LACTOSE INTOLERANCE

Lactose intolerance generally occurs due to impaired production of the lactase-phlorizin hydrolase (LPH) enzyme in intestinal epithelial cells. Most babies are born with enough lactase to digest the lactose in breast milk. It is stated that the production of this enzyme will genetically decrease or stop during childhood. The condition resulting from this natural process is defined as lactase nonpersistence (LNP). Lactase persistence (LP) is characterized by the continuous production of the enzyme throughout life. Lactase is located proximally in the small intestine and breaks down the disaccharide lactose (milk sugar) into the monosaccharides glucose and galactose. In the case of LNP, if lactose is not broken down and passes into the colon intact, negative symptoms ranging from mild bloating to severe abdominal pain and diarrhea occur due to the breakdown of lactose by bacteria in the intestine. The incidence of LP is generally found at high frequency in populations of European descent (such as the Netherlands and Sweden) (Dzialanski, Z. et al., 2015).

What is the LCT Gene?

The small intestinal enzyme lactase or lactase-phlorizin hydrolase (LPH) is encoded by the LCT gene and is located in the brush border membrane of small intestinal enterocytes. The activity of the lactase enzyme is to hydrolyze lactose, the main carbohydrate in milk (Friedrich, D. C. et al., 2012).

What is the MCM6 Gene?

MCM6, a member of the minichromosome maintenance complex (MCM) family, is thought to play a role in the “licensing” of DNA replication during the cell cycle (Mattar, R. et al., 2012).

LACTOSE INTOLERANCE
Genes	rs	Minor Allele	Minor Allele Description	Reference
MCM6	rs182549 A −22018	C	High relative risk for lactose intolerance.	(Troelsen, J. T., 2005), (Kato, K. et al., 2018)
MCM6	rs41380347 13915*G	T	High relative risk for lactose intolerance.	(Liebert, A. et al., 2017; Itan, Y. et al., 2010; Hassan, H. Y. et al., 2016; Tishkoff, S.et al., 2006)
MCM6	rs41525747 13907*G	C	High relative risk for lactose intolerance.
LCT	rs4988235 13910*T	G	High relative risk for lactose intolerance.	(Baffour-Awuah, N.et al., 2015)

The table above contains the genes and their polymorphisms involved in lactose metabolism. Two specific SNPs in the LCT gene have been reported to be tightly associated with adult-type hypolactasia. T −13910 and A −22018 variants are associated with lactase persistence (Troelsen, J. T., 2005). A statistically significant relationship was shown between the T allele and lactase persistence in the rs4988235 polymorphism. Lactase enzyme activity was found to be lowest in C/C homozygotes, moderate in T/C heterozygotes, and highest in T/T homozygotes (Baffour-Awuah, N.et al., 2015). The genetic trait for persistence of intestinal lactase activity into adult life arises from five or more independent single nucleotide variants in a regulatory region upstream of the lactase gene LCT. One of these, − 13910*T (rs4988235) is in Europe, − 13907*G (rs41525747), − 13915*G (rs41380347), − 14009*G (rs869051967) and − 14010*C (rs145946881) in the Middle East and Africa. It is also found at variable frequencies (Liebert, A. et al., 2017; Itan, Y. et al., 2010; Hassan, H. Y. et al., 2016; Tishkoff, S. et al., 2006). The GG genotype at rs182549 polymorphism has been reported to contribute to lactase persistence in Japanese-Brazilian and Chinese populations, whose genetic backgrounds are more closely related to the Japanese population than to the European population (Kato, K. et al., 2018).

 

REFERENCE

Baffour-Awuah, N. Y., Fleet, S., Baker, S. S., Butler, J. L., Campbell, C., Tischfield, S., Mitchell, P. D., Moon, J. E., Allende-Richter, S., Fishman, L., Bousvaros, A., Fox, V., Kuokkanen, M., Montgomery, R. K., Grand, R. J., & Hirschhorn, J. N. (2015). Functional Significance of Single Nucleotide Polymorphisms in the Lactase Gene in Diverse United States Subjects and Evidence for a Novel Lactase Persistence Allele at -13909 in Those of European Ancestry. Journal of Pediatric Gastroenterology and Nutrition, 60(2), 182. https://doi.org/10.1097/MPG.0000000000000595

Dzialanski, Z., Barany, M., Engfeldt, P., Magnuson, A., Olsson, L. A., & Nilsson, T. K. (2016). Lactase persistence versus lactose intolerance: Is there an intermediate phenotype? Klinik Biyokimya, 49(3), 248-252. https://doi.org/10.1016/j.clinbiochem.2015.11.001

Friedrich, D. C., B. Santos, S. E., & Hutz, M. H. (2012). Several Different Lactase Persistence Associated Alleles and High Diversity of the Lactase Gene in the Admixed Brazilian Population. PLoS ONE, 7(9). https://doi.org/10.1371/journal.pone.0046520

Hassan, H. Y., Jaeger, M., Tahir, H., Oosting, M., B. Joosten, L. A., & Netea, M. G. (2016). Genetic diversity of lactase persistence in East African populations. BMC Research Notes, 9. https://doi.org/10.1186/s13104-015-1833-1

Itan, Y., Jones, B. L., Ingram, C. J., Swallow, D. M., & Thomas, M. G. (2010). A worldwide correlation of lactase persistence phenotype and genotypes. BMC Evolutionary Biology, 10, 36. https://doi.org/10.1186/1471-2148-10-36

Kato, K., Ishida, S., Tanaka, M., Mitsuyama, E., & Odamaki, T. (2018). Association between functional lactase variants and a high abundance of Bifidobacterium in the gut of healthy Japanese people. PLoS ONE, 13(10). https://doi.org/10.1371/journal.pone.0206189

Liebert, A., López, S., Jones, B. L., Montalva, N., Gerbault, P., Lau, W., Thomas, M. G., Bradman, N., Maniatis, N., & Swallow, D. M. (2017). World-wide distributions of lactase persistence alleles and the complex effects of recombination and selection. Human Genetics, 136(11), 1445-1453. https://doi.org/10.1007/s00439-017-1847-y

Mattar, R., Mazo, C., & Carrilho, F. J. (2012). Lactose intolerance: Diagnosis, genetic, and clinical factors. Clinical and Experimental Gastroenterology, 5, 113-121. https://doi.org/10.2147/CEG.S32368

Tishkoff, S. A., Reed, F. A., Ranciaro, A., Voight, B. F., Babbitt, C. C., Silverman, J. S., Powell, K., Mortensen, H. M., Hirbo, J. B., Osman, M., Ibrahim, M., Omar, S. A., Lema, G., Nyambo, T. B., Ghori, J., Bumpstead, S., Pritchard, J. K., Wray, G. A., & Deloukas, P. (2006). Convergent adaptation of human lactase persistence in Africa and Europe. Nature Genetics, 39(1), 31. https://doi.org/10.1038/ng1946

Troelsen, J. T. (2005). Adult-type hypolactasia and regulation of lactase expression. Biochimica et Biophysica Acta (BBA)-General Subjects, 1723(1-3), 19-32.