Michaëlsson and colleagues [1] have reported a correlation between high milk intake and higher mortality. The higher mortality of fluid milk consumers may be unrelated to milk consumption, but may instead reflect the different genetic backgrounds of those able to digest lactose compared with those who cannot.
DNA mutations that led to the ability to drink milk into adulthood had such a profound affect on the survival of our ancestors that this allele rapidly became dominant. This happened repeatedly in independent populations [2-4]. Lactase persistence has exerted stronger selective pressure than any other known human gene [5].
It is well known that positive selection of a highly favorable mutation enables nearby deleterious mutations also to become more frequent [6]. This “hitchhiking” of deleterious mutations has even been observed near the lactase (LCT) gene [7]. As genome wide association studies point to thousands of DNA variants that contribute to cardiovascular disease [8] and osteoporosis [9], there is reason to believe that those who can consume lactose will have a different disease risk from those who cannot, independent of whether they actually drink milk. This may be especially true among Europeans, given the strong sweep of their 13,910*T allele [10].
In the study by Michaëlsson and colleagues [1], it is likely that a higher proportion of the study subjects drinking 0 or 1 glass of milk per day were lactose intolerant, compared with study subjects drinking more glasses of milk per day. It is also likely that the lactose intolerant subset of the study population consumed more cheese and fermented milk products. The presence of one or two lactase persistence alleles has been shown to have a dosage effect on lactase activity [11]. Therefore, it could even be argued that the presence of one or two lactase persistence alleles provides a dosage effect on both the ability to consume more glasses of milk per day and the exposure to more unfavorable genetic mutations. Thus, the genetic background of study subjects is a confounding variable that may explain the association between high milk intake and higher mortality.
Further study of the genetic backgrounds of those who can and cannot digest fluid milk is needed to assess disease risk independent of modern-day milk consumption. When those who can consume milk do not, the disease risk associated with their genetic heritage is unchanged, and it is possible they may make things worse by not drinking milk. Long-term prospective randomized trials are sorely needed. In the meantime, observational studies involving milk consumption need to consider the genetic backgrounds of their study subjects.
Danielle G. Lemay, PhD, Genome Center, University of California-Davis. Email: dglemay@ucdavis.edu
References
1. Michaelsson K, Wolk A, Langenskiold S, Basu S, Warensjo Lemming E, Melhus H, Byberg L: Milk intake and risk of mortality and fractures in women and men: cohort studies. BMJ 2014, 349:g6015.
2. Tishkoff SA, Reed FA, Ranciaro A, Voight BF, Babbitt CC, Silverman JS, Powell K, Mortensen HM, Hirbo JB, Osman M et al: Convergent adaptation of human lactase persistence in Africa and Europe. Nature genetics 2007, 39(1):31-40.
3. Enattah NS, Jensen TG, Nielsen M, Lewinski R, Kuokkanen M, Rasinpera H, El-Shanti H, Seo JK, Alifrangis M, Khalil IF et al: Independent introduction of two lactase-persistence alleles into human populations reflects different history of adaptation to milk culture. American journal of human genetics 2008, 82(1):57-72.
4. Jones BL, Raga TO, Liebert A, Zmarz P, Bekele E, Danielsen ET, Olsen AK, Bradman N, Troelsen JT, Swallow DM: Diversity of lactase persistence alleles in Ethiopia: signature of a soft selective sweep. American journal of human genetics 2013, 93(3):538-544.
5. Bersaglieri T, Sabeti PC, Patterson N, Vanderploeg T, Schaffner SF, Drake JA, Rhodes M, Reich DE, Hirschhorn JN: Genetic signatures of strong recent positive selection at the lactase gene. American journal of human genetics 2004, 74(6):1111-1120.
6. Hartfield M, Otto SP: Recombination and hitchhiking of deleterious alleles. Evolution; international journal of organic evolution 2011, 65(9):2421-2434.
7. Chun S, Fay JC: Evidence for hitchhiking of deleterious mutations within the human genome. PLoS genetics 2011, 7(8):e1002240.
8. Ndiaye NC, Azimi Nehzad M, El Shamieh S, Stathopoulou MG, Visvikis-Siest S: Cardiovascular diseases and genome-wide association studies. Clinica chimica acta; international journal of clinical chemistry 2011, 412(19-20):1697-1701.
9. Urano T, Inoue S: Genetics of osteoporosis. Biochemical and biophysical research communications 2014, 452(2):287-293.
10. Itan Y, Powell A, Beaumont MA, Burger J, Thomas MG: The origins of lactase persistence in Europe. PLoS computational biology 2009, 5(8):e1000491.
11. Flatz G: Gene-dosage effect on intestinal lactase activity demonstrated in vivo. American journal of human genetics 1984, 36(2):306-310.
Competing interests:
Dr. Lemay receives funding from the California Dairy Research Foundation. She is also the Executive Editor of “SPLASH! milk science update”, the monthly e-newletter of the International Milk Genomics Consortium (http://milkgenomics.org/splash-newsletter).
11 December 2014
Danielle G Lemay
Associate Professional Researcher and Genome Center Faculty Member
Rapid Response:
Michaëlsson and colleagues [1] have reported a correlation between high milk intake and higher mortality. The higher mortality of fluid milk consumers may be unrelated to milk consumption, but may instead reflect the different genetic backgrounds of those able to digest lactose compared with those who cannot.
DNA mutations that led to the ability to drink milk into adulthood had such a profound affect on the survival of our ancestors that this allele rapidly became dominant. This happened repeatedly in independent populations [2-4]. Lactase persistence has exerted stronger selective pressure than any other known human gene [5].
It is well known that positive selection of a highly favorable mutation enables nearby deleterious mutations also to become more frequent [6]. This “hitchhiking” of deleterious mutations has even been observed near the lactase (LCT) gene [7]. As genome wide association studies point to thousands of DNA variants that contribute to cardiovascular disease [8] and osteoporosis [9], there is reason to believe that those who can consume lactose will have a different disease risk from those who cannot, independent of whether they actually drink milk. This may be especially true among Europeans, given the strong sweep of their 13,910*T allele [10].
In the study by Michaëlsson and colleagues [1], it is likely that a higher proportion of the study subjects drinking 0 or 1 glass of milk per day were lactose intolerant, compared with study subjects drinking more glasses of milk per day. It is also likely that the lactose intolerant subset of the study population consumed more cheese and fermented milk products. The presence of one or two lactase persistence alleles has been shown to have a dosage effect on lactase activity [11]. Therefore, it could even be argued that the presence of one or two lactase persistence alleles provides a dosage effect on both the ability to consume more glasses of milk per day and the exposure to more unfavorable genetic mutations. Thus, the genetic background of study subjects is a confounding variable that may explain the association between high milk intake and higher mortality.
Further study of the genetic backgrounds of those who can and cannot digest fluid milk is needed to assess disease risk independent of modern-day milk consumption. When those who can consume milk do not, the disease risk associated with their genetic heritage is unchanged, and it is possible they may make things worse by not drinking milk. Long-term prospective randomized trials are sorely needed. In the meantime, observational studies involving milk consumption need to consider the genetic backgrounds of their study subjects.
Danielle G. Lemay, PhD, Genome Center, University of California-Davis. Email: dglemay@ucdavis.edu
References
1. Michaelsson K, Wolk A, Langenskiold S, Basu S, Warensjo Lemming E, Melhus H, Byberg L: Milk intake and risk of mortality and fractures in women and men: cohort studies. BMJ 2014, 349:g6015.
2. Tishkoff SA, Reed FA, Ranciaro A, Voight BF, Babbitt CC, Silverman JS, Powell K, Mortensen HM, Hirbo JB, Osman M et al: Convergent adaptation of human lactase persistence in Africa and Europe. Nature genetics 2007, 39(1):31-40.
3. Enattah NS, Jensen TG, Nielsen M, Lewinski R, Kuokkanen M, Rasinpera H, El-Shanti H, Seo JK, Alifrangis M, Khalil IF et al: Independent introduction of two lactase-persistence alleles into human populations reflects different history of adaptation to milk culture. American journal of human genetics 2008, 82(1):57-72.
4. Jones BL, Raga TO, Liebert A, Zmarz P, Bekele E, Danielsen ET, Olsen AK, Bradman N, Troelsen JT, Swallow DM: Diversity of lactase persistence alleles in Ethiopia: signature of a soft selective sweep. American journal of human genetics 2013, 93(3):538-544.
5. Bersaglieri T, Sabeti PC, Patterson N, Vanderploeg T, Schaffner SF, Drake JA, Rhodes M, Reich DE, Hirschhorn JN: Genetic signatures of strong recent positive selection at the lactase gene. American journal of human genetics 2004, 74(6):1111-1120.
6. Hartfield M, Otto SP: Recombination and hitchhiking of deleterious alleles. Evolution; international journal of organic evolution 2011, 65(9):2421-2434.
7. Chun S, Fay JC: Evidence for hitchhiking of deleterious mutations within the human genome. PLoS genetics 2011, 7(8):e1002240.
8. Ndiaye NC, Azimi Nehzad M, El Shamieh S, Stathopoulou MG, Visvikis-Siest S: Cardiovascular diseases and genome-wide association studies. Clinica chimica acta; international journal of clinical chemistry 2011, 412(19-20):1697-1701.
9. Urano T, Inoue S: Genetics of osteoporosis. Biochemical and biophysical research communications 2014, 452(2):287-293.
10. Itan Y, Powell A, Beaumont MA, Burger J, Thomas MG: The origins of lactase persistence in Europe. PLoS computational biology 2009, 5(8):e1000491.
11. Flatz G: Gene-dosage effect on intestinal lactase activity demonstrated in vivo. American journal of human genetics 1984, 36(2):306-310.
Competing interests: Dr. Lemay receives funding from the California Dairy Research Foundation. She is also the Executive Editor of “SPLASH! milk science update”, the monthly e-newletter of the International Milk Genomics Consortium (http://milkgenomics.org/splash-newsletter).