中華民國 102 年消化系聯合學術演講年會 聯絡資料 * 聯 絡 人 陳昇弘 * 電子信箱 [email protected] * 電 話 0975680973 傳 真 04-22023119 * 服務單位 中國醫藥大學附設醫院 內科部消化系 作者群 作者群 演講者 中文姓名 英文姓名 所屬機構代號(上標) 第一作者 陳昇弘 Sheng-Hung Chen 1,2 第二作者 彭成元 Cheng-Yuan Peng 1,3 第三作者 賴學洲 Hsueh-Chou Lai 1,2,4 第四作者 蘇文邦 Wen-Pang Su 1 第五作者 莊伯恒 Po-Heng Chuang 1 第六作者 高榮達 Jung-Ta Kao 1,2,3 * 所屬機構 中文全名 ※若有所屬機構代號（即上標），請以英文半形大括號標明，如： {1} 中國醫藥大學附設醫院 內科部消化系{1} 中國醫藥大學 臨床醫學研究所{2} 中國醫藥大學 醫學系{3} 中國醫藥大學 中醫學系{4} * 所屬機構 英文全名 ※若有所屬機構代號（即上標），請以英文半形大括號標明，如： {1}
Division of Hepatogastroenterology{1}, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
Graduate Institute of Clinical Medical Science{2}, School of Medicine{3}, China Medical University, Taichung, Taiwan
School of Chinese Medicine{4}, China Medical University, Taichung, Taiwan
中華民國 102 年消化系聯合學術演講年會 投稿資料 作者群 陳昇弘、彭成元、賴學洲、蘇文邦、莊伯恒、高榮達 研究負責人: 彭成元 * 希望發表方式 V 消化系醫學會 V 一般演講 * 中文題目 以肌苷三磷酸焦磷酸酶(ITPA)基因之單一核苷酸多型性為基礎之預測模式用以 預測感染第一型病毒基因型之亞洲 C 型肝炎病患接受長效型干擾素合併 Ribavirin 治療時之溶血性貧血 * 英文題目
A Predictive Index using the Inosine Triphosphate Pyrophosphatase Gene Allele Status to Predict Ribavirin-induced Hemolytic Anemia in Genotype 1 Hepatitis C Virus-infected Asian Patients Receiving Pegylated Interferon and Ribavirin Combination Therapy
* 內 文 背景/Background :
Associations between single-nucleotide polymorphisms (SNP) in the inosine triphosphate pyrophosphatase (ITPA) gene and ribavirin (RBV)-induced anemia in hepatitis C virus (HCV)-infected patients receiving pegylated interferon and RBV combination therapy have been reported. Identification of HCV-infected patients at risk of anemia using ITPA status is a priority during combination therapy.
目的/Aims :
This study aimed to evaluate the impact of ITPA SNP status on severe anemia and treatment responses, to examine the association of severe anemia and treatment responses, and to construct a clinically practical predictive index for severe anemia during HCV combination therapy.
方法/Methods :
Genotype 1 HCV (HCV-1) infected Taiwanese patients (n = 311) received 24 or 48 weeks of combination therapy. Participants' DNA was genotyped for a functional ITPA SNP (C/C, A/A or C/A) on chromosome 20 at rs1127354. A predictive index was constructed by incorporating predictors identified through logistic regressions for severe anemia (hemoglobin < 10 g/dL). Areas under the receiver operating
characteristic curves (AUCs) represent the diagnostic accuracies of the predictive index in the randomly assigned development and validation cohorts.
結果/Results :
OR = 5.9 (95% confidence interval, 95% CI = 2.4-14.2); 55-64: 7.5 (3.1-18.2); ≧ 65: 12.7 (3.7-43.9)), ITPA rs1127354 (C/C: 4.1 (2.1-8.0)), baseline hemoglobin (< 14.0 g/dL: 7.8 (3.7-16.2); 14.0-14.9: 3.2 (1.5-6.8)) as predictors of severe anemia
throughout the course of treatment. Therefore, the predictive index incorporating age, ITPA SNP status and baseline Hb was expressed as 1/ (1 + exp [-x]), where x = -3.4803 + 1.7696 (if age = 45-54) + 2.0137 (if age = 55-64) + 2.5388 (if age ≧ 65) + 1.4107 (if ITPA SNP = C/C) + 2.0483 (if Hb < 14.0) + 1.1591 (if Hb = 14.0-14.9). For severe anemia, the predictive index incorporating age, ITPA SNP status and baseline hemoglobin yielded diagnostic accuracies (AUC) of 0.816 (95% CI = 0.764-0.868) in the development (n = 249) and 0.912 (0.841-0.984) in the validation (n = 62) cohorts.
結論/Conclusions :
In HCV-1-infected patients receiving combination therapy, the ITPA SNP-based index is an accurate and practical predictive solution for severe anemia in clinical practice.
========================================================== A Predictive Index using the Inosine Triphosphate Pyrophosphatase Gene Allele Status to Predict Ribavirin-induced Hemolytic Anemia in Genotype 1 Hepatitis C Virus-infected Asian Patients Receiving Pegylated Interferon and Ribavirin Combination Therapy
Sheng-Hung Chen1,2; Cheng-Yuan Peng1,3; Hsueh-Chou Lai1,2,4; Wen-Pang Su1; Chia-Hsin Lin1; Yu-Fen Li5; Po-Heng Chuang1; Jung-Ta Kao1,2,3; Ching-Hsiang Chen1 1
Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, 40447, Taiwan
2
Graduate Institute of Clinical Medical Science, School of Medicine, China Medical University, Taichung, 40402, Taiwan
3
School of Medicine, China Medical University, Taichung, 40402, Taiwan 4
College of Chinese Medicine, China Medical University, Taichung, 40402, Taiwan 5
Institute of Biostatistics, China Medical University, Taichung, 40402, Taiwan
E-mail: Sheng-Hung Chen: [email protected]; Cheng-Yuan Peng: [email protected]; Hsueh-Chou Lai: [email protected]; Wen-Pang Su: [email protected]; Chia-Hsin Lin: [email protected]; Yu-Fen Li: [email protected]; Po-Heng Chuang: [email protected]; Jung-Ta Kao: [email protected] and Ching-Hsiang Chen: [email protected] Correspondence: Cheng-Yuan Peng, MD, PhD, Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, China Medical University, No 2, Yuh-Der Road, Taichung, 40447, Taiwan
Tel: +886 4 2205 2121 ext. 2260 Fax: +886 4 2207 1600
Abstract
Background: Associations between single-nucleotide polymorphisms (SNP) in the inosine triphosphate pyrophosphatase (ITPA) gene and ribavirin (RBV)-induced anemia in hepatitis C virus (HCV)-infected patients receiving pegylated interferon and RBV combination therapy have been reported. Identification of HCV-infected patients at risk of anemia using ITPA status is a priority during combination therapy. Methods: Genotype 1 HCV (HCV-1) infected Taiwanese patients (n = 311) received 24 or 48 weeks of combination therapy. Participants' DNA was genotyped for a functional ITPA SNP (C/C, A/A or C/A) on chromosome 20 at rs1127354. A predictive index was constructed by incorporating predictors identified through logistic regressions for severe anemia (hemoglobin < 10 g/dL). Areas under the receiver operating characteristic curves (AUCs) represent the diagnostic accuracies of the predictive index in the randomly assigned development and validation cohorts. Results: Multivariate logistic regression analysis identified age (45-54 years: odds ratio, OR = 5.9 (95% confidence interval, 95% CI = 2.4-14.2); 55-64: 7.5 (3.1-18.2);
65: 12.7 (3.7
14.0 g/dL: 7.8 (3.7-16.2); 14.0-14.9: 3.2 (1.5-6.8)) as predictors of severe anemia throughout the course of treatment. For severe anemia, the predictive index incorporating age, ITPA SNP status and baseline hemoglobin yielded diagnostic accuracies (AUC) of 0.816 (95% CI = 0.764-0.868) in the development (n = 249) and 0.912 (0.841-0.984) in the validation (n = 62) cohorts.
Conclusions: In HCV-1-infected patients receiving combination therapy, the ITPA SNP-based index is an accurate and practical predictive solution for severe anemia in clinical practice.
Keywords single-nucleotide polymorphisms (SNP); inosine triphosphate pyrophosphatase (ITPA); hemolytic anemia; hepatitis C virus (HCV)
感染第二型病毒基因型之 C 型肝炎病患接受長效型干擾素合併 Ribavirin 治療時 肌苷三磷酸焦磷酸酶(ITPA)基因之單一核苷酸多型性與溶血性貧血之相關性 陳昇弘1,2 彭成元1,3 賴學洲1,2,4 高榮達1,2,3 莊伯恒1 蘇文邦1 林志明1 陳景祥 1 中國醫藥大學附設醫院內科部消化系1 中國醫藥大學臨床醫學研究所2, 醫學系3, 中醫學系4 背景： 最近的基因組關聯性研究報告指出， C 型肝炎病患接受長效型干擾素(pegIFN) 合併 Ribavirin(RBV)治療時， 肌苷三磷酸焦磷酸酶(ITPA)基因之單一核苷酸多型 性(SNP)與溶血性貧血之間有顯著相關性。 然而， 有限的研究曾分析感染第二 基因型 C 型肝炎病毒(HCV-2）之台灣患者。 本研究旨在探討這些 SNP， 對貧 血， 血紅素（Hb）下降， 以及治療效果的影響。 材料與方法： 共有二百三十五位符合資格的 HCV-2 感染患者接受合併治療 24 週。 並從周邊 血液單核球細胞基因組， 分析位於 20 號染色體 rs1127354 位置的功能性 ITPA 基因變異。 以確認重度貧血（血紅蛋白<10 克/dL）和血紅素下降（ 4≧ 克/dL） 的預測因子。 結果：
多變項邏輯斯回歸分析確定年齡（≧60歲）（odds ratio, OR, 2.337; 95％confidence interval, CI, 1.180-4.627; P = 0.015）， 女性（OR, 3.463; 95％CI, 1.913-6.269, P <0.001）， 和 ITPA rs1127354 C/C（OR, 2.227; 95％CI, 1.168-4.247, P = 0.015）， 可
以獨立預測整個 24 週的治療過程中的嚴重貧血。 年齡（ 60≧ 歲）（OR, 1.633; 95
％ CI, 0.832-3.203, P = 0.154）， 男性（OR, 2.224; 95％CI, 1.275-3.879; P = 0.005）和 ITPA rs1127354 C/C（OR, 3.135; 95％CI, 1.702-5.775; P <0.001）， 與血 紅素下降相關。 多變項 Cox 回歸分析顯示年齡（ 60≧ 歲）(hazard ratio, HR, 1.915; 95％CI, 1.226-2.993; P = 0.004）， 女性（HR, 2.712; 95％CI, 1.680-4.380; P < 0.001）， 和 ITPA rs1127354 C/C（HR, 2.162; 95％CI, 1.302-3.590; P = 0.003）， 亦 可獨立預測整個 24 週的治療過程中的嚴重貧血。 持續病毒學反應(SVR)和貧血
或 ITPA SNP 不相關。 結論： 感染 HCV-2 之慢性 C 型肝炎台灣病患， 接受合併治療時， ITPA SNP 可預測 RBV 引起之溶血性貧血， 以及血紅素下降， 但並不影響 SVR 率。 關鍵語: 單一核苷酸多型性(SNP) ， 肌苷三磷酸焦磷酸酶(ITPA) ， 溶血性貧血， C 型 肝炎病毒
