Killer Immunoglobulin-Like Receptor (KIR) Centromeric-AA Haplotype Is Associated with Ethnicity and Tuberculosis Disease in a Canadian First Nations Cohort

et al. (2013) Killer Immunoglobulin-Like Receptor (KIR) Centromeric-AA Haplotype Is Associated with Ethnicity and Tuberculosis Disease in a Canadian First Nations Cohort. PLoS ONE 8(7): e67842. doi:10.1371/journal.pone.0067842 Killer Immunoglobulin-Like Receptor (KIR) Centromeric- AA Haplotype Is Associated with Ethnicity and Tuberculosis Disease in a Canadian First Nations Cohort Kali Braun 0 Linda Larcombe 0 Pamela Orr 0 Peter Nickerson 0 Joyce Wolfe 0 Meenu Sharma 0 Johan K. Sandberg, Karolinska Institutet, Sweden 0 1 Department of Medical Microbiology, University of Manitoba , Winnipeg, Manitoba , Canada , 2 Department of Internal Medicine, University of Manitoba , Winnipeg, Manitoba , Canada , 3 National Reference Centre for Mycobacteriology, Public Health Agency of Canada , Winnipeg, Manitoba , Canada Killer immunoglobulin-like receptors (KIR) on natural killer (NK) cells interact with other immune cells to monitor the immune system and combat infectious diseases, such as tuberculosis (TB). The balance of activating and inhibiting KIR interactions helps determine the NK cell response. In order to examine the enrichment or depletion of KIRs as well as to explore the association between TB status and inhibitory/stimulatory KIR haplotypes, we performed KIR genotyping on samples from 93 Canadian First Nations (Dene, Cree, and Ojibwa) individuals from Manitoba with active, latent, or no TB infection, and 75 uninfected Caucasian controls. There were significant differences in KIR genes between Caucasians and First Nations samples and also between the First Nations ethnocultural groups (Dene, Cree, and Ojibwa). When analyzing ethnicity and tuberculosis status in the study population, it appears that the KIR profile and centromeric haplotype are more predictive than the presence or absence of individual genes. Specifically, the decreased presence of haplotype B centromeric genes and increased presence of centromeric-AA haplotypes in First Nations may contribute to an inhibitory immune profile, explaining the high rates of TB in this population. - Funding: No specific funding was sought for this project. Kali Braun is Dr. Sharmas graduate student and was funded by a graduate student stipend from the University of Manitoba. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. Natural killer (NK) cells bridge the innate and adaptive immune response to infection by the production of cytokines [1]. The activity of NK cells is controlled by a balance of inhibitory and stimulatory signals generated when a ligand binds to a killer immunoglobulin-like receptor (KIR) on the NK cell surface. The interaction of KIR and self-human leukocyte antigen (HLA) class I allows NK cells to identify and inhibit immune responses to normally functioning cells. Inhibitory KIRs contain an immunoreceptor tyrosine-based inhibition motif (ITIM) which interacts with a phosphatase, preventing phosphorylation of the activation cascade (NK cell cytotoxicity and cytokine release). Activating KIRs lack ITIMs but interact with a signalling adaptor that contains an immunoreceptor tyrosine-based activation motif (ITAM) that interacts with a kinase, allowing progression of the activation cascade [2]. When the stimulatory interactions overcome the inhibitory interactions, the outcome is NK cell cytotoxicity resulting in cytokine release [1], which plays a significant role in the immune response to infectious diseases such as tuberculosis (TB) [3]. KIR genes are highly variable in nature due to both polygenic and multi-allelic polymorphisms [1]. KIR genes have a high level of sequence similarity leading to a predisposition for homologous recombination, explaining the expansion and contraction of the KIR locus [4]. Genetic susceptibility or resistance to infectious disease has been highly correlated with ethnicity, which in conjunction with host risk factors, can determine disease progression [58]. The KIR diversity, as well as activating/ inhibiting balance of KIR genes, contributes to distinct disease outcomes between ethnic populations. For example, KIR2DL3 has been found to be significantly more prevalent in Lebanese and Mexican TB patients compared to control populations without TB [9,10]. Distinct outcomes of immune-regulated diseases are primarily due to differential expression of cytokines between different populations such as Caucasians, First Nations, and other ethnicities. Tuberculosis is caused by infection with the bacterium Mycobacterium tuberculosis, spread by airborne particles generated by an infectious person [11]. It is the inability of the infected macrophage to contain the M. tuberculosis that is fundamental to the pathogenesis of TB. Approximately 90% of infected nonimmunosuppressed individuals never develop active disease, while up to 10% may develop disease at some point during their lifetime [11,12]. Latent TB infection (LTBI) refers to the condition in which M. tuberculosis remains viable in the macrophage but retains only a small amount of metabolic activity [13]. LTBI has historically been captured as exposed or unexposed, as compared to a gradient or degree of exposure [14]. Current evidence suggests LTBI may be better explained as a spectrum of disease correlating to degree, duration, and proximity of exposure [14]. The World Health Organization estimated the global prevalence of LTBI at 33%, with 9.2 million new cases of TB in 2010 Number of Isolates (%) n = 75 Female 50 (67.7) n = 63 n = 19 34 (54.0) 8 (42.1) 29 (46.0) 11 (57.9) 19 (30.1) 1 (5.3) 24 (38.1) 14 (73.7) 17 (27.0) 5 (26.3) 10 (15.9) 4 (21.1) 15 (23.8) 4 (21.1) n = 11 Disease Status No TB 38 (60.3) 11 (57.9) (128/100,000 population) [15]. In the same year, 1.1 million people died of TB. Canada reported 1577 new active cases of TB (4.6/100,000) in 2010 [16]. The incidence of TB in Manitoba in 2010 was 10.7/100,000, with a disproportionate incidence in Canadian born Aboriginal (First Nations, Metis, and Inuit) peoples (39.8/100,000) compared with Canadian born non-Aboriginal peoples (1.6/100,000) [16]. The overall incidence of TB on First Nations reserve communities (including those of the Dene, Cree, and Ojibwa ethnocultural groups) in the Canadian province of Manitoba reached 58.3/100,000 in 2010 [16]. Rates of TB in certain Manitoba First Nations communities exceeds 400/100,000 [1719]. The determinants of TB in Canadian First Nations peoples include those associated with host virulence [17,20], host susceptibility [21,22] and social/environmental factors [23]. The discovery of an unexpected level of diversity within the KIR genes has led to a search for their role in human disease [4]. The presence or absence of KIR genes may be associated with tuberculosis status (active disease, latent disease, uninfected) as well as ethnicity of an individual [9,10,24] (...truncated)