Melissa J Blumenthal1, Charlotte Schutz2, Graeme Meintjes2, Zainab Mohamed3, Marc Mendelson4, Jon M Ambler5, Denise Whitby6, Romel D Mackelprang7, Sinead Carse1, Arieh A Katz1, Georgia Schäfer8. 1. Division of Medical Biochemistry and Structural Biology, Department of Integrative Biomedical Sciences, University of Cape Town, South Africa; Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa. 2. Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa; Wellcome Centre for Infectious Diseases Research in Africa, University of Cape Town, South Africa. 3. Division of Radiation Oncology, Department of Radiation Medicine, University of Cape Town, South Africa. 4. Division of Infectious Diseases & HIV Medicine, Department of Medicine, University of Cape Town, South Africa. 5. Computational Biology Group, Department of Integrative Biomedical Sciences, University of Cape Town, South Africa. 6. Viral Oncology Section, AIDS and Cancer Virus Program, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, NIH, USA. 7. University of Washington, USA. 8. Division of Medical Biochemistry and Structural Biology, Department of Integrative Biomedical Sciences, University of Cape Town, South Africa; Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa. Electronic address: georgia.schafer@uct.ac.za.
Abstract
BACKGROUND: To determine if variations exist in the KSHV host receptor EPHA2's coding region that affect KSHV infectivity and/or KS prevalence among South African HIV-infected patients. METHODS: A retrospective candidate gene association study was performed on 150 patients which were randomly selected from a total of 756 HIV-infected patients and grouped according to their KS status and KSHV serodiagnosis; namely group 1: KS+/KSHV+; group 2: KS-/KSHV+; group 3: KS-/KSHV-. Peripheral blood DNA was used to extract DNA and PCR amplify and sequence the entire EPHA2 coding region, which was compared to the NCBI reference through multiple alignment. RESULTS: 100% (95% CI 92.9-100%) of the KS positive patients, and 31.6% (95% CI 28.3-35.1%) of the KS negative patients were found to be KSHV seropositive. Aggregate variation across the entire EPHA2 coding region identified an association with KS (OR = 6.6 (95% CI 2.8, 15.9), p = 2.2 × 10-5). This was primarily driven by variation in the functionally important protein tyrosine kinase domain (Pkinase-Tyr; OR = 4.9 (95% CI 1.9, 12.4), p = 0.001) and the sterile-α-motif (SAM; OR = 13.8 (95% CI 1.7, 111.6), p = 0.014). Mutation analysis revealed two novel, non-synonymous heterozygous variants (c.2254 T > C: OR undefined, adj. p = 0.02; and c.2990 G > T: OR undefined, adj. p = 0.04) in Pkinase-Tyr and SAM, respectively, to be statistically associated with KS; and a novel heterozygous transition (c.2727C > T: OR = 6.4 (95% CI 1.4, 28.4), adj. p = 0.03) in Pkinase-Tyr to be statistically associated with KSHV. CONCLUSIONS: Variations in the KSHV entry receptor gene EPHA2 affected susceptibility to KSHV infection and KS development in a South African HIV-infected patient cohort.
RCT Entities:
BACKGROUND: To determine if variations exist in the KSHV host receptor EPHA2's coding region that affect KSHV infectivity and/or KS prevalence among South African HIV-infectedpatients. METHODS: A retrospective candidate gene association study was performed on 150 patients which were randomly selected from a total of 756 HIV-infectedpatients and grouped according to their KS status and KSHV serodiagnosis; namely group 1: KS+/KSHV+; group 2: KS-/KSHV+; group 3: KS-/KSHV-. Peripheral blood DNA was used to extract DNA and PCR amplify and sequence the entire EPHA2 coding region, which was compared to the NCBI reference through multiple alignment. RESULTS: 100% (95% CI 92.9-100%) of the KS positive patients, and 31.6% (95% CI 28.3-35.1%) of the KS negative patients were found to be KSHV seropositive. Aggregate variation across the entire EPHA2 coding region identified an association with KS (OR = 6.6 (95% CI 2.8, 15.9), p = 2.2 × 10-5). This was primarily driven by variation in the functionally important protein tyrosine kinase domain (Pkinase-Tyr; OR = 4.9 (95% CI 1.9, 12.4), p = 0.001) and the sterile-α-motif (SAM; OR = 13.8 (95% CI 1.7, 111.6), p = 0.014). Mutation analysis revealed two novel, non-synonymous heterozygous variants (c.2254 T > C: OR undefined, adj. p = 0.02; and c.2990 G > T: OR undefined, adj. p = 0.04) in Pkinase-Tyr and SAM, respectively, to be statistically associated with KS; and a novel heterozygous transition (c.2727C > T: OR = 6.4 (95% CI 1.4, 28.4), adj. p = 0.03) in Pkinase-Tyr to be statistically associated with KSHV. CONCLUSIONS: Variations in the KSHV entry receptor gene EPHA2 affected susceptibility to KSHV infection and KS development in a South African HIV-infectedpatient cohort.
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