SNP Highlight - Lactose Intolerance & MCM6

As your inner-child might attest to, there is nothing quite like a scoop of ice cream on a hot summer’s day. However, for many of us this tasty dairy treat comes with a few consequences, namely an upset stomach, bloating, gas and nausea. What exactly is going on here, and what can your genes tell you?

Today we dive into the underlying causes of lactose intolerance and discuss what variations in the MCM6 gene may tell you about our ability to consume dairy products.

A Brief on Lactase

Lactase is the single enzyme that decides the fate between fully enjoying dairy products and feeling those regretful side effects. Lactase works by breaking down lactose, the sugar found exclusively in milk and dairy products, into the simple sugars glucose and galactose for absorption in the small intestines.

All mammals express the gene for lactase, called LCT, as it is a high-energy sugar suitable to meet the needs of fast-growing infants. If lactase is not present, the lactose sugar cannot be absorbed and instead continues down the digestive tract into the large intestines where it is fermented by bacteria.

The familiar symptoms of lactose intolerance occur here by the combination of gas produced by fermenting bacteria (bloating & abdominal pain), a water-drawing gradient produced by an acidified colon (diarrhea), and in some cases bacterial methane production that slows gastric transit (1-2).

Lactose Tolerance in Adulthood: A Recent Human Adaptation

The lactase enzyme is normally present in infancy, but levels rapidly fall by the first year of life corresponding with mother’s milk weaning. In adulthood, the absence of lactase translates to lactose intolerance.

Lactose is one of the most common food intolerances primarily because it is our human ancestral or “wild type” state. In fact, the ability to digest lactose into adulthood, or what scientists call lactase persistence, is a relatively recent evolution that occurred only about 5,000 to 10,000 years ago (3).

Scientist believe that this corresponded with the domestication of the dairy cow and gave an evolutionary advantage to those who could digest milk in periods of famine. Notably the groups with the highest rates of lactose persistence are found in northern europeans and arab ancestries (4).

How is the MCM6 Gene Involved?

Although there are some rare genetic variants to the actual lactase gene, tolerance to lactose in adulthood can be attributed to polymorphisms (SNPs) in the MCM6 gene (5).

MCM6 lies just upstream of the lactase gene and contains a regulatory region that allows for lactase expression (6). Two sites of variation, rs4988235 and rs182549 independently evolved, and a mutation from the more common “wild type” C allele to a T allele causes continued expression of lactase into adulthood (3, 7).

This lactase persistence allele is seen most commonly in those with european caucasian ancestry. In Arab and Northern African populations there is a third MCM6 variant, rs41380347, where the minor allele G allows for lactase persistence in a similar fashion (8).

Lifestyle Recommendations

Individuals with either the CC genotype (in rs4988235 or rs182549) or the TT genotype (in rs41380347) for lactase non-persistence are at risk for lactose intolerance.

However, this does not necessarily mean they will experience sypmtoms of lactose intolerance.

There are many other factors that can affect symptoms such as the makeup of your intestinal bacteria or “microbiome.” Remember the symptoms are primarily from bacteria’s effects on breaking down lactose, and bacteria can vary greatly in their gaseous byproducts. In fact, some blinded studies have shown a disconnect between lactose intake and intolerance symptoms in lactose non-persisters (9).

Instead a stronger association appears with different food types. It is is important to note that intolerance symptoms may actually be due to a milk protein allergy or an underlying digestive problem such as Irritable Bowel Syndrome rather than pure lactose intolerance. Therefore, if you’re experiencing continued intolerance symptoms you’ll want to talk with your doctor.

For those individuals that do experience symptoms of lactose intolerance, it may be best to avoid dairy products altogether, but it may not be entirely necessary. If lactose intake is kept low, around 12 to 15 grams or roughly one glass of milk on any one occasion, most people with lactose intolerance will not experience any symptoms at all (10).

Fermented dairy products such as cheese or yogurt will have lower to no levels of lactose while still providing valuable osteoporosis-preventing calcium (9). There are also a wide-range of lactose-free or lactase-added dairy products which can help circumvent the issue. And lastly, studies have indicated that probiotic intake from foods like yogurt may help to reduce or prevent some intolerance symptoms (11).

Getting genetics tested and listening to the body is the first step to a healthy lifestyle. But when it comes to lactose intolerance, there may be nothing wrong with a scoop of ice cream every once and awhile!

References:

1. Mattar R, de Campos Mazo DF, Carrilho FJ. Lactose intolerance: diagnosis, genetic, and clinical factors. Clin & Exp Gastrointest. 2012; 5: 113-121.

2. Pimentel M, Lin HC, Enayati P, et al. Methane, a gas produced by enteric bacteria, slows intestinal transit and augments small intestinal contractile activity. Am J Physiol Gastrointest Liver Physiol. 2005; 290: G1089-G1095.

3. Enattah NS, Jensen TGK, Nielsen M, et al. Independent introduction of two lactase-persistence alleles into human populations reflects different history of adaption to milk culture. Am J Human Genetics. 2008; 82: 57-72.

4. Coelho M, Lusielli D, Bertorelle G. Microsatellite variation and evolution of human lactase persistence. Hum. Genet. 2005; 117: 329-339.

5. Enattah NS, Sahi T, Savilahti, Terwilliger JD, Peltonen L, Järvelä I. Identification of a variant associated with adult-type hypolactasia. Nature Genetics. 2002; 30: 233-237.

6. Harvey CB, Wang Y, Darmoul D, Phillips A, Mantei N, Swallow DM. Characterisation of a human homologue of a yeast cell division cycle gene, MCM6, located adjacent to the 5’ end of the lactase gene on chromosome 2q21. FEBS Letters: 1996; 398: 135-140.

7. Olds LC, Sibley E. Lactase persistence DNA variant enhances lactase promoter activity in vitro: functional role as a cis regulatory element. Human Molecular Genetics 2003; 12(18): 2333-2340.

8. Ingram CJE, Elamin MF, Mulcare CA, et al. A novel polymorphism associated with lactose tolerance in Africa: multiple causes for lactase persistence? Hum Genet. 2007; 120: 779-788.

9. Lukito W, Malik SG, Surono IS, Wahlqvist ML. From ‘lactose intolerance’ to ‘lactose nutrition’. Asia Pac J Clin Nutr. 2015; 24: S1-S8.

10. Lomer MCE, Parkes GC, Sanderson JD. Review article: lactose intolerance in clinical practice - myths and realities. Aliment Pharmacol Ther. 2008; 27: 97-103.

11. Almeida CC, Lorena SLS, Pavan CR, et al. Beneficial effects of long-term consumption of a probiotic combination of Lactobacillus casei Shirota Bifidobacterium breve Yakult may persist after suspension of therapy in lactose-intolerant patients. Nutrition in Clinical Practice. 2012; 27(2): 247-251.