Stephen Tukwasibwe1,2, James A Traherne3, Olympe Chazara3,4, Jyothi Jayaraman3,4, John Trowsdale3, Ashley Moffett3,4, Wei Jiang3, Joaniter I Nankabirwa1,2, John Rek2, Emmanuel Arinaitwe2, Samuel L Nsobya1,2, Maxine Atuheirwe1, Mubiru Frank1, Anguzu Godwin1, Prasanna Jagannathan5, Stephen Cose6, Moses R Kamya1,2, Grant Dorsey7, Philip J Rosenthal7, Francesco Colucci4,8, Annettee Nakimuli9. 1. Department of Obstetrics and Gynaecology, School of Medicine, Makerere University College of Health Sciences, P.O BOX 7072, Kampala, Uganda. 2. Infectious Diseases Research Collaboration, 2C Nakasero Hill Road, Kampala, Uganda. 3. Department of Pathology, University of Cambridge, Cambridge, UK. 4. University of Cambridge Centre for Trophoblast Research, Cambridge, UK. 5. Stanford University, School of Medicine, Stanford, USA. 6. MRC/UVRI and LSHTM Uganda Research Unit, Kampala, Uganda. 7. University of California, San Francisco, USA. 8. Department of Obstetrics & Gynaecology, University of Cambridge, National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, CB2 0SW, UK. 9. Department of Obstetrics and Gynaecology, School of Medicine, Makerere University College of Health Sciences, P.O BOX 7072, Kampala, Uganda. annettee.nakimuli@gmail.com.
Abstract
BACKGROUND: Malaria 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. METHODS: High 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. RESULTS: The 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. CONCLUSIONS: The 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.
BACKGROUND: Malaria 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. METHODS: High 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. RESULTS: The 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. CONCLUSIONS: The 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.
Authors: Vivien Béziat; James A Traherne; Lisa L Liu; Jyothi Jayaraman; Monika Enqvist; Stella Larsson; John Trowsdale; Karl-Johan Malmberg Journal: Blood Date: 2013-05-01 Impact factor: 22.113
Authors: Mary Carrington; Sophia Wang; Maureen P Martin; Xiaojiang Gao; Mark Schiffman; Jie Cheng; Rolando Herrero; Ana Cecilia Rodriguez; Robert Kurman; Rodrigue Mortel; Peter Schwartz; Andrew Glass; Allan Hildesheim Journal: J Exp Med Date: 2005-04-04 Impact factor: 14.307
Authors: Paul J Norman; Jill A Hollenbach; Neda Nemat-Gorgani; Lisbeth A Guethlein; Hugo G Hilton; Marcelo J Pando; Kwadwo A Koram; Eleanor M Riley; Laurent Abi-Rached; Peter Parham Journal: PLoS Genet Date: 2013-10-31 Impact factor: 5.917
Authors: R Biassoni; M Falco; A Cambiaggi; P Costa; S Verdiani; D Pende; R Conte; C Di Donato; P Parham; L Moretta Journal: J Exp Med Date: 1995-08-01 Impact factor: 14.307