肌浆网钙结合蛋白-1基因中的新型单核苷酸多态性与格雷夫斯眼病和桥本甲状腺炎相关。
Novel single-nucleotide polymorphisms in the calsequestrin-1 gene are associated with Graves' ophthalmopathy and Hashimoto's thyroiditis.
作者信息
Lahooti Hooshang, Cultrone Daniele, Edirimanne Senarath, Walsh John P, Delbridge Leigh, Cregan Patrick, Champion Bernard, Wall Jack R
机构信息
Thyroid Research Laboratory, Sydney Medical School - Nepean Clinical School, The University of Sydney, Kingswood, NSW, Australia ; Nepean Blue Mountains Local Health District, Nepean Hospital, Kingswood, NSW, Australia.
Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, Australia ; School of Medicine and Pharmacology, The University of Western Australia, Crawley, WA, Australia.
出版信息
Clin Ophthalmol. 2015 Sep 18;9:1731-40. doi: 10.2147/OPTH.S87972. eCollection 2015.
BACKGROUND
The eye disorder associated with Graves' disease, called Graves' ophthalmopathy (GO), greatly reduces the quality of life in affected patients. Expression of the calsequestrin (CASQ1) protein in thyroid tissue may be the trigger for the development of eye muscle damage in patients with GO. We determined the prevalence of rs74123279, rs3747673, and rs2275703 single-nucleotide polymorphism (SNPs) in patients with autoimmune thyroid disorders, GO, Graves' hyperthyroidism (GH), or Hashimoto's thyroiditis (HT) and control subjects with no personal or family history of autoimmune thyroid disorders. Furthermore, we measured the concentration of the CASQ1 protein in normal and Graves' thyroid tissue, correlating levels with parameters of the eye signs, CASQ1 antibody levels, and the CASQ1 gene polymorphism rs74123279 and rs2275703.
METHODS
High-quality genomic DNA was isolated from fresh blood samples, assayed for identification of rs74123279, rs3747673, and rs2275703 SNPs in CASQ1 gene by MassARRAY SNP analysis using iPLEX technology of SEQUENOM.
RESULTS
DNA samples from 300 patients and 106 control subjects (100 males, 306 females) with GO (n=74), GH (n=130), HT (n=96) and control subjects (n=106) were genotyped for the SNPs rs74123279, rs3747673 (n=405), and rs2275703 (n=407). The SNP rs74123279, rs3747673, and rs2275703 were identified as 1) common homozygous or wild type, 2) heterozygote, and 3) rare homozygous. Minor allele frequency for rs74123279, rs3747763, and rs2275703 were 21%, 40%, and 44%, respectively. Multiple comparisons of genotype frequency for rs74123279, rs3747763, and rs2275703 in the GO, GH, HT, and control groups showed P=0.06, 0.641, and 0.189, respectively. These results were substantiated by multiple comparison of alleles frequency for rs74123279, rs3838216, rs3747763, and rs2275703 in the GO, GH, HT, and control groups showed, P=0.36, 0.008, 0.66, and 0.05, respectively. Pairwise analysis of alleles frequency distribution in patients with GO showed significant probability for rs2275703, P=0.008.
CONCLUSION
Based on their evolutionary conservation and their significant prevalence, we suggest that CASQ1 gene SNPs rs74123279, rs3838216, and rs2275703 may be considered as genetic markers for GO.
背景
与格雷夫斯病相关的眼部疾病，称为格雷夫斯眼病（GO），会极大地降低受影响患者的生活质量。甲状腺组织中肌集钙蛋白（CASQ1）蛋白的表达可能是GO患者眼肌损伤发展的触发因素。我们确定了自身免疫性甲状腺疾病、GO、格雷夫斯甲亢（GH）或桥本甲状腺炎（HT）患者以及无自身免疫性甲状腺疾病个人或家族史的对照受试者中rs74123279、rs3747673和rs2275703单核苷酸多态性（SNP）的患病率。此外，我们测量了正常甲状腺组织和格雷夫斯甲状腺组织中CASQ1蛋白的浓度，并将其水平与眼部体征参数、CASQ1抗体水平以及CASQ1基因多态性rs74123279和rs2275703进行关联。
方法
从新鲜血液样本中分离出高质量的基因组DNA，使用SEQUENOM的iPLEX技术通过MassARRAY SNP分析检测CASQ1基因中的rs74123279、rs3747673和rs2275703 SNP。
结果
对300例患者和106例对照受试者（100例男性，306例女性）进行基因分型，这些患者包括GO患者（n = 74）、GH患者（n = 130）、HT患者（n = 96）以及对照受试者（n = 106），检测SNP rs74123279、rs3747673（n = 405）和rs2275703（n = 407）。SNP rs74123279、rs3747673和rs2275703被鉴定为1）常见纯合子或野生型，2）杂合子，3）罕见纯合子。rs74123279、rs3747763和rs2275703的次要等位基因频率分别为21%、40%和44%。GO、GH、HT和对照组中rs74123279、rs3747763和rs2275703基因型频率的多重比较显示P值分别为0.06、0.641和0.189。rs74123279、rs3838216、rs3747763和rs2275703等位基因频率在GO、GH、HT和对照组中的多重比较结果分别为P = 0.36、0.008、0.66和0.05，证实了上述结果。GO患者等位基因频率分布的成对分析显示rs2275703具有显著概率，P = 0.008。
结论
基于它们的进化保守性和显著的患病率，我们建议将CASQ1基因SNP rs74123279、rs3838216和rs2275703视为GO的遗传标记。
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