Abstract
BackgroundMalaria is one of the most serious infectious diseases in the world. The malaria burden is greatly affected by human immunity, and immune responses vary between populations. Genetic diversity in KIR and HLA-C genes, which are important in immunity to infectious diseases, is likely to play a role in this heterogeneity. Several studies have shown that KIR and HLA-C genes influence the immune response to viral infections, but few studies have examined the role of KIR and HLA-C in malaria infection, and these have used low-resolution genotyping. The aim of this study was to determine whether genetic variation in KIR and their HLA-C ligands differ in Ugandan populations with historically varied malaria transmission intensity using more comprehensive genotyping approaches.MethodsHigh throughput multiplex quantitative real-time PCR method was used to genotype KIR genetic variants and copy number variation and a high-throughput real-time PCR method was developed to genotype HLA-C1 and C2 allotypes for 1344 participants, aged 6 months to 10 years, enrolled from Ugandan populations with historically high (Tororo District), medium (Jinja District) and low (Kanungu District) malaria transmission intensity.ResultsThe prevalence of KIR3DS1, KIR2DL5, KIR2DS5, and KIR2DS1 genes was significantly lower in populations from Kanungu compared to Tororo (7.6 vs 13.2%: p = 0.006, 57.2 vs 66.4%: p = 0.005, 33.2 vs 46.6%: p < 0.001, and 19.7 vs 26.7%: p = 0.014, respectively) or Jinja (7.6 vs 18.1%: p < 0.001, 57.2 vs 63.8%: p = 0.048, 33.2 vs 43.5%: p = 0.002, and 19.7 vs 30.4%: p < 0.001, respectively). The prevalence of homozygous HLA-C2 was significantly higher in populations from Kanungu (31.6%) compared to Jinja (21.4%), p = 0.043, with no significant difference between Kanungu and Tororo (26.7%), p = 0.296.ConclusionsThe KIR3DS1, KIR2DL5, KIR2DS5 and KIR2DS1 genes may partly explain differences in transmission intensity of malaria since these genes have been positively selected for in places with historically high malaria transmission intensity. The high-throughput, multiplex, real-time HLA-C genotyping PCR method developed will be useful in disease-association studies involving large cohorts.
Highlights
Malaria is one of the most serious infectious diseases in the world
Study samples and populations Samples from cohorts enrolled at 3 sites in Uganda were utilized, that is, Nagongera Sub-county in Tororo District, a rural area in southeastern Uganda with historically high malaria transmission intensity; Walukuba Sub-county in Jinja District, a peri-urban area near the city of Jinja in south-central Uganda with historically moderate malaria transmission intensity; and Kihihi Subcounty in Kanungu District, a rural area in southwestern Uganda with historically low malaria transmission intensity
The aim of this study was to determine whether KIR and HLA-C genetic variants and copy number variation (CNV) in KIR genes from 3 populations of Uganda with historically varied malaria transmission intensity have been shaped by selection pressure from falciparum malaria
Summary
The malaria burden is greatly affected by human immunity, and immune responses vary between populations. The aim of this study was to determine whether genetic variation in KIR and their HLA-C ligands differ in Ugandan populations with historically varied malaria transmission intensity using more comprehensive genotyping approaches. Red blood cell alterations are the most studied genetic abnormalities that impact on malaria [2]. These include mutations in the alpha- and beta-globin genes that lead to sickle cell anaemia or thalassemias, glucose-6-phosphate dehydrogenase (G6PD) deficiency and the Duffy antigen protein [3]. 3 haemoglobin variants (HbS, HbC, and HbE) appear to confer protection against malaria in different parts of the world [6]. The HbS allele is common in Africa, but rare in Southeast Asia, and the opposite is true for the HbE allele [7, 8]
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