MCM6 Gene Detail
The MCM6 gene contains two of the regulatory regions for LCT, the gene that encodes for the lactase enzymes to enable the digestion of lactose in milk. These are located in two nearby MCM6 introns, rs182549 and rs4988235, upstream from LCT.
Mutations in these genes are often associated with lactose intolerance in adult life. The mutations result in a decreased ability of the epithelial cells in the small intestine to digest lactose due to the decline in the lactase enzyme.
MCM6 -13910 C>T
MCM6 -13910 has been found to be associated with changes in the lactase gene expression. MCM6 -13910 sees a base change from a T to a C, resulting in these changes in gene expression.
Individuals carrying the homozygous CC variation of MCM6 -13910 have been found to be lactose intolerant/ lactose non-persistent, compared to those with the TT or TC variant, which has been correlated with lactase persistence.
The T-13910 allele has been 100% associated with lactase persistence in the Finnish study and 86-98% in other European populations. Individuals carrying the CC genotype have been found to have almost undetectable levels of intestinal lactase production compared to TT and TC individuals.
Pohl et al conducted a study in Europeans to evaluate the agreement between genetic testing of LCT C/T – 13910 and the lactose hydrogen breath test, lactose H2-B2, which was declared as the gold standard of diagnosing lactose intolerance. Two hundred and one patients were assessed. It was found that genetic testing had an excellent agreement with the standard lactose hydrogen breath test and it was concluded that genetic testing could replace hydrogen breath testing for diagnosis of lactase deficiency.
The frequency of this ‘lactase persistence’ trait is high in Northern European populations (>90% in Scandinavia and Holland), decreases in frequency across Southern Europe and the Middle East (approximately 50% in Spain, Italy and pastoralist Arab populations) and is low in Asia and most of Africa (approx. 1% in Chinese, 5-20% in West African agriculturist). More than half of the World’s population is lactose non-persistence.
Background On Lactose Intolerance
Young children can generally digest lactose in their mother’s milk as LCT activity remains high until weaning but then tends to be ‘switched off’ in most of the adult population. About 2/3rds of the world’s population undergoes a genetically programmed decrease in lactase activity synthesis after weaning and so only about 35% of the population can digest milk past the age of 6 or 7 years.
After 2-12 years of age, two distinct groups tend to emerge i.e. a ‘lactase non-persistence’ group with low lactase activity (hypolactasia) and a ‘lactase-persistent’ group of individuals who can retain their neonatal level of lactase into adulthood. A reduction in lactase activity causes primary maldigestion of lactose and when symptoms are present, lactose intolerance is diagnosed. Symptoms of lactose intolerance generally do not occur unless there is <50% of lactase activity. People who are lactase persistence have a continued activity of the lactase enzyme into adulthood. Lactase persistence post weaning is thought to be as a result of migration, settlement, food shortage or local climatic conditions and is thought to have co-evolved with dairying around 7500 years ago in Central Europe. People whose ancestors herded cattle were thought to have undergone some form of evolution over a short time period, allowing them to make better use of milk.
Lactose intolerance refers to the inability to digest milk and can be defined as a condition where unpleasant GI symptoms result from ingestion of lactose i.e. flatulence, gas, bloating, cramps, diarrhoea, abdominal pain and rarely vomiting.
Lactase persistence (LP) refers to the dominant genetic trait in adults who have a continuous ability to digest lactose through adulthood and lactase non-persistence (LNP) refers to a natural decline in intestinal lactase to <10ug/tissue resulting in minimal ability for adults to digest lactose. Lactase deficiency (LD) refers to the reduction of the intestinal lactase enzyme from either genetic (LNP) or secondary causes due to diseases of the proximal small bowel mucosa. Lactose maldigestion (LM) is the inability to digest lactose, due to primary (LNP) or secondary causes which result in undigested lactose reaching the colon.
Symptoms Of Lactose Intolerance
Hypolactasia does not cause disturbances or discomfort unless lactose containing food is consumed. Colonic microflora ferment undigested lactose in the intestinal lumen, leading to production of short chain fatty acids, hydrogen, carbon dioxide and methane.
These by-products cause bloating, flatulence and abdominal pain. Undigested lactose increases osmotic load in the colon, leading to loose stools and diarrhoea. Some patients experience constipation due to reduced intestinal motility, possibly as a result of methane production.
Valid evidence is missing for a relationship between symptoms and the amount of lactose ingested although it appears that most individuals can tolerate up to 12g lactose per day. Available data demonstrate that a single dose of lactose (up to 12g or equivalent to that in a glass of milk), administered alone, produces no or minor symptoms in people with lactose intolerance. Lactose doses of 15-18g are well tolerated when offered with other nutrients. In doses above 18g, the intolerance becomes more frequent and, with quantities above 50g lactose eliciting symptoms present in most individuals. Other reports suggest that most of the population are lactose non – persistence (LNP) and they can generally tolerate >9-12g (+-200ml milk) and up to 25g lactose on one occasion.
Intra-individuality and inter-individuality exists with regard to severity of symptoms, amount of lactose ingested and ability to digest the lactose. Osmolality, the fat content of lactose containing foods, gastric emptying rate, ability of colonic microflora to ferment lactose, intestinal transit time, colonic water absorption capacity and individual’s perception of abdominal pain and discomfort all contribute to this variability. The food and meal pattern context, age and microbiome characteristics can also affect digestion.
Lactose Intolerance And Bone Health
Some available data suggest that deficient calcium intake plays a major role in lactose intolerance which, in turn, may be related to bone disease. Mattar et al recommended that the initial recommendation for lactose intolerance is to aim for remission of symptoms by avoiding milk and dairy products, keeping in mind that most individuals can tolerate up to 12g lactose per day. Thereafter, lactose should be gradually reintroduced until a patient’s threshold for symptoms is reached. Including fermented and matured milk products in the diet, consuming lactose together with other foods and distributing lactose through the day might assist in improving tolerance. If these measures do not result in symptom reduction, use of lactase supplements, lactose-hydrolysed or lactose reduced milk, probiotics, colonic adaption and rifaximin might assist in reducing symptoms. Probiotics containing lactase may improve lactose digestion in intolerant patients, however there are conflicting results on this. Yoghurt containing live cultures such providing endogenous beta galactosidase are often well tolerated by lactose intolerant patients and provide additional calories and calcium. Evidence is insufficient to ascertain efficacy of interventions.
Ensuring a sufficient calcium and vitamin D intake is important to meet recommended requirements, with appropriate supplementation as needed. Vitamin D levels should be monitored. Calcium is a mineral that helps you build and maintain strong teeth and bones and a good Calcium intake through life can help to prevent osteoporosis. It is also involved in muscle and cardiac functions.
Non-dairy dietary sources of Calcium include green leafy vegetables such as broccoli, cabbage, spinach, kale and okra, soya beans and tofu, soya drinks with added Calcium, nuts and fish where you eat the bones such as sardines, pilchards, salmon and mackerel. Almond milk, rice milk and orange juice that have been fortified with Calcium are also good sources. Recommended intake for Calcium from foods and supplements is 1000mg/day, with this increasing to 1200mg/day in women 51 years and older and men 71 years and older.
See table 1 under intervention section, for Calcium content of commonly eaten foods.
Lactase Persistence, Obesity And Blood Pressure
Pires Hartwig et al investigated the association of milk intake with obesity and blood pressure using genetically defined lactase persistence based on the rs4988235 polymorphism in a Mendelian randomization design in the 1982 Pelotas (Southern Brazil) Birth cohort. These subjects had been followed up since birth. These results were combined with published reports that had been identified using a systematic review using meta-analysis.
The study found that genetically defined lactase persistence (LP) was associated with more milk intake in the 1982 Pelotas Birth Cohort, with this association being more pronounced among individuals of European ancestry. In the conventional observational analysis in the 1982 Pelotas birth cohort, milk intake was negatively associated with obesity and blood pressure and in this meta-analysis, which was based on a systematic literature review, lactase persistence was positively associated with BMI and overweight/ obesity. No reliable associations were found between LP and blood pressure.
Lactose Content Of Foods
The lactose content of milk differs between various animals. Cow’s milk contains significantly lower concentrations of lactose than human milk, which has the highest lactose content. The lactose content in fermented cow’s milk such as yoghurt and buttermilk are about 1/3rd of that in fresh milk due to the conversion of lactose by lactic acid bacteria. Hard cheeses contain virtually no lactose, as almost all the lactose in milk is converted into whey and the remaining lactose is then fully converted into lactic acid by starter bacteria.
The lactose content of specific foods may vary brand to brand and may also vary depending on the source used. See Table 2 and Table 3 under intervention section, which give an indication of the lactose content of dairy foods, using two different sources respectively.
The CC genotype for MCM6 -13910 C<T has been associated with lactose intolerance/ lactase non-persistence, whereas individuals carrying the CT and TT allele are considered to be lactase persistent. Individuals with the CC genotype should avoid lactose containing foods or limit lactose to approximately 12g lactose per day, depending on the individual.
Consuming lactose containing foods with other foods or spreading intake through the day and selecting fermented dairy products may assist in improving tolerance. The use of lactase containing probiotics may also add benefit.
Each person’s individual tolerance should be assessed.
Adequate calcium supplementation and monitoring of Vitamin D levels is recommended in lactose intolerant individuals. An increased intake of Calcium from low lactose food sources is also recommended. Table 1 below gives the calcium content of some commonly eaten foods and tables 2 and 3 give an estimation of the lactose content of certain foods.
Food Sources Of Calcium
Please note that the exact Calcium content of food may vary from source to source and this table is meant to give an indication.
Food Sources of Lactose
Lactose is found in all milk products and may be added as an ingredient to many different foods and beverages. Reading the ingredient list on product labels is recommended to check if a food contains lactose.
Food items that typically contain lactose include milk, milk solids, malted milk, buttermilk, curds, cheese flavours, non-fat milk powder, non-fat milk solids, sweet or sour cream, lactose, whey, yoghurt.
Review article: from ‘lactose intolerance’ to ‘lactose nutrition’
Lukito et al, 2015.