OSBPL10, RXRA and lipid metabolism confer African-ancestry protection against dengue haemorrhagic fever in admixed Cubans

Abstract

Ethnic groups can display differential genetic susceptibility to infectious diseases. The arthropod-born viral dengue disease is one such disease, with empirical and limited genetic evidence showing that African ancestry may be protective against the haemorrhagic phenotype. Global ancestry analysis based on high-throughput genotyping in admixed populations can be used to test this hypothesis, while admixture mapping can map candidate protective genes. A Cuban dengue fever cohort was genotyped using a 2.5 million SNP chip. Global ancestry was ascertained through ADMIXTURE and used in a fine-matched corrected association study, while local ancestry was inferred by the RFMix algorithm. The expression of candidate genes was evaluated by RT-PCR in a Cuban dengue patient cohort and gene set enrichment analysis was performed in a Thai dengue transcriptome. OSBPL10 and RXRA candidate genes were identified, with most significant SNPs placed in inferred weak enhancers, promoters and lncRNAs. OSBPL10 had significantly lower expression in Africans than Europeans, while for RXRA several SNPs may differentially regulate its transcription between Africans and Europeans. Their expression was confirmed to change through dengue disease progression in Cuban patients and to vary with disease severity in a Thai transcriptome dataset. These genes interact in the LXR/RXR activation pathway that integrates lipid metabolism and immune functions, being a key player in dengue virus entrance into cells, its replication therein and in cytokine production. Knockdown of OSBPL10 expression in THP-1 cells by two shRNAs followed by DENV2 infection tests led to a significant reduction in DENV replication, being a direct functional proof that the lower OSBPL10 expression profile in Africans protects this ancestry against dengue disease.

Dengue and Chikungunya among Febrile Outpatients in Kinshasa, Democratic Republic of Congo: a cross-sectional study

“…Importantly, neither DENV nor CHIKV was clinically suspected or was considered in the clinical differential diagnosis and 64.3% of patients were treated with at least one antibacterial drug, of whom almost one in six (11.7%) received dual or triple antimicrobial therapy. A possible explanation of the apparent absence of clinical and/or severe DENV cases in our study, but also in other African settings, is that African heritage genetically protects against severe DENV, more specifically the lower OSBPL10 expression profile in Africans is protective against viral hemorrhagic fever and dengue shock syndrome (31,32).…”

Population genetics-informed meta-analysis in seven genes associated with risk to dengue fever disease

“…As there are only hundreds of ancestral blocks, these tests have considerable lower statistical burdens than the traditional GWAS with thousands of SNPs. We took advantage of joined admixture-association studies and conducted work in Cuban [59] and Thai (Oliveira et al submitted) cohorts, mapping new candidate genes: lipid metabolism-related OSBPL10 and RXRA; and the already mentioned four genes involved in xenobiotic metabolism (CHST10, AHRR, GRIP1 and PPP2R5E) and…”

“…Lastly, the OAS family presented the lower sample sizes screened so far, and with the exceptions of a few individuals from India [35] and Cuba [59] typed for OAS1-rs10774671-G, the Thai cohorts from Simon-Loriere et al [36] dominate these meta-analyses. Notice that Simon-Loriere et al [36] did not provide controls, and in order to be consistent in our tests we included our Thai population screening as controls to compare with these Thai patient cohorts.…”

“…In this work, we applied population genetics-informed meta-analyses to evaluate the genetic risk/protection conferred by 10 SNPs across seven genes mostly associated with dengue in the literature (PLCE1, TNFA, DC-SIGN/CD209, OAS1, OAS3, FCGR2A/CD32 and MICB; Table 1). We surveyed the literature for case-control cohorts [25,26,27,29,30,35,36,38,40,42,43,44,48,49,53,54,55,56,57,58], took advantage of available datasets chip-genotyped ( [47,59]and Oliveira et al 2018), and added a few case-control cohorts of our own (mostly Cambodia, Vietnam and few Brazilian individuals).…”

CLEC5A: A Promiscuous Pattern Recognition Receptor to Microbes and Beyond

“…For example, migrant Chinese have a higher risk of severe dengue fever than local Chinese in Singapore (Xu et al 2018). Furthermore, African ethnicity has been identified as a protective factor for severe symptoms in Cuban dengue patients (Sierra et al 2017). Using data from the 1000 Genomes project, we screened the frequency of rs1285933 alleles of CLEC5A in the African, European, American, South Asian and East Asian populations.…”