Laboratory of Human Molecular Genetics, Postgraduate Program in Genetics, Department of Genetics, Federal University of Paraná, Curitiba, Brazil.
Laboratory of Molecular Immunopathology, Postgraduate Program in Internal Medicine and Health Sciences, Department of Clinical Pathology, Hospital de Clínicas, Federal University of Paraná, Curitiba, Brazil.
Front Immunol. 2021 Feb 11;11:574457. doi: 10.3389/fimmu.2020.574457. eCollection 2020.
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 (, ) encoding components of the lectin pathway, and two genes encoding complement receptors () 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: (OR = 3.4, p = 0.02), (OR = 4.0, p = 0.015) and (OR = 5.4, p = 0.03). Conversely, haplotype, associated with higher gene expression, was protective (OR = 0.56, P = 0.033). Other haplotypes associated with HBV susceptibility were: (OR = 19.25, P = 0.003), (OR = 2.65, P = 0.011) and (OR = 12.55, P = 0.014). Some polymorphisms in ficolin genes associated with lower protein levels increased susceptibility to leprosy/HBV infection: (OR = 1.66, P = 0.029), (OR = 6.73, P = 0.008), and (OR = 12.54, P = 0.037), and to lepromatous disease/HBV infection: (OR = 2.5, P = 0.009), whereas 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 , except . Associations for , and 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.
数千例麻风病患者不仅遭受身体畸形，而且还患有或曾经患有乙型肝炎病毒（HBV）合并感染。补体系统的多态性调节麻风病的易感性，但对过去或现在 HBV 感染的遗传易感性尚不清楚。我们使用测序和多重序列特异性 PCR 对 190 例患者的七个基因（、）编码补体系统成分的 72 个多态性和两个编码补体受体（）的基因进行基因分型，其中 74 例 HBsAg 和/或抗-HBc 阳性（HBV+，93.2%为已解决的感染），116 例瘤型麻风病患者和 408 例 HBV 献血者。此外，我们还检测了凝集素途径蛋白的水平。我们发现，在多达 167 例 HBV+和 HBV-患者中，ELISA 或 TRIFMA 测量的甘露聚糖结合凝集素（MBL）、MBL 相关丝氨酸蛋白酶（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 激活的血清浓度之间没有差异。降低蛋白水平或编码功能失调蛋白的单倍型增加 HBV 感染易感性：（OR=3.4，p=0.02），（OR=4.0，p=0.015）和（OR=5.4，p=0.03）。相反，与更高基因表达相关的单倍型是保护性的（OR=0.56，P=0.033）。与 HBV 易感性相关的其他单倍型包括：（OR=19.25，P=0.003），（OR=2.65，P=0.011）和（OR=12.55，P=0.014）。与 ficolin 基因相关的一些与低蛋白水平相关的多态性增加了麻风病/HBV 感染的易感性：（OR=1.66，P=0.029），（OR=6.73，P=0.008）和（OR=12.54，P=0.037），以及瘤型麻风病/HBV 感染的易感性：（OR=2.5，P=0.009），而（OR=0.29，P=0.026）与 FCN-2 表达增加和对合并感染的抵抗力有关。这些关联独立于人口统计学因素，并且除了之外，不会增加麻风病的易感性。与和的变体相关的关联彼此也独立。总之，补体凝集素途径激活的多态性降低增加了 HBV 感染的易感性，ficolin 多态性在调节麻风病患者的易感性方面起着主要作用。
