title: Human Cytokine Genetic Variants Associated With HBsAg Reverse Seroconversion in Rituximab-Treated Non-Hodgkin Lymphoma Patients.
abstract: Hepatitis B virus (HBV) reactivation has been noted in HBV surface antigen (HBsAg)-seronegative patients with CD20 B-cell non-Hodgkin lymphoma (NHL) undergoing rituximab treatment. Clinically, hepatitis flares are usually associated with the reappearance of HBsAg (reverse seroconversion of HBsAg, HBV-RS). It is unclear whether human genetic factors are related to rituximab-associated HBV reactivation. Unvaccinated HBsAg-seronegative adults (n = 104) with CD20 NHL who had received rituximab-containing therapy without anti-HBV prophylaxis were enrolled. Eighty-nine candidate single nucleotide polymorphisms (SNPs) of 49 human cytokine genes were chosen and were analyzed using the iPLEX technique. Competing risk regression was used to identify the factors associated with HBV-RS. Participants had a median age of 66.1 years and 56.7% were male (n = 59). The anti-HBs and anti-HBc positivity rates were 82.4% and 94.1%, respectively, among patients for whom data were available (approximately 81%). A mean of 7.14 cycles of rituximab therapy were administered, and a total of 14 (13.4%) patients developed HBV-RS. Nine SNPs showed significant differences in frequency between patients with or without HBV-RS: CD40 rs1883832, IL4 rs2243248 and rs2243263, IL13 rs1295686, IL18 rs243908, IL20 rs1518108, and TNFSF13B rs12428930 and rs12583006. Multivariate analysis showed that ≥6 cycles of rituximab therapy, IL18 rs243908, and the IL4 haplotype rs2243248∼rs2243263 were independently associated with HBV-RS. The IL4 haplotype rs2243248∼rs2243263 was significantly associated with HBV-RS regardless of anti-HBs status. Polymorphisms in human cytokine genes impact the risk of rituximab-associated HBV-RS.
authors.affiliation: From the Division of Hematology and Oncology, Department of Medicine (L-TH, H-YW, J-PG, Y-BY, H-LL, W-CC, P-MC, C-HT, M-HY, J-HL), Taipei Veterans General Hospital; Institute of Clinical Medicine (L-TH, H-YW, C-FY, T-JC, J-PG, Y-BY, P-MC, C-HT, M-HY, J-HL, Y-HH), National Yang-Ming University School of Medicine; Department of Pathology and Laboratory Medicine (C-FY); Division of Transfusion Medicine, Department of Medicine (T-JC); Division of Microbiology, Department of Pathology and Laboratory Medicine (Y-JC); Division of Infectious Diseases, Department of Medicine (Y-JC), Taipei Veterans General Hospital; Institute of Public Health (Y-JC), National Yang-Ming University; and Division of Gastroenterology and Hepatology, Department of Medicine (Y-HH), Taipei Veterans General Hospital, Republic of China.
authors.forename: Liang-Tsai
authors.initials: LT
authors.lastname: Hsiao
authors.forename: Hao-Yuan
authors.initials: HY
authors.lastname: Wang
authors.forename: Ching-Fen
authors.initials: CF
authors.lastname: Yang
authors.forename: Tzeon-Jye
authors.initials: TJ
authors.lastname: Chiou
authors.forename: Jyh-Pyng
authors.initials: JP
authors.lastname: Gau
authors.forename: Yuan-Bin
authors.initials: YB
authors.lastname: Yu
authors.forename: Hsiao-Ling
authors.initials: HL
authors.lastname: Liu
authors.forename: Wen-Chun
authors.initials: WC
authors.lastname: Chang
authors.forename: Po-Min
authors.initials: PM
authors.lastname: Chen
authors.forename: Cheng-Hwai
authors.initials: CH
authors.lastname: Tzeng
authors.forename: Yu-Jiun
authors.initials: YJ
authors.lastname: Chan
authors.forename: Muh-Hwa
authors.initials: MH
authors.lastname: Yang
authors.forename: Jin-Hwang
authors.initials: JH
authors.lastname: Liu
authors.forename: Yi-Hsiang
authors.initials: YH
authors.lastname: Huang
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects*; D016207:Cytokines / Q000235:genetics*; D005260:Female; D006239:Haplotypes; D006509:Hepatitis B / Q000139:chemically induced* / Q000150:complications / Q000276:immunology; D006801:Humans; D015847:Interleukin-4 / Q000235:genetics; D008228:Lymphoma, Non-Hodgkin / Q000150:complications / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012008:Recurrence; D012044:Regression Analysis; D012189:Retrospective Studies; D000069283:Rituximab / Q000009:adverse effects*; D000069078:Seroconversion / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; C508598:IL4 protein, human; D015847:Interleukin-4; D000069283:Rituximab