CAJ | 학술논문

目的探讨中国汉族血友病A(HA)患者肿瘤坏死因子α(TNF-α)-308基因多态性及细胞毒性T淋巴细胞相关抗原4(CTLA-4)-318基因多态性与凝血因子Ⅷ(FⅧ)抑制物的相关性.方法采用聚合酶链反应结合限制性内切酶片段长度多态性(PCR-RFLP),对140例经过FⅧ替代治疗的HA患者和108名正常对照者的TNF-α及CTLA-4基因的单碱基多态性进行检测.所有HA患者样本均应用改良的Nijmegen方法检测FⅧ抑制物活性.结果在HA患者中,TNF-α-308 G/G基因型118例(84.3%),G/A基因型18例(12.8%),A/A基因型4例(2.9%);CTLA-4-318 C/C基因型108例(77.2%),C/T基因型30例(21.4%),T/T基因型2例(1.4%).TNF-α-308、CTLA-4-318等位基因频率在HA病例组与正常对照组间差异均无统计学意义(P＞0.05),关联分析显示携带TNF-α-308 A等位基因HA患者发生FⅧ抑制物的风险是非A等位基因携带患者的7.519倍(OR=7.519,95%CI=3.168～17.844);而携带TNF-α-308 A等位基因重型HA患者发生FⅧ抑制物的风险是非A等位基因携带重型患者的8.163倍(OR=8.163,95%CI=2.521～26.434).携带CTLA-4-318 T等位基因血友病A患者发生FⅧ抑制物的风险与非T等位基因携带患者的差异无统计学意义(OR=1.586,95%CI=0.729～3.450).结论 TNF-α-308基因多态性与中国汉族人群重型HA患者发生FⅧ抑制物具有相关性,该基因可能为HA患者替代治疗产生抑制物的调节基因之一.
목적 탐토중국한족혈우병A(HA)환자종류배사인자α(TNF-α)-308기인다태성급세포독성T림파세포상관항원4(CTLA-4)-318기인다태성여응혈인자Ⅷ(FⅧ)억제물적상관성.방법 채용취합매련반응결합한제성내절매편단장도다태성(PCR-RFLP),대140례경과FⅧ체대치료적HA환자화108명정상대조자적TNF-α급CTLA-4기인적단감기다태성진행검측.소유HA환자양본균응용개량적Nijmegen방법검측FⅧ억제물활성.결과 재HA환자중,TNF-α-308 G/G기인형118례(84.3%),G/A기인형18례(12.8%),A/A기인형4례(2.9%);CTLA-4-318 C/C기인형108례(77.2%),C/T기인형30례(21.4%),T/T기인형2례(1.4%).TNF-α-308、CTLA-4-318등위기인빈솔재HA병례조여정상대조조간차이균무통계학의의(P＞0.05),관련분석현시휴대TNF-α-308 A등위기인HA환자발생FⅧ억제물적풍험시비A등위기인휴대환자적7.519배(OR=7.519,95%CI=3.168～17.844);이휴대TNF-α-308 A등위기인중형HA환자발생FⅧ억제물적풍험시비A등위기인휴대중형환자적8.163배(OR=8.163,95%CI=2.521～26.434).휴대CTLA-4-318 T등위기인혈우병A환자발생FⅧ억제물적풍험여비T등위기인휴대환자적차이무통계학의의(OR=1.586,95%CI=0.729～3.450).결론 TNF-α-308기인다태성여중국한족인군중형HA환자발생FⅧ억제물구유상관성,해기인가능위HA환자체대치료산생억제물적조절기인지일.
Objective To investigate the potential association between factor Ⅷ inhibitor development and polymorphisms of tumor necrosis factor-α(TNF-α)-308 and cytotoxic T-lymphocyte associated protein-4 gene in Chinese Han patients with hemophilia A(HA). Methods The single base change polymorphism in TNF-α and CTLA-4 gene was analyzed in 140 Chinese Han patients with hemophilia A who have been treated with plasma-derived FⅧ concentrates and 108 normal controls by using PCR-restrictive fragment length polymorphism(RFLP). All of the HA patients' plasma samples were measured by modified-Nijmegen assay simultaneously. Results In HA patients,G/G genotype,G/A genotype and A/A genotype were detected in 118 (84.3%) ,18( 12.8% ) and 4 cases(2.9% )respectively; C/C genotype,C/T genotype and T/T genotype were detected in 108(77.2% ), 30 (21.4%) and 2 cases( 1.4% )respectively. The difference in the genotype frequencies between HA patients and controls was nonsignificant ( P ＞ 0.05 ). Patients who were carriers of homozygotes for A allele had a higher risk of inhibitor development compared with those who were not( OR =7. 519, 95% CI = 3. 168 - 17. 844). Severe HA patients who were carriers of homozygotes for A allele had a higher risk of inhibitor development compared with those who were not ( OR =8. 163, 95% CI =2.521 -26. 434 ). There was no statistical difference in the risk of inhibitor development between the patients who were carriers or not ( OR = 1. 586, 95% CI = 0. 729 - 3. 450 ). Conclusion TNF-α-308 gene polymorphism is significantly associated with inhibitor development in Chinese Han patients with severe hemophilia A. TNF-α gene may be a useful marker and potential modulator of the immune response to replacement therapy for hemophilia A patients.