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Throughout evolutionary history, malaria-induced natural selection has profoundly influenced human genetic evolution, leading to the emergence of numerous genetic variations that confer resistance to the disease. These adaptations highlight the complicated interplay between pathogens and human genetics. This review focuses on key genetic variations associated with malaria resistance, including hemoglobinopathies (such as sickle cell trait and thalassemia), glucose-6-phosphate dehydrogenase deficiency, blood group polymorphisms and genetic variants related to inflammation and immune regulation. The prevalence of these genetic adaptations varies widely across different geographic regions, reflecting the historical burden of malaria in those areas. Despite significant advancements in genetic research, the precise mechanisms by which these mutations confer protection against malaria remain incompletely understood. Furthermore, the interactions between these genetic factors and environmental influences add to another layer of complexity. A comprehensive understanding of these genetic variations and their functional implications is crucial for advancing malaria epidemiology, improving diagnostic tools, and developing targeted prevention and control strategies, ultimately contributing to global efforts to eradicate malaria.<\/jats:p>","DOI":"10.1186\/s12967-025-07017-w","type":"journal-article","created":{"date-parts":[[2025,9,24]],"date-time":"2025-09-24T15:32:13Z","timestamp":1758727933000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Human genetic variations conferring resistance to malaria"],"prefix":"10.1186","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-8645-9910","authenticated-orcid":false,"given":"Xiaokun","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunxing","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lan","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xi","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guoying","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9999-1411","authenticated-orcid":false,"given":"Yirong","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoan","family":"Yi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,9,24]]},"reference":[{"key":"7017_CR1","doi-asserted-by":"publisher","first-page":"2328","DOI":"10.1016\/S0140-6736(23)01249-7","volume":"402","author":"JR Poespoprodjo","year":"2023","unstructured":"Poespoprodjo JR, Douglas NM, Ansong D, Kho S, Anstey NM. 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