Lactase Persistence - Genetics

Genetics

Multiple studies indicate that the presence of the two phenotypes "lactase persistent" and "lactase non-persistent (hypolactasia)" is genetically programmed, and that lactase persistence is not necessarily conditioned by the consumption of dairy products after the suckling period.

The lactase persistent phenotype involves high mRNA expression, high lactase activity and thus the ability to digest lactose. On the other hand, the lactase non-persistent phenotype involves low mRNA expression and low lactase activity. The enzyme lactase is encoded by the gene LCT.

Hypolactasia is known to be recessively and autosomally inherited, which means that an individual with the non-persistent phenotype is homozygous and received the two copies of the lactase gene from their parents, who may be homozygous or at least heterozygous. Also, only one active lactase gene is required to be lactase persistent, because lactase persistence is dominant to hypolactasia. Lactase persistence behaves as a dominant trait because half levels of lactase activity are sufficient to show significant digestion of lactose. Cis-acting transcriptional silence of the lactase gene is responsible for the hypolactasia phenotype. Furthermore, studies show that only 8 cases were found where the parents of a child with lactase persistence were both hypolactasic. While a variety of genetic, as well as nutritional factors determine lactase expression, there is no evidence for adaptive alteration of lactase expression within an individual in response to changes in lactose consumption levels. There are two distinct phenotypes of hypolactasia. Phenotype I is characterized by reduced synthesis of precursor LPH while the mechanism of decreased lactase activity in phenotype II is associated with ample precursor synthesis but reduced conversion of the protein to its mature molecular form. The lactase enzyme has two active sites which break down lactose. The first is at Glu1273 and the second is at Glu1749, which separately break down lactose into two separate kinds of molecules.

Two mutations or SNP (single-nucleotide polymorphism) have been associated to lactase expression. It was found that C−13910 (C at position -13910 upstream of the gene LCT) and G−22018 (G at position -22018) are related to lactase non-persistence while the T−13910 and A−22018 are related to lactase persistence. In addition, studies have demonstrated that the lactase gene has a higher expression when T−13910 and A−22018 are present and a lower expression when C−13910 and G−22018 are present. It was also proven that the position -13910 has an enhancer function on the lactase promoter (the promoter facilitates the transcription of the LCT gene). T−13910 is a greater enhancer than C−13910, so it is thought that this mutation is responsible for the differences in lactase expression although there is not enough evidence to prove that lactase persistence is only caused by C−13910→T−13910.

In one study involving a Finnish population, a CT SNP at –14 kb was found in all lactase persistent individuals and absent in all hypolactasia individuals. A second SNP (G-22 kbA) was concordant with phenotype in all but a few rare individuals. Since both SNPs are located in the same gene, this has led to a genetic means of testing lactase expression in individuals. Outside of the Finnish study, a separate study also confirmed that the CT SNP at -14kb is an indicator of lactase persistence, with the exception of two individuals.