ACP1 and human adaptability: Association with past malarial morbidity in the Sardinian population

Acid Phosphatase locus 1 (ACP1) is a polymorphic enzyme controlled by a loc us on chromosome 2 with three common codominant alleles: *A, *B, and *C. AC P1 shows two major isoforms, F and S. The ratio of their concentration diff ers markedly among genotypes. Two functions have been proposed for the enzy me: flavin-mononucleotide phosphatase and tyrosine phosphatase activity. An association between ACP1 polymorphism and past malarial morbidity in Sardi nia and the Po Valley has been described. Genetic polymorphisms could contr ibute to natural resistance or susceptibility to the disease. On the other hand, malaria pressure may select for genes that increase susceptibility to common diseases of modern civilization. Thus, the association between ACP1 and malaria in Sardinia in the light of recent understanding of the functi on of ACP1 and the molecular basis of malaria pathophysiology, especially a spects of the structure of band 3 protein (B3P) and the role of cytokines h ave been revisited. There is a significant negative correlation between ACP 1 S isoform concentration, directly related to the ACP1*C allele, and past malarial morbidity in Sardinia. Populations subjected in the past to a heav y malarial burden show, at present, a lower concentration of the S isoform compared to a nearby malaria-free population, suggesting that genotypes wit h high S isoform concentration have been subjected to negative selection in a malarial environment. Correlation analysis and analysis of the joint G-6 -PD/ACP1 distribution suggest that the relationship between past endemic ma laria and the S isoform has not been mediated by glucose-6-phosphate dehydr ogenase (G-6-PD) deficiency, thus pointing to a direct effect of malaria on ACP1. (C) 2001 Wiley-Liss, Inc.