title: A novel polymorphism associated with lactose tolerance in Africa: multiple causes for lactase persistence?
abstract: Persistence or non-persistence of lactase expression into adult life is a polymorphic trait that has been attributed to a single nucleotide polymorphism (C-13910T) in an enhancer element 13.9 kb upstream of the lactase gene (LCT). The -13910*T allele occurs at very high frequency in northern Europeans as part of a very long haplotype (known as A), and promotes binding of the transcription factor Oct-1. However, -13910*T is at very low frequency in many African milk drinking pastoralist groups where lactase persistence phenotype has been reported at high frequency. We report here for the first time, a cohort study of lactose digester and non-digester Sudanese volunteers and show there is no association of -13910*T or the A haplotype with lactase persistence. We support this finding with new genotype/phenotype frequency comparisons in pastoralist groups of eastern African and Middle Eastern origin. Resequencing revealed three new SNPs in close proximity to -13910*T, two of which are within the Oct-1 binding site. The most frequent of these (-13915*G) is associated with lactose tolerance in the cohort study, providing evidence for a cis-acting effect. Despite its location, -13915*G abolishes, rather than enhances Oct-1 binding, indicating that this particular interaction is unlikely to be involved in lactase persistence. This study reveals the complexity of this phenotypic polymorphism and highlights the limitations of C-13910T as a diagnostic test for lactase persistence status, at least for people with non-European ancestry.
authors.affiliation: Department of Biology, Galton Laboratory, University College London, Wolfson House, 4 Stephenson Way, London, UK.
authors.forename: Catherine J E
authors.initials: CJ
authors.lastname: Ingram
authors.forename: Mohamed F
authors.initials: MF
authors.lastname: Elamin
authors.forename: Charlotte A
authors.initials: CA
authors.lastname: Mulcare
authors.forename: Michael E
authors.initials: ME
authors.lastname: Weale
authors.forename: Ayele
authors.initials: A
authors.lastname: Tarekegn
authors.forename: Tamiru Oljira
authors.initials: TO
authors.lastname: Raga
authors.forename: Endashaw
authors.initials: E
authors.lastname: Bekele
authors.forename: Farouk M
authors.initials: FM
authors.lastname: Elamin
authors.forename: Mark G
authors.initials: MG
authors.lastname: Thomas
authors.forename: Neil
authors.initials: N
authors.lastname: Bradman
authors.forename: Dallas M
authors.initials: DM
authors.lastname: Swallow
mesh_terms: D000328:Adult; D000349:Africa; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D015331:Cohort Studies; D004247:DNA / Q000235:genetics / Q000378:metabolism; D015342:DNA Probes / Q000235:genetics; D004742:Enhancer Elements, Genetic; D005006:Ethnicity / Q000235:genetics; D005787:Gene Frequency; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007438:Introns; D043322:Lactase / Q000235:genetics*; D007787:Lactose Intolerance / Q000201:enzymology* / Q000235:genetics*; D008877:Middle East; D050811:Octamer Transcription Factor-1 / Q000378:metabolism; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012689:Sequence Homology, Nucleic Acid
chemical_list: D015342:DNA Probes; D050811:Octamer Transcription Factor-1; D004247:DNA; D043322:Lactase