RESUMO
OBJECTIVES: Genes of host immunity play an important role in disease pathogenesis and are determinants of clinical courses of infections, including hepatitis B virus (HBV). Killer-cell immunoglobulin-like receptor (KIR), expressed on the surface of natural killer cells (NK), regulate NK cell cytotoxicity by interacting with human leukocyte antigen (HLA) class I molecules and are candidates for influencing the course of HBV. This study evaluated whether variations in KIR gene content and HLA-C ligands are associated with HBV and with the development of liver cirrhosis and hepatocellular carcinoma. METHODS: A Vietnamese study cohort (HBV n = 511; controls n = 140) was genotyped using multiplex sequence-specific polymerase chain reaction (PCR-SSP) followed by melting curve analysis. RESULTS: The presence of the functional allelic group of KIR2DS4 was associated with an increased risk of chronic HBV (OR = 1.86, pcorr = 0.02), while KIR2DL2+HLA-C1 (OR = 0.62, pcorr = 0.04) and KIR2DL3+HLA-C1 (OR = 0.48, pcorr = 0.04) were associated with a decreased risk. The pair KIR2DL3+HLA-C1 was associated with liver cirrhosis (OR = 0.40, pcorr = 0.01). The presence of five or more activating KIR variants was associated with hepatocellular carcinoma (OR = 0.53, pcorr = 0.04). CONCLUSIONS: KIR gene content variation and combinations KIR-HLA influence the outcome of HBV infection.
Assuntos
Vírus da Hepatite B/fisiologia , Hepatite B Crônica/genética , Receptores KIR2DL2/genética , Receptores KIR2DL3/genética , Receptores KIR/genética , Adulto , Idoso , Alelos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/virologia , Estudos de Coortes , Feminino , Variação Genética , Genótipo , Antígenos HLA-C/genética , Antígenos HLA-C/imunologia , Vírus da Hepatite B/genética , Vírus da Hepatite B/imunologia , Hepatite B Crônica/imunologia , Hepatite B Crônica/virologia , Humanos , Cirrose Hepática/genética , Cirrose Hepática/imunologia , Cirrose Hepática/virologia , Masculino , Pessoa de Meia-Idade , Receptores KIR/imunologia , Receptores KIR2DL2/imunologia , Receptores KIR2DL3/imunologia , Vietnã , Adulto JovemRESUMO
Even though immunoglobulins are critical for immune responses and human survival, the diversity of the immunoglobulin heavy chain gene (IGH) is poorly known and mostly characterized only by serological methods. Moreover, this genomic region is not well-covered in genomic databases and genome-wide association studies due to particularities that impose technical difficulties for its analysis. Therefore, the IGH gene has never been systematically sequenced across populations. Here, we deliver an unprecedented and comprehensive characterization of the diversity of the IGHG1, IGHG2, and IGHG3 gene segments, which encode the constant region of the most abundant circulating immunoglobulins: IgG1, IgG2, and IgG3, respectively. We used Sanger sequencing to analyze 357 individuals from seven different Brazilian populations, including five Amerindian, one Japanese-descendant and one Euro-descendant population samples. We discovered 28 novel IGHG alleles and provided evidence that some of them may have been originated by gene conversion between common alleles of different gene segments. The rate of synonymous substitutions was significantly higher than the rate of the non-synonymous substitutions for IGHG1 and IGHG2 (p = 0.01 and 0.03, respectively), consistent with purifying selection. Fay and Wu's test showed significant negative values for most populations (p < 0.001), which indicates that positive selection in an adjacent position may be shaping IGHG variation by hitchhiking of variants in the vicinity, possibly the regions that encode the Ig variable regions. This study shows that the variation in the IGH gene is largely underestimated. Therefore, exploring its nucleotide diversity in populations may provide valuable information for comprehension of its evolution, its impact on diseases and vaccine research.
Assuntos
Alelos , Conversão Gênica , Genes de Cadeia Pesada de Imunoglobulina , Variação Genética , Genética Populacional , Cadeias gama de Imunoglobulina/genética , Seleção Genética , Brasil/epidemiologia , Frequência do Gene , Geografia , Haplótipos , Humanos , Alótipos Gm de Imunoglobulina/genética , Desequilíbrio de Ligação , Polimorfismo de Nucleotídeo ÚnicoRESUMO
We here describe the KIR gene-content genotypes in the highly admixed population from Ilhéus, a city located in Bahia State, Northeast Brazil. Bahia is the State with the largest contribution of African ethnicity in comparison to other Brazilian areas and this is the first report of a population from this region. A total of 32 KIR gene-content genotypes have been found, from which 18 were observed in single individuals. The distinct KIR gene-content distribution observed in Ilhéus, along with the elevated diversity of genotypes point to importance of describing KIR polymorphism in unique populations from Brazil.
