KIR content genotypes associate with carriage of hepatitis B surface antigen, e antigen and HBV viral load in Gambians

Abstract

BackgroundHepatocellular 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.MethodsWe 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.ResultsHomozygosity 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.ConclusionCertain 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.

Insights into the interplay between KIR gene frequencies and chronic HBV infection in Burkina Faso

“…In the Gambia, a study showed that carriers of the KIR3DS1 gene were HBV-positive and had a high viral load while KIR2DL3 gene carriers had a low HBV viral load. 33 Genotypes and haplotypes containing more activator genes would play an essential role in chronic infection or elimination of HBV. 47 Combinations of KIR genes and HLA molecules are associated with the development of hepatocellular carcinoma in patients infected with chronic hepatitis B virus.…”

“… 32 Only one study has been conducted in West Africa and showed that Gambian carriers for the KIR3DS1 gene had a high risk of being positive for HBeAg as well as carrying a high HBV viral load, while KIR2DL3 gene carriers had low viral load. 33 In Burkina Faso, there are no reports on the association between the KIR gene frequencies and chronic carriage of HBV. Therefore, our pilot study sought to assess the interplay between the KIR gene frequencies and chronic HBV infection in the population of Burkina Faso and to identify which genes are strongly correlated to the risk of developing CHB.…”

KIR/HLA ligands immunogenetics markers associated with outcome of hepatitis B virus infection in the Bulgarian population

“…Consequently, the functional activity of KIRs and the activating or inhibiting signals which they transmit would be dependent on the KIRs/KIR HLA class I ligands genotype of the individual. Recently, considerable data from case-control studies demonstrate the hypothetical role of KIRs and their HLA ligands as genetic factors involved in viral clearance 4,5,[13][14][15][16][17][18][19][20][21] .…”

Association analysis of KIR/HLA genotype with liver cirrhosis, hepatocellular carcinoma, and NUC freedom in chronic hepatitis B patients

“…We earlier demonstrated that KIR/HLA receptor-ligand combinations were associated with chronic liver disease progression and HCC development in HCV-infected patients 16 , 17 . However, no reports have addressed such associations in Japanese patients with HBV to date even though a few studies suggested such associations in other ethnicities 18 , 19 .…”