Co-infection was indeed a strong predictor of inter-individual variability in antibody responses and highlighted significant and complex interactions between EBV and KSHV. virus alone is insufficient to cause disease, suggests other co-factors are involved. Here we present epidemiological analysis and genome-wide association study (GWAS) in 4365 individuals from an African population cohort, to assess the influence of host genetic and non-genetic factors on virus antibody responses. EBV/KSHV co-infection (OR?=?5.71(1.58C7.12)), HIV positivity (OR?=?2.22(1.32C3.73)) and living in a more rural area (OR?=?1.38(1.01C1.89)) are strongly associated with immunogenicity. GWAS reveals associations with KSHV antibody response in the region ((value thresholds of between 0.01 and 0.05, which failed to correct for multiple testing to declare association for variants Alizapride HCl in immunomodulatory genes with virus biological function, pathogenesis and tumourigenesis21C24. In addition, they had other limitations including, very small sample sizes (between 1 and 350 cases), failure to adjust for environmental factors such as co-infection with other pathogens, or Alizapride HCl confounding by strong associations with HIV and AIDS, and did not stratify controls by KSHV serostatus or include KSHV seronegative controls for comparison, and all lack replication in independent samples. Lastly, only two studies23,25 have been conducted in African populations. To overcome the limitations of previous studies and attempt to identify convincing associations with KSHV and EBV immune response traits, we assess systematic differences in >4000 individuals from an African population cohort, where both viruses Alizapride HCl are endemic, using socio-demographic and clinical data to assess intrinsic and environmental determinants of infection and then perform a GWAS using antibody responses as markers of infection. We use whole-genome sequence data, dense genotyping array data and imputation to a panel with African sequence data to identify genetic loci associated with both infections and attempt to replicate previously identified genetic loci in the context Alizapride HCl of the environment. Results Characteristics of samples in the Uganda General Population Cohort (GPC) To investigate the?seroprevalence of infections, we tested serum samples from 4365 individuals in the General Population Cohort (GPC) collected during medical survey round 22 (in 2011). The GPC is a population-based cohort in Kyamulibwa, rural south-west Uganda, comprising inhabitants of 25 Alizapride HCl neighbouring villages26. Participants were over the age of 13 years and belonged mainly (>70%) to the Baganda ethnolinguistic group. Villages were categorised according to urbanicity quartiles reflecting shared urban characteristics based on differences in economic activity, civil infrastructure, and availability of educational and healthcare services as previously described27, with 28% living in quartile 1 (very rural i.e. no educational facilities and no households with electricity) (Table?1). In this study, 91% of individuals were categorised as seropositive for EBV based on detectable IgG levels against either EBNA-1 or VCA28 and 91% categorised as seropositive for KSHV based on detectable IgG levels against either ORF73, K10.5 or K8.1?29,30 (Table?1). HIV infection seroprevalence in this study was 6.5%, Hepatitis C virus (HCV) seroprevalence was 3.7% and Hepatitis B virus (HBV) infection had the lowest seroprevalence among the pathogens examined at 2.9% (Table?1). Nearly 95% of participants, 4134 individuals, were infected with at least one of these viruses. The majority of participants, 2743 (63%) were seropositive to at least two of the viruses tested, 23 (0.5%) participants were seropositive for four viruses and 231 (5.3%) participants were seronegative for all viruses (Supplementary Fig.?1). Co-infection with KSHV and EBV was the most common with >95% of dually infected individuals (Supplementary Table?1.). Co-infections of other pathogens with EBV or KSHV was similarly frequent and mirrored the seroprevalence estimates seen in the cohort (Supplementary Table?1). Table 1 Characteristics of individuals in the GPC. the number of unique individuals. To investigate the inter-individual variation of IgG antibody responses marking different stages of the viral life cycles (latent vs lytic) to KSHV and EBV infections, distributions of antibody levels were determined to the latent (ORF73, K10.5, EBNA-1) KIAA0849 and lytic antigens (K8.1, VCA and EAD) in.
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