LACTOSE INTOLERANCE (also known as lactase non-persistence) is the range of symptoms that arise when one is unable to digest the sugar lactose; hypolactasia is defined as a low level of lactase, the sugar that breaks down lactose [1]. Hypolactasia causes lactose intolerance. A 2005 study found that 100% of the 133 lactose intolerant individuals tested experience abdominal pain, gut distension, borborygmi, and flatuence, in addition to a number of other gut and systemic symptoms including but not limited to diarrhea, vomiting, headache, muscle pain, and exhaustion [1].
WHAT DOES THAT MEAN FOR ME? Lactose is digested in humans by the enzyme lactase (lactase phlorizin-hydrolase) which breaks down lactose into the hexoses glucose and galactose via hydrolysis, see Figure 1. Lactase is present primarily in the brush border of the small intestine where the intestinal absorptive cells, or enterocytes, reside [2]. Figure 2 depicts the relative amounts of lactose in the small intestine in a person with the ability to digest lactose and the purpose of Figure 3 is to give perspective on the locations of the parts of the small intestine in your body. When a lactose intolerant individual consumes lactose, it passes through the small intestine and into the large intestine where it is fermented by bacteria causing the symptoms described above [6]. Normally, infants produce the lactase enzyme and are able to digest lactose, the primary carbohydrate in breast milk from their mother, often until weaning [2]. More rarely, individuals experience congenital (from birth) lack of lactase leading to lactose intolerance, and sometimes damage to the intestines by infections or hormone imbalance can also result in lactose intolerance [1]. These contribute to a wide range of severity of the illness. I spoke to six individuals who are self-described as lactose intolerant about their experiences and symptoms. The age of onset ranged from birth (congenital) to nineteen years old. Effects of dairy consumption included extreme stomach discomfort, vomiting, bloating and exhaustion; these subside within twenty-four hours. For everyone, the worst of these symptoms were caused by milks compared to milk products. When testing for lactose intolerance, a simple method involves administering 50g of lactose (approximately one liter of cow's milk), some individuals may feel symptoms after this large amount of lactose that have never had problems in the past, further depicting the range of sensitivity [1]. An additional complication that can occur as a result of lactose intolerance is a calcium deficiency. Even lactose tolerant individuals can have difficulty consuming the recommended amount of calcium and those who are lactose intolerant have an additional obstacle and must be careful to consume enough. The consequences of not consuming enough calcium include osteoporosis, or weak bones which are more easily fractured[11]. Fortunately, there are many non-dairy foods that contain calcium in amounts sufficient to reach the recommended daily amount. For example, soy-based foods, fruits, grains, seafood, beans, salad greens and other vegetables, nuts, seeds and even some spices contain significant amounts of calcium [3]. In addition, lactase pills can be purchased over the counter and can be eaten with foods that contain lactose to allow for lactose digestion and thus easier calcium absorption. Jerry Seinfeld tells us his feelings about lactose: EPIDEMIOLOGY The prevalence of hypolactasia and lactose intolerance in adults varies widely across different populations and areas of the world. It is estimated that 65% of people worldwide are lactose intolerant, this number is substantially lower in Europe and parts of Africa [4]. A 1994 study summarized previously published findings on the percentages of individuals with hypolactasia, see Table 1. There have been many papers published estimating the prevalence within often small populations, yet no extensive review paper with a compilation of the multitudes of data but Figure 4 is the most representative schematic I was able to find, although it is rather inexact. In addition, the sexes are affected equally and the age of onset is between the time of weaning and 40 years old [5]. GENETIC CAUSES The purpose of this website is to study the genetic causes of lactose intolerance (and alternatively, lactase persistence). The focus will be on the a gene that is located upstream of the lactase gene in humans, called MCM6, which encodes a DNA replication licensing factor called minichromosome maintenance complex component 6. There are six identified allelic variants of the MCM6 gene associated with lactase persistence [6-8]. Each of these variants acts as an enhancer of lactase gene expression so that individuals with these allelic variants are able to produce lactase longer and in higher quantities than those with the alternative variant. The most important of these variants is 13,910 nucleotide bases upstream of the lactase (LCT) gene in humans and will be referred to as -13910 (see Figure 5). A 2005 study found that 100% of people with a C/C (meaning both chromosomes had a C) at this location were lactose intolerant, with symptoms 12 hours after ingesting 50g of lactose following a 12-week lactose free diet [1]. In the same study, 82% of individuals who were C/T (one chromsome C and the other, T) at the -13910 location were lactose intolerant, and 68% of individuals who were T/T (you get the idea, both are T's in this scenario) at the same location were lactose intolerant [1]. These results indicate that the T polymorphism reduces one's likelihood of being lactose intolerant. A previous study found that 100% of the individuals tested were lactose intolerant if they contained even one C at the -13910 site more strongly correlating the polymorphism with lactose intolerance control [7]. The additional allelic variants are found 3712, 13907, 13915, 14010 and 22018 bases upstream of LCT [8]. Support of the -13910 region as an enhancer: I found two papers in support of the -13910 region as an enhancer [6, 12]. I found this intriguing and wondered how this might work. See my Projects page for my hypothetical experiments to determine whether or not a transcription factor binds to this site and is able to enhance or repress transcription of lactase. |
Figure 1: Conversion of lactose to galactose and glucose
Figure 2: Longitudinal expression of lactase along the intestines in a lactase persistent individual; this is a portion of an image taken from a 2005 paper by Jesper T. Trolesen [10].
Figure 3: The location of the duodenum, jejunum and ileum in your body. The stomach empties into the duodenum, which empties into the jejunum, which empties into the ileum, which empties into the large intestine.
Cyndi Lauper sings about her lactose intolerance to the David Letterman Show audience in 1995: Table 1: Prevalence of hypolactasia in various populations; these are approximate numbers obtained from a graph which was reviewing other published results and will be updated with accurate numbers from the original papers shortly [9].
Figure 4: Worldwide prevalence of lactose intolerance in recent populations by the Food Intolerance Network
Figure 5: The T/C allelic variant 13910 bases upstream of LCT enhances LCT expression; an edited portion of an image taken from a 2005 paper by Jesper T. Trolesen [10].
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REFERENCES
[1] Matthews, S. B. "Systemic Lactose Intolerance: A New Perspective on an Old Problem." Postgraduate Medical Journal 81.953 (2005): 167-73. Web. 5 Feb. 2013.
[2] Friedrich DC, Santos SEB, Ribeiro-dos-Santos ÂKC, Hutz MH (2012) Several Different Lactase Persistence Associated Alleles and High Diversity of the Lactase Gene in the Admixed Brazilian Population. PLoS ONE 7(9): e46520. doi:10.1371/journal.pone.0046520
[3] Fleming, Alisa. "Non-Dairy Calcium: Dairy-Free Calcium Chart." Go Dairy Free. Fleming Marrs Inc, 2012. Web. 05 Feb. 2013.
[4] Vuorisalo, T., O. Arjamaa, A. Vasemägi, JP Taavitsainen, A. Tourunen, and I. Saloniemi. "High Lactose Tolerance in North Europeans: A Result of Migration, Not in Situ Milk Consumption." Perspect Biol Med 22.2 (2012): 163-74. Web.
[5] "Lactose Intolerance." Medscape. WebMD LLC, 16 June 2011. Web. 06 Feb. 2013.
[6] Olds, L. C., and Eric Sibley "Lactase Persistence DNA Variant Enhances Lactase Promoter Activity in Vitro: Functional Role as a Cis Regulatory Element." Human Molecular Genetics 12.18 (2003): 2333-340. Web. 5 Feb. 2013.
[7] Enattah, Nabil S., Timo Sahi, Erkki Savilahti, Joseph D. Terwilliger, Leena Peltonen, and Irma Järvelä. "Identification of a Variant Associated with Adult-type Hypolactasia." Nature Genetics 30 (2002): 233-37. 14 Jan. 2002. Web. 6 Feb. 2013.
[8] McKusick-Nathans Institute of Genetic Medicine. "OMIM Entry- * 601806 - MINICHROMOSOME MAINTENANCE, S. POMBE, HOMOLOG OF, 6; MCM6." Online Mendelian Inheritance in Man. Johns Hopkins University, 15 Nov. 2011. Web. 02 Feb. 2013.
[9] Sahi, T. "Genetics and Epidemiology of Adult-type Hypolactasia." Scandinavian Journal of Gastroenterology 29 (1994): 7-20. Web. 31 Jan. 2013.
[10] Troelsen, Jesper T. "Adult-type Hypolactasia and Regulation of Lactase Expression." Biochimica Et Biophysica Acta (BBA) - General Subjects 1723.1-3 (2005): 19-32. Web. 6 Feb. 2013.
[11] A. El Maghraoui, A. Rezqi, A. Mounach, L. Achemlal, A. Bezza, I. Ghozlani, Systematic vertebral fracture assessment in asymptomatic postmenopausal women, Bone, Volume 52, Issue 1, January 2013, Pages 176-180, ISSN 8756-3282, 10.1016/j.bone.2012.09.023.
[12] Troelsen, J. "An Upstream Polymorphism Associated with Lactase Persistence Has Increased Enhancer Activity." Gastroenterology 125.6 (2003): 1686-694. Web. 7 Mar. 2013.
[1] Matthews, S. B. "Systemic Lactose Intolerance: A New Perspective on an Old Problem." Postgraduate Medical Journal 81.953 (2005): 167-73. Web. 5 Feb. 2013.
[2] Friedrich DC, Santos SEB, Ribeiro-dos-Santos ÂKC, Hutz MH (2012) Several Different Lactase Persistence Associated Alleles and High Diversity of the Lactase Gene in the Admixed Brazilian Population. PLoS ONE 7(9): e46520. doi:10.1371/journal.pone.0046520
[3] Fleming, Alisa. "Non-Dairy Calcium: Dairy-Free Calcium Chart." Go Dairy Free. Fleming Marrs Inc, 2012. Web. 05 Feb. 2013.
[4] Vuorisalo, T., O. Arjamaa, A. Vasemägi, JP Taavitsainen, A. Tourunen, and I. Saloniemi. "High Lactose Tolerance in North Europeans: A Result of Migration, Not in Situ Milk Consumption." Perspect Biol Med 22.2 (2012): 163-74. Web.
[5] "Lactose Intolerance." Medscape. WebMD LLC, 16 June 2011. Web. 06 Feb. 2013.
[6] Olds, L. C., and Eric Sibley "Lactase Persistence DNA Variant Enhances Lactase Promoter Activity in Vitro: Functional Role as a Cis Regulatory Element." Human Molecular Genetics 12.18 (2003): 2333-340. Web. 5 Feb. 2013.
[7] Enattah, Nabil S., Timo Sahi, Erkki Savilahti, Joseph D. Terwilliger, Leena Peltonen, and Irma Järvelä. "Identification of a Variant Associated with Adult-type Hypolactasia." Nature Genetics 30 (2002): 233-37. 14 Jan. 2002. Web. 6 Feb. 2013.
[8] McKusick-Nathans Institute of Genetic Medicine. "OMIM Entry- * 601806 - MINICHROMOSOME MAINTENANCE, S. POMBE, HOMOLOG OF, 6; MCM6." Online Mendelian Inheritance in Man. Johns Hopkins University, 15 Nov. 2011. Web. 02 Feb. 2013.
[9] Sahi, T. "Genetics and Epidemiology of Adult-type Hypolactasia." Scandinavian Journal of Gastroenterology 29 (1994): 7-20. Web. 31 Jan. 2013.
[10] Troelsen, Jesper T. "Adult-type Hypolactasia and Regulation of Lactase Expression." Biochimica Et Biophysica Acta (BBA) - General Subjects 1723.1-3 (2005): 19-32. Web. 6 Feb. 2013.
[11] A. El Maghraoui, A. Rezqi, A. Mounach, L. Achemlal, A. Bezza, I. Ghozlani, Systematic vertebral fracture assessment in asymptomatic postmenopausal women, Bone, Volume 52, Issue 1, January 2013, Pages 176-180, ISSN 8756-3282, 10.1016/j.bone.2012.09.023.
[12] Troelsen, J. "An Upstream Polymorphism Associated with Lactase Persistence Has Increased Enhancer Activity." Gastroenterology 125.6 (2003): 1686-694. Web. 7 Mar. 2013.
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Page created by: Renae Geier, undergraduate student in genetics at the University of Wisconsin - Madison ([email protected])
Page last updated: 5/16/2013
Page last updated: 5/16/2013