generating. Linkage analysis for GD, although yielded inconsistent results across studies [8], [10]–[14], did demonstrate that the HLA region is linked to GD susceptibility in both Caucasian and Chinese Han populations according to others' [10] and our [13] studies. Association studies have been more replicable, with a few promising loci such as the HLA region, CTLA4 , PTPN22 , CD40 , FCRL3 , CD25 , TG and TSHR [8], [9], [15], [16].…”

Section: Introductionmentioning

confidence: 52%

Comprehensive Genotyping in Two Homogeneous Graves' Disease Samples Reveals Major and Novel HLA Association Alleles

et al. 2011

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BackgroundGraves' disease (GD) is the leading cause of hyperthyroidism and thyroid eye disease inherited as a complex trait. Although geoepidemiology studies showed relatively higher prevalence of GD in Asians than in Caucasians, previous genetic studies were contradictory concerning whether and/or which human leukocyte antigen (HLA) alleles are associated with GD in Asians.Methodology/Principal FindingsWe conducted a case-control association study (499 unrelated GD cases and 504 controls) and a replication in an independent family sample (419 GD individuals and their 282 relatives in 165 families). To minimize genetic and phenotypic heterogeneity, we included only ethnic Chinese Han population in Taiwan and excluded subjects with hypothyroidism. We performed direct and comprehensive genotyping of six classical HLA loci (HLA-A, -B, -C, -DPB1, -DQB1 and -DRB1) to 4-digit resolution. Combining the data of two sample populations, we found that B*46:01 (odds ratio under dominant model [OR] = 1.33, Bonferroni corrected combined P [PBc] = 1.17×10−2), DPB1*05:01 (OR = 2.34, PBc = 2.58×10−10), DQB1*03:02 (OR = 0.62, PBc = 1.97×10−2), DRB1*15:01 (OR = 1.68, PBc = 1.22×10−2) and DRB1*16:02 (OR = 2.63, PBc = 1.46×10−5) were associated with GD. HLA-DPB1*05:01 is the major gene of GD in our population and singly accounts for 48.4% of population-attributable risk.Conclusions/SignificanceThese GD-associated alleles we identified in ethnic Chinese Hans, and those identified in other Asian studies, are totally distinct from the known associated alleles in Caucasians. Identification of population-specific association alleles is the critical first step for individualized medicine. Furthermore, comparison between different susceptibility/protective alleles across populations could facilitate generation of novel hypothesis about GD pathophysiology and indicate a new direction for future investigation.

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“…80 Linkage analysis revealed a positive association between Graves' disease (GD) and the HLA region in a Taiwanese population. 81 HLA-DR2 and DR9 were the first two associated alleles found. 82 HLA-B*4601, the predominant allele across Asian countries, was also reported to be a susceptible allele for both GD and Hashimoto thyroiditis (HT) in Taiwan.…”

Section: Susceptible Loci In the Human Leukocyte Antigen Regionmentioning

confidence: 97%

A systematic review of genetic studies of thyroid disorders in Taiwan

Huang

Jap

2015

Journal of the Chinese Medical Association

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A systematic review of genetic studies of thyroid disorders in Taiwan identified studies of gene mutations involved in the synthesis and binding of thyroid hormone, as well as mutations of proto-oncogenes and tumor suppressor genes in thyroid cancer. Studies related to gene polymorphisms in patients with autoimmune thyroid disease (AITD) and thyroid cancer were also reviewed. The most prevalent mutations in the Han-Chinese population were c.2268insT in the thyroid peroxidase (TPO) gene and c.919-2A>G in the Pendred syndrome (PDS) gene. Additional mutations have also been revealed in the genes encoding TPO (n = 5), thyroglobulin (TG; n = 6), pendrin (n = 2), and thyroxine-binding globulin (TBG; n = 2), which were novel at the time they were reported. The prevalence of various somatic mutations in differentiated thyroid cancer was similar in Taiwan and Western countries, with the RAS kinase mutation and tyrosine receptor kinase (TRK) and rearranged during transfection (RET) proto-oncogenes being detected in lower frequencies and the B-type RAF kinase (BRAF) mutation accounting for the majority of cases. Recent microRNA analysis revealed an association between miR146b and the BRAF mutation, which was associated with poor prognosis of papillary thyroid carcinoma (PTC). Susceptibility to Graves' disease (GD) was linked to the human leukocyte antigen (HLA) region. The associated alleles were different in Han-Chinese and Caucasians; HLA-DPB1*0501, the major allele in Taiwan, has a low frequency in the West. By contrast, a high frequency of HLA-DRB1*0301 was detected in Caucasians but not Han-Chinese. In addition to the HLA region, cytotoxic T lymphocyte-associated molecule-4 (CTLA4) gene polymorphisms +49G>A and +6230G>A (CT60) were positively associated with GD. The GG genotype and G allele of single nucleotide polymorphism (SNP) +49G>A were also related to relapse of Graves' hyperthyroidism after antithyroid drug withdrawal. Differences in the genetic patterns between Han-Chinese and Caucasians for some thyroid disorders suggest the importance of variable genetic influences in different populations.

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Linkage of Graves’ disease to the human leucocyte antigen region in the Chinese‐Han population in Taiwan

Abstract: Our results provide strong support for linkage of GD to the HLA region. Further dissection of this region to identify the candidate gene for GD is warranted in our population.

Cited by 9 publications

References 48 publications

Family-based association study of cytotoxic T-lymphocyte antigen-4 with susceptibility to Graves' disease in Han population of Taiwan

Family-based association study of cytotoxic T-lymphocyte antigen-4 with susceptibility to Graves' disease in Han population of Taiwan

Comprehensive Genotyping in Two Homogeneous Graves' Disease Samples Reveals Major and Novel HLA Association Alleles

A systematic review of genetic studies of thyroid disorders in Taiwan

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