SNP Highlight - MCM6 & Lactose Intolerance

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 will take a look at lactose intolerance, why it occurs, and what variations in a gene called MCM6 may tell you about your 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 normal mother’s milk weaning. In adulthood, the absence of lactase translates to lactose intolerance.

It is one of the most common food intolerances primarily because it is our human ancestral or “wild type” state. In fact, what scientists call lactase persistence or the ability to digest lactose into adulthood was 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 MCM6 Gene Involved?

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

MCM6 (Mini Chromosome 6) 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 european caucasian ancestry. In Arab and Northern African populations there is a third MCM6 variant, rs41380347, where the minor allele G gives lactase persistence in a similar fashion (8).

Lifestyle Recommendations

If you contain either CC genotype (in rs4988235 or rs182549) or the TT genotype (in rs41380347) for lactase non-persistence, then you are at risk for lactose intolerance.

However, this does not necessarily mean you’ll experience those lactose intolerance symptoms.

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 showed a disconnect between lactose intake and intolerance symptoms in lactose non-persisters (9).

Instead a larger association points to 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 a pure lactose intolerance. Therefore, if you’re experiencing continuing intolerance symptoms you’ll want to talk with your doctor.

If you do experience symptoms of lactose intolerance, you may want to avoid dairy products altogether, but you also don’t necessarily have to. If you keep your lactose intake 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 giving you valuable osteoporosis-preventing calcium (9). There are also a wide-range lactose-free or lactase-added dairy products which can help circumvent the issue. And lastly, studies have indicated that probiotic intake such as those found in yogurt may help to reduce or prevent some intolerance symptoms (11).

Knowing your genetics and listening to your 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.