Causal effect of severe and non‐severe malaria on dyslipidemia in African Ancestry individuals: A Mendelian randomization study

Abstract Background Dyslipidemia is becoming prevalent in Africa, where malaria is endemic. Observational studies have documented the long‐term protective effect of malaria on dyslipidemia; however, these study designs are prone to confounding. Therefore, we used Mendelian randomization (MR, a method robust to confounders and reverse causation) to determine the causal effect of severe malaria (SM) and the recurrence of non‐severe malaria (RNM) on lipid traits. Method We performed two‐sample MR using genome wide association study (GWAS) summary statistics for recurrent non‐severe malaria (RNM) from a Benin cohort ( N = 775) and severe malaria from the MalariaGEN dataset ( N = 17,000) and lipid traits from summary‐level data of a meta‐analyzed African lipid GWAS (MALG, N = 24,215) from the African Partnership for Chronic Disease Research (APCDR) ( N = 13,612) and the Africa Wits‐IN‐DEPTH partnership for genomics studies (AWI‐Gen) dataset ( N = 10,603). Result No evidence of significant causal association was obtained between RNM and high‐density lipoprotein cholesterol (HDL‐C), low‐density lipoprotein cholesterol (LDL‐C), total cholesterol and triglycerides. However, a notable association emerged between severe malarial anaemia (SMA) which is a subtype of severe malaria and reduced HDL‐C levels, suggesting a potential subtype‐specific effect. Nonetheless, we strongly believe that the small sample size likely affects our estimates, warranting cautious interpretation of these results. Conclusion Our findings challenge the hypothesis of a broad causal relationship between malaria (both severe and recurrent non‐severe forms) and dyslipidemia. The isolated association with SMA highlights an intriguing area for future research. However, we believe that conducting larger studies to investigate the connection between malaria and dyslipidemia in Africa will enhance our ability to better address the burden posed by both diseases.