An upstream polymorphism associated with lactase persistence has increased enhancer activity

Gastroenterology. 2003 Dec;125(6):1686-94. doi: 10.1053/j.gastro.2003.09.031.


Background & aims: Intestinal lactase activity declines during childhood in some humans. This phenotypic polymorphism of lactase persistence or nonpersistence into adult life has been shown in a recent study to be 100% associated with a T/C nucleotide polymorphism at position -13910 and approximately 97% with an A/G nucleotide polymorphism at position -22018. The aim of this study was to investigate the role of these nucleotide polymorphisms for lactase-phlorizin hydrolase (LPH) gene expression.

Methods: The -13910 and -22018 regions were cloned from lactase-persistent and -nonpersistent individuals, and the regions were analyzed for gene regulatory activity of a luciferase reporter gene by transfection experiments using the intestinal cell line Caco-2. Electrophoretic mobility shift assays (EMSAs) were used to investigate protein/DNA interactions with the -13910 sequence.

Results: We show that the -13910 region contains a strong enhancer. The -13910 regions from both lactase persistent (-13910T variant) and lactase nonpersistent (-13910C variant) have enhancer activity. However, the -13910T variant enhances the LPH promoter approximately 4 times more than the -13910C variant when analyzed in differentiated Caco-2 cells. A nuclear factor from both an intestinal and a nonintestinal extract binds strongly to the -13910T variant whereas the binding to the -13910C variant is much weaker.

Conclusions: The discovery of a functional difference between the 2 alleles at position -13910 supports the notion that the molecular difference between lactase persistence and nonpersistence is caused by the mutation at position -13910.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Caco-2 Cells
  • Enhancer Elements, Genetic*
  • HeLa Cells
  • Humans
  • Lactase-Phlorizin Hydrolase / genetics*
  • Lactose Intolerance / genetics*
  • Polymorphism, Genetic*
  • Promoter Regions, Genetic
  • Sucrase-Isomaltase Complex / genetics


  • Sucrase-Isomaltase Complex
  • Lactase-Phlorizin Hydrolase