Concerning the KIR gene frequencies reported by Dr Araujo et al.

Killer cell immunoglobulin-like receptors (KIRs) are transmembrane glycoproteins expressed by natural killer cells and subsets of T cells. The KIR genes are polymorphic, highly homologous and found in a cluster on chromosome 19q13.4 within the 1 Mb leukocyte receptor complex. The gene content of the KIR gene cluster varies among haplotypes, although several framework genes are found in all haplotypes (including KIR3DL3, KIR3DP1, KIR2DL4 and KIR3DL2). In spite of the extended diversity of the KIR genomic region, these four framework loci are nearly ubiquitous in the population, and the pseudogene (KIR3DP1) is not expressed.¹

In the article published by Araujo et al. in Cellular and Molecular Immunology,² the authors investigated the interaction between KIR genes and their human leukocyte antigen ligands in order to understand the mechanisms involved in the susceptibility or resistance to hepatitis B virus (HBV) infection. They used 20 individuals with occult HBV infection, 40 spontaneous HBV resolvers, 42 HBV carriers and 80 healthy blood donors recruited from the COLSAN blood bank (Associação Beneficente de Coleta de Sangue, São Paulo, Brazil). However, we have concerns about the gene frequencies found in those populations, especially for the well-defined haplotype including the framework genes KIR3DL3, KIR3DP1, KIR2DL4 and KIR3DL2. The frequencies of these genes, published by Araujo et al., were lower than those found in the Allele Frequency Database (http://www.allelefrequencies.net/) in different populations. Taking the healthy blood donors, a control group, as an example, the gene frequencies were 41.2% (vs 99–100%, the range found in databases from different worldwide populations) for KIR3DL3, 51.2% (vs 86–100%) for KIR3DP1, 46.2% (vs 95–100%) for KIR2DL4 and 45.0% (vs 95.7–100%) for KIR3DL2. The same was also observed for other genes, including KIR2DP1 (50.0% vs 80–100%) and KIR2DS4 (43.7% vs 80–100%). Highlighting the framework genes and healthy blood donors, the distribution of KIR gene frequencies found by the authors² seems to be inconsistent with those published in the literature. We believe that this remarkable difference is not justified. Brazilians are an admixed population presenting differences in genetic characteristics and geographic distribution. Even when considering this fact, the KIR distribution was similar in different studies (also included in the allele frequency database), as published by our research group on a population from Southern Brazilian (Paraná).³ Perce-da-Silva et al.⁴ published a study on a population from Northern Brazil in which 377 randomly selected unrelated individuals from rural communities, descendants of Amazon Amerindians, European settlers and Sub-Saharan Africans displayed framework gene frequencies equal to 100% for all groups. Supporting the allele frequency database, Hollenbach et al.⁵ presented the data at the 15th International Histocompatibility Workshop on KIR loci distribution in 27 populations worldwide from six broad ethnic groups, including two from Brazil. The range of frequency distributions was the same for the framework genes (76–100%).

Underlying the diversity of the KIR genomic region, it has been accepted that there are patterns that appear conserved within the population, such as the regular spacing of KIR genes 2.4 kb between each other, and the presence of the framework genes KIR3DL3 and KIR3DL2 at the terminus of the region with KIR2DL4 in the middle.⁶ Strong linkage disequilibrium was observed in the centromeric and telomeric regions, but not between them. Therefore, there have been descriptions for the two main haplotype groups, A and B, found within the population.^{7, 8} Haplotype A is well defined and comprises a common complement of KIR genes KIR3DL3, -2DL3, -2DL1, -2DL4, -3DL1, -2DS4 and -3DL2 with an estimated frequency of 47–59% within the Caucasian population. In contrast, although haplotype B has limited definition due to higher variability, it has been observed that its genotypes contain more activating receptor genes.