抗甲狀腺藥物引發顆粒性白血球低下之遺傳學研究

Abstract

由甲狀腺亢進引起的葛瑞夫茲氏症，約佔了族群裡的1.0%-1.6%，抗甲狀腺藥物是最基本的治療，但藥物引發之顆粒性白血球低下則是一嚴重的副作用。在本篇論文中，我們以臺大醫院收案之服用抗甲狀腺藥物引發之顆粒性白血球低下患者共42人為研究對象，使用1208位葛瑞夫茲氏病患者做為對照組進行直接偵測人類白血球抗原基因分型及單一核甘酸多型性全基因體相關分析，結果發現到在HLA-B*38:02及HLA-DRB1*08:03兩個對偶基因對於引發顆粒性白血球低下具有高度相關性(Armitage trend Pcombined = 6.75 × 10-32)及(Pcombined = 1.83 × 10-9)，全基因組相關分析也顯示出在此兩區域出現相同的訊號。評估帶有此兩個對偶基因比沒有帶有此對偶基因容易引發顆粒性白血球低下分別約為21.48倍(95%信賴區間=11.13-41.48)及6.13倍(95%信賴區間=3.28-11.46)；研究顯示同時帶HLA-B*38:02及HLA-DRB1*08:03兩個對偶基因其引發顆粒性白血球低下的風險更增加至48.41倍(Pcombined = 3.32 × 10-21, 95% 信賴區間= 21.66-108.22)。此次研究結果對於因抗甲狀腺藥物引發之顆粒性白血球低下的淺在的致病風險將會有很大的幫助。

Graves’ disease is the leading cause of hyperthyroidism affecting 1.0-1.6% of the population. Anti-thyroid drugs are the treatment cornerstone, but may causelife-threatening agranulocytosis. Here we conduct a two-stage association study on two separate subject sets (in total 42 agranulocytosis cases and 1,208 Graves’ disease controls), using direct humanleukocyte antigen genotyping and SNP-based genome-wide association study. Wedemonstrate HLA-B*38:02 (Armitage trend Pcombined = 6.75 × 10-32) andHLA-DRB1*08:03 (Pcombined = 1.83 × 10-9) as independent susceptibility loci. The genome-wide association study identifies the same signals. Estimated odds ratios for these two loci comparing effective allele carriers to non-carriers are 21.48 (95% confidence interval = 11.13-41.48) and 6.13 (95% confidence interval = 3.28-11.46), respectively. Carrying both HLA-B*38:02 and HLA-DRB1*08:03 increases odds ratio to 48.41 (Pcombined = 3.32 × 10-21, 95% confidence interval = 21.66-108.22). Our results could be useful for anti-thyroid-induced agranulocytosis and potentially for agranulocytosis caused by other chemicals.