University of Oxford, Nuffield Department of Medicine, Oxford, United Kingdom.
Medical Research Council (UK), Fajara, The Gambia.
PLoS One. 2017 Nov 17;12(11):e0188307. doi: 10.1371/journal.pone.0188307. eCollection 2017.
Hepatocellular carcinoma (HCC) causes over 800,000 deaths worldwide annually, mainly in low income countries, and incidence is rising rapidly in the developed world with the spread of hepatitis B (HBV) and C (HCV) viruses. Natural Killer (NK) cells protect against viral infections and tumours by killing abnormal cells recognised by Killer-cell Immunoglobulin-like Receptors (KIR). Thus genes and haplotypes encoding these receptors may be important in determining both outcome of initial hepatitis infection and subsequent chronic liver disease and tumour formation. HBV is highly prevalent in The Gambia and the commonest cause of liver disease. The Gambia Liver Cancer Study was a matched case-control study conducted between September 1997 and January 2001 where cases with liver disease were identified in three tertiary referral hospitals and matched with out-patient controls with no clinical evidence of liver disease.
We typed 15 KIR genes using the polymerase chain reaction with sequence specific primers (PCR-SSP) in 279 adult Gambians, 136 with liver disease (HCC or Cirrhosis) and 143 matched controls. We investigated effects of KIR genotypes and haplotypes on HBV infection and associations with cirrhosis and HCC.
Homozygosity for KIR group A gene-content haplotype was associated with HBsAg carriage (OR 3.7, 95% CI 1.4-10.0) whilst telomeric A genotype (t-AA) was associated with reduced risk of e antigenaemia (OR 0.2, 95% CI 0.0-0.6) and lower viral loads (mean log viral load 5.2 vs. 6.9, pc = 0.022). One novel telomeric B genotype (t-ABx2) containing KIR3DS1 (which is rare in West Africa) was also linked to e antigenaemia (OR 8.8, 95% CI 1.3-60.5). There were no associations with cirrhosis or HCC.
Certain KIR profiles may promote clearance of hepatitis B surface antigen whilst others predispose to e antigen carriage and high viral load. Larger studies are necessary to quantify the effects of individual KIR genes, haplotypes and KIR/HLA combinations on long-term viral carriage and risk of liver cancer. KIR status could potentially inform antiviral therapy and identify those at increased risk of complications for enhanced surveillance.
肝细胞癌（HCC）每年在全球导致超过 80 万人死亡，主要发生在低收入国家，随着乙型肝炎（HBV）和丙型肝炎（HCV）病毒的传播，该疾病在发达国家的发病率迅速上升。自然杀伤（NK）细胞通过杀死被杀伤细胞免疫球蛋白样受体（KIR）识别的异常细胞来预防病毒感染和肿瘤。因此，编码这些受体的基因和单倍型可能在决定初始肝炎感染的结果以及随后的慢性肝病和肿瘤形成中起着重要作用。HBV 在冈比亚非常普遍，是肝病最常见的原因。冈比亚肝癌研究是一项在 1997 年 9 月至 2001 年 1 月期间进行的匹配病例对照研究，在三家三级转诊医院中确定了患有肝病的病例，并与没有临床肝脏疾病证据的门诊对照病例相匹配。
我们使用聚合酶链反应与序列特异性引物（PCR-SSP）在 279 名冈比亚成年人中对 15 种 KIR 基因进行了分型，其中 136 名患有肝病（HCC 或肝硬化），143 名匹配的对照。我们研究了 KIR 基因型和单倍型对 HBV 感染的影响，并探讨了其与肝硬化和 HCC 的关联。
KIR 组 A 基因含量单倍型的纯合性与 HBsAg 携带相关（OR3.7，95%CI1.4-10.0），而端粒 A 基因型（t-AA）与 e 抗原血症减少相关（OR0.2，95%CI0.0-0.6）和病毒载量降低（平均对数病毒载量 5.2 与 6.9，pc=0.022）。一种新型端粒 B 基因型（t-ABx2）包含 KIR3DS1（在西非很少见），也与 e 抗原血症相关（OR8.8，95%CI1.3-60.5）。与肝硬化或 HCC 无关。
某些 KIR 特征可能促进清除乙型肝炎表面抗原，而其他特征则易发生 e 抗原携带和高病毒载量。需要进行更大的研究来量化个体 KIR 基因、单倍型和 KIR/HLA 组合对长期病毒携带和肝癌风险的影响。KIR 状态可能有助于指导抗病毒治疗，并确定那些因增强监测而增加并发症风险的患者。
