成千上万的麻风病人不仅身体畸形,但也有或曾有乙型肝炎病毒(HBV)共感染。补体系统的多态性调节麻风病的易感性,但遗传易感性过去或现在的HBV感染是未知的。我们使用测序和多重序列特异性PCR对7个基因(MBL2,FCN1,FCN2,FCN3,MASP1,MASP2,C3)的72个多态性进行了基因型分析,和两个基因编码补体受体(CR1,VSIG4)190例患者,其中74例HBsAg和/或抗HBc阳性(HBV+,93.2%的感染已解决)和116名麻发病人,和408HBV献血者。此外,我们测试了凝集素途径的蛋白质水平。我们发现甘露聚糖结合凝集素(MBL)的血清浓度之间没有差异,MBL相关丝氨酸蛋白(MASP-1,MASP-2,MASP-3,MAp44),ficolin-3(FCN-3),可溶性补体受体1(sCR1)和MBL介导的C4激活,通过ELISA或TRIFMA测量多达167HBV+和HBV-患者。单倍型降低蛋白质水平或编码功能失调的蛋白质增加对HBV感染的易感性:MBL2*LYQC(OR=3.4,p=0.02),MASP1*AC_CC(OR=4.0,p=0.015)和MASP2*1C2-1(OR=5.4,p=0.03)。相反,FCN1*3C2单倍型,与更高的基因表达相关,具有保护作用(OR=0.56,P=0.033)。与HBV易感性相关的其他单倍型为:MASP2*2B1-i(OR=19.25,P=0.003),CR1*3A(OR=2.65,P=0.011)和VSIG4*TGGRCG(OR=12.55,P=0.014)。与较低的蛋白质水平相关的ficolin基因中的一些多态性增加了麻风病/HBV感染的易感性:FCN*1(OR=1.66,P=0.029),FCN2*GGGCAC(OR=6.73,P=0.008),和FCN3*del_del_C(OR=12.54,P=0.037),和麻风病/HBV感染:FCN2*TA(OR=2.5,P=0.009),而FCN2*MAG与FCN-2表达增加和对合并感染的抗性相关(OR=0.29,P=0.026)。这些关联与人口统计学因素无关,并没有增加麻风病本身的易感性,除了MASP2*1C2-l。FCN2、FCN3、MASP1、MASP2和VSIG4变体的关联也彼此独立。总之,多态性损害补体的凝集素途径的激活增加对HBV感染的易感性,ficolin多态性在调节麻风病人的易感性中起主要作用。
Thousands of leprosy patients not only suffer from physical deformities, but also either have or have had hepatitis B virus (HBV) coinfection. Polymorphisms of the complement system modulate susceptibility to leprosy, but genetic susceptibility to past or present HBV infection is unknown. We used sequencing and multiplex sequence-specific PCR to genotype 72 polymorphisms of seven genes (MBL2, FCN1, FCN2, FCN3, MASP1, MASP2, C3) encoding components of the lectin pathway, and two genes encoding complement receptors (CR1, VSIG4) in 190 patients, of which 74 were positive for HBsAg and/or anti-HBc (HBV+, 93.2% with a resolved infection) and 116 lepromatous patients, and 408 HBV-blood donors. In addition, we tested for levels of proteins of the lectin pathway. We found no difference between serum concentrations of mannan-binding lectin (MBL), MBL-associated serine proteins (MASP-1, MASP-2, MASP-3, MAp44), ficolin-3 (FCN-3), soluble complement receptor 1 (sCR1) and MBL mediated C4 activation, measured by ELISA or TRIFMA in up to 167 HBV+ and HBV- patients. Haplotypes lowering protein levels or encoding dysfunctional proteins increased susceptibility to HBV infection: MBL2*LYQC (OR = 3.4, p = 0.02), MASP1*AC_CC (OR = 4.0, p = 0.015) and MASP2*1C2-l (OR = 5.4, p = 0.03). Conversely, FCN1*3C2 haplotype, associated with higher gene expression, was protective (OR = 0.56, P = 0.033). Other haplotypes associated with HBV susceptibility were: MASP2*2B1-i (OR = 19.25, P = 0.003), CR1*3A (OR = 2.65, P = 0.011) and VSIG4*TGGRCG (OR = 12.55, P = 0.014). Some polymorphisms in ficolin genes associated with lower protein levels increased susceptibility to leprosy/HBV infection: FCN*1 (OR = 1.66, P = 0.029), FCN2*GGGCAC (OR = 6.73, P = 0.008), and FCN3*del_del_C (OR = 12.54, P = 0.037), and to lepromatous disease/HBV infection: FCN2*TA (OR = 2.5, P = 0.009), whereas FCN2*MAG was associated with increased FCN-2 expression and resistance against coinfection (OR = 0.29, P = 0.026). These associations were independent of demographic factors and did not increase susceptibility to leprosy per se, except MASP2*1C2-l. Associations for FCN2, FCN3, MASP1, MASP2, and VSIG4 variants were also independent of each other. In conclusion, polymorphisms compromising activation of the lectin pathway of complement increase susceptibility to HBV infection, with ficolin polymorphisms playing a major role in modulating the susceptibility among leprosy patients.