{"doi":"10.1016/j.ijid.2023.02.008","title":"The effect of interleukin-6 signaling on severe malaria: A Mendelian randomization analysis","abstract":"OBJECTIVES: Severe malaria remains a deadly disease for many young children in low- and middle-income countries. Levels of interleukin (IL)-6 have been shown to identify cases of severe malaria and associate with severity, but it is unknown if this association is causal. METHODS: A single nucleotide polymorphism (SNP; rs2228145) in the IL-6 receptor was chosen as a genetic variant that is known to alter IL-6 signaling. We tested this, then took this forward as an instrument to perform Mendelian randomization (MR) in MalariaGEN, a large cohort study of patients with severe malaria at 11 worldwide sites. RESULTS: In MR analyses using rs2228145, we did not identify an effect of decreased IL-6 signaling on severe malaria (odds ratio 1.14, 95% confidence interval 0.56-2.34, P = 0.713). The estimates of the association with any severe malaria subphenotype were similarly null, although with some imprecision. Further analyses using other MR approaches had similar results. CONCLUSION: These analyses do not support a causal role for IL-6 signaling in the development of severe malaria. This result suggests IL-6 may not be causal for severe outcomes in malaria, and that therapeutic manipulation of IL-6 is unlikely to be a suitable treatment for severe malaria.","journal":"International Journal of Infectious Diseases","year":2023,"id":347444,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":11,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9664,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":614742,"name":"Ruth E. Mitchell","orcid":"0000-0002-3506-160X","position":1,"is_corresponding":false},{"id":998214,"name":"Andrei‐Emil Constantinescu","orcid":"0000-0002-7974-5245","position":2,"is_corresponding":false},{"id":94945,"name":"David A. Hughes","orcid":"0000-0002-9644-8998","position":3,"is_corresponding":false},{"id":269827,"name":"Aubrey J. Cunnington","orcid":"0000-0002-1305-3529","position":4,"is_corresponding":false},{"id":6364,"name":"Peter Ghazal","orcid":"0000-0003-0035-2228","position":5,"is_corresponding":false},{"id":42602,"name":"Nicholas J. Timpson","orcid":"0000-0002-7141-9189","position":6,"is_corresponding":false},{"id":805322,"name":"Fergus Hamilton","orcid":"0000-0002-9760-4059","position":0,"is_corresponding":true}],"reference_count":40,"raw_metadata":null,"created_at":"2026-07-19T01:11:57.720122Z","pmid":"36801374","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}