title: Functional significance of single nucleotide polymorphisms in the lactase gene in diverse US patients and evidence for a novel lactase persistence allele at -13909 in those of European ancestry.
abstract: OBJECTIVE
  Recent data from mainly homogeneous European and African populations implicate a 140-bp region 5' to the transcriptional start site of LCT (the lactase gene) as a regulatory site for lactase persistence and nonpersistence. Because there are no studies of US nonhomogeneous populations, we performed genotype/phenotype analysis of the -13910 and -22018 LCT single nucleotide polymorphisms (SNPs) in New England children, mostly of European ancestry.
  
  
  METHODS
  Duodenal biopsies were processed for disaccharidase activities, RNA quantification by reverse transcription polymerase chain reaction (RT-PCR), allelic expression ratios by PCR, and genotyping and SNP analysis. Results were compared with clinical information.
  
  
  RESULTS
  Lactase activity and mRNA levels, and sucrase-to-lactase ratios of enzyme activity and mRNA, showed robust correlations with genotype. None of the other LCT SNPs showed as strong a correlation with enzyme or mRNA levels as did -13910. Data were consistent, with the -13910 being the causal sequence variant instead of -22018. Four individuals heterozygous for -13910T/C had allelic expression patterns similar to individuals with -13910C/C genotypes; of these, 2 showed equal LCT expression from the 2 alleles and a novel variant (-13909C>A) associated with lactase persistence.
  
  
  CONCLUSIONS
  The identification of -13910C/C genotype is likely to predict lactase nonpersistence, consistent with prior published studies. A -13910T/T genotype will frequently, but not perfectly, predict lactase persistence in this mixed European-ancestry population; a -13910T/C genotype will not predict the phenotype. A long, rare haplotype in 2 individuals with -13910T/C genotype but equal allele-specific expression contains a novel lactase persistence allele present at -13909.
authors.affiliation: *Division of Gastroenterology and Nutrition, Boston Children's Hospital, Harvard Medical School, Boston, MA †Division of Gastroenterology and Nutrition, Children's Hospital of Buffalo, Buffalo, NY ‡Division of Genetics §Clinical Research Program ||Division of Endocrinology, Department of Medicine ¶Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA.
authors.forename: Nana Yaa
authors.initials: NY
authors.lastname: Baffour-Awuah
authors.forename: Sarah
authors.initials: S
authors.lastname: Fleet
authors.forename: Robert K
authors.initials: RK
authors.lastname: Montgomery
authors.forename: Susan S
authors.initials: SS
authors.lastname: Baker
authors.forename: Johannah L
authors.initials: JL
authors.lastname: Butler
authors.forename: Catarina
authors.initials: C
authors.lastname: Campbell
authors.forename: Samuel
authors.initials: S
authors.lastname: Tischfield
authors.forename: Paul D
authors.initials: PD
authors.lastname: Mitchell
authors.forename: Sophie
authors.initials: S
authors.lastname: Allende-Richter
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Moon
authors.forename: Laurie
authors.initials: L
authors.lastname: Fishman
authors.forename: Athos
authors.initials: A
authors.lastname: Bousvaros
authors.forename: Victor
authors.initials: V
authors.lastname: Fox
authors.forename: Mikko
authors.initials: M
authors.lastname: Kuokkanen
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Grand
authors.forename: Joel N
authors.initials: JN
authors.lastname: Hirschhorn
mesh_terms: D000293:Adolescent; D000483:Alleles; D002648:Child; D004386:Duodenum / Q000201:enzymology* / Q000378:metabolism; D005260:Female; D005838:Genotype; D006801:Humans; D043322:Lactase / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000378:metabolism*; D013393:Sucrase / Q000378:metabolism; D014481:United States / Q000208:ethnology; D044465:White People / Q000235:genetics*; D055815:Young Adult
chemical_list: D012333:RNA, Messenger; D043322:Lactase; D013393:Sucrase