INTERPLAY BETWEEN PROMOTER AND STRUCTURAL GENE VARIANTS CONTROL BASALSERUM LEVEL OF MANNAN-BINDING PROTEIN

Mannan-binding protein (MBP) is a serum lectin participating in the in nate immune defense by opsonizing various microorganisms for phagocyto sis. Opsonization defect due to MBP deficiency and low levels of the p rotein can partially be explained by the dominant effect of three diff erent mutations in the structural part of the MBP gene. Large interrac ial differences in the frequencies of these variants have previously b een described, but they cannot explain the large interindividual varia tion in MBP serum concentration. We describe the existence of addition al polymorphisms at positions -550 (H/L variants) and -221 (X/Y varian ts) in the promoter region of the gene. The promoter haplotypes, HY, L Y, and LX, show associations with high, medium, and low levels of MBP serum concentrations, respectively. Moreover, this represents a geneti c system with additive effect of haplotypes in which a low producing L X haplotype in the homozygous state down-regulates the basal expressio n of MBP as effectively as a single structural variant. Populations of pure Eskimos, Caucasoids, and black Africans show marked interethnic differences in the frequencies of promoter haplotypes regulating the e xpression of the normal peptide, with the HY haplotype frequency varyi ng from 0.83 in Eskimos via 0.33 in Caucasoids to 0.08 in Africans. Th e LY haplotype frequency varies from; 0.04 in Eskimos via 0.39 in Cauc asoids to 0.23 in Africans. The LX haplotype frequency varies from 0.0 3 in Eskimos via 0.24 in Caucasoids to 0.23 in Africans. The effect of the promoter variants can explain almost all of the ethnic difference s not explainable by the structural variants alone.