Nitric Oxide Synthase 2Lambaréné(G‐954C), Increased Nitric Oxide Production, and Protection against Malaria

Abstract

A point mutation in the promoter of the nitric oxide synthase 2 gene (NOS2), termed NOS2^Lambaréné (NOS2‐G954C), protects heterozygous carriers against severe malaria as effectively as the sickle cell trait. In a prospective longitudinal study, 841 individual infections of initially 200 children (151 wild‐type vs. 49 NOS2^Lambaréné carriers) were monitored for 4 years, to assess the rates of malarial attacks in the 2 groups; carriers of the NOS2^Lambaréné polymorphism were significantly less likely to experience malarial attacks than were others (P=.002). The distribution of the NOS2^Lambaréné polymorphism was investigated in malaria‐endemic areas. It was found to be present with the highest frequency in Africa and at a lower frequency in Asia. Ex vivo studies showed that cells isolated from people with this polymorphism have a 7‐fold higher baseline NOS activity, compared with the levels detected in cells from subjects with the wild‐type gene (P=.003).