title: Theodore E. Woodward Award: lactase persistence SNPs in African populations regulate promoter activity in intestinal cell culture.
abstract: Lactase-phlorizin hydrolase, lactase, is the intestinal enzyme responsible for the digestion of the milk sugar lactose. The majority of the world's human population experiences a decline in expression of the lactase gene by late childhood (lactase non-persistence). Individuals with lactase persistence, however, continue to express high levels of the lactase gene throughout adulthood. Lactase persistence is a heritable autosomal dominant condition and has been strongly correlated with several single nucleotide polymorphisms (SNPs) located ∼14 kb upstream of the lactase gene in different ethnic populations: -13910*T in Europeans and -13907*G, -13915*G, and -14010*C in several African populations. The coincidence of the four SNPs clustering within 100 bp strongly suggests that this region mediates the lactase non-persistence/persistence phenotype. Having previously characterized the European SNP, we aimed to determine whether the African SNPs similarly mediate a functional role in regulating the lactase promoter. Human intestinal Caco-2 cells were transfected with lactase SNP/promoter-reporter constructs and assayed for promoter activity. The -13907*G and -13915*G SNPs result in a significant enhancement of lactase promoter activity relative to the ancestral lactase non-persistence genotype. Such differential regulation by the SNPs is consistent with a causative role in the mechanism specifying the lactase persistence phenotype.
authors.affiliation: Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition Stanford University School of Medicine, 300 Pasteur Drive, G310, Stanford, CA 94305, USA. eric.sibley@stanford.edu
authors.forename: Eric
authors.initials: E
authors.lastname: Sibley
authors.forename: Jong Kun
authors.initials: JK
authors.lastname: Ahn
mesh_terms: D001363:Awards and Prizes; D044383:Black People / Q000235:genetics*; D018938:Caco-2 Cells; D002239:Carbohydrate Metabolism, Inborn Errors / Q000201:enzymology / Q000208:ethnology / Q000235:genetics*; D015971:Gene Expression Regulation, Enzymologic; D020022:Genetic Predisposition to Disease; D006801:Humans; D006868:Hydrolysis; D007413:Intestinal Mucosa / Q000201:enzymology*; D043322:Lactase / Q000235:genetics* / Q000378:metabolism; D010694:Lactase-Phlorizin Hydrolase / Q000235:genetics* / Q000378:metabolism; D007785:Lactose / Q000378:metabolism; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D014162:Transfection
chemical_list: D043322:Lactase; D010694:Lactase-Phlorizin Hydrolase; D007785:Lactose