Lactose digestion and the evolutionary genetics of lactase persistence

Human Genetics

Volumn 124, Issue 6, 2009, Pages 579-591

  Ingram, Catherine J E ^a   Mulcare, Charlotte A ^a   Itan, Yuval ^a   Thomas, Mark G ^a   Swallow, Dallas M ^a  

^a UNIVERSITY COLLEGE LONDON   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

CYTOSINE; HEPATOCYTE NUCLEAR FACTOR 3ALPHA; HEPATOCYTE NUCLEAR FACTOR 4ALPHA; LACTASE; LACTOSE; MINICHROMOSOME MAINTENANCE PROTEIN 6; OCTAMER TRANSCRIPTION FACTOR 1; THYMINE; TRANSCRIPTION FACTOR CDX2; TRANSCRIPTION FACTOR GATA;

ALLELE; DIGESTION; ENHANCER REGION; ENZYME SYNTHESIS; EUROPE; GENE EXPRESSION REGULATION; GENE FREQUENCY; GENE SEQUENCE; GENETIC CONSERVATION; GENETIC POLYMORPHISM; GENETIC SELECTION; GENETIC TRAIT; GENETIC VARIABILITY; HAPLOTYPE; HETEROZYGOSITY; HOMOZYGOSITY; HUMAN; LACTOSE INTOLERANCE; NEGRO; NONHUMAN; PATHOGENESIS; PHENOTYPE; POPULATION GENETICS; PRIORITY JOURNAL; RACE DIFFERENCE; REVIEW; SINGLE NUCLEOTIDE POLYMORPHISM;

AFRICA; ALLELES; BASE SEQUENCE; CELL CYCLE PROTEINS; DIGESTION; EVOLUTION, MOLECULAR; GENETICS, POPULATION; HAPLOTYPES; HUMANS; LACTASE; LACTOSE; LACTOSE INTOLERANCE; LACTOSE TOLERANCE TEST; MOLECULAR SEQUENCE DATA; POLYMORPHISM, SINGLE NUCLEOTIDE;

EID: 58049125559     PISSN: 03406717     EISSN: None     Source Type: Journal    
DOI: 10.1007/s00439-008-0593-6     Document Type: Review

References (108)

1. Anderson B, Vullo C (1994) Did malaria select for primary adult lactase deficiency? Gut 35:1487-1489
2. Aoki K (1986) A stochastic model of gene-culture coevolution suggested by the culture-historical hypothesis. Proc Natl Acad Sci USA 83:2929-2933
3. Auricchio S, Rubino A, Semenza G, Landolt M, Prader A (1963) Isolated intestinal lactase deficiency in the adult. Lancet 2:324-326
4. Bayoumi RA, Saha N, Salih AS, Bakkar AE, Flatz G (1981) Distribution of the lactase phenotypes in the population of the Democratic Republic of the Sudan. Hum Genet 57:279-281
5. Bayoumi RA, Flatz SD, Kuhnau W, Flatz G (1982) Beja and Nilotes: Nomadic pastoralist groups in the Sudan with opposite distributions of the adult lactase phenotypes. Am J Phys Anthropol 58:173-178
6. Beja-Pereira A, Luikart G, England PR, Bradley DG, Jann OC, Bertorelle G, Chamberlain AT, Nunes TP, Metodiev S, Ferrand N, Erhardt G (2003) Gene-culture coevolution between cattle milk protein genes and human lactase genes. Nat Genet 35:311-313
7. Bernardes-Silva CF, Pereira AC, de Fatima Alves da Mota, Krieger JE, Laudanna AA (2007) Lactase persistence/non-persistence variants, C/ T_13910 and G/A_22018, as a diagnostic tool for lactose intolerance in IBS patients. Clin Chim Acta 386:7-11
8. Bersaglieri T, Sabeti PC, Patterson N, Vanderploeg T, Schaffner SF, Drake JA, Rhodes M, Reich DE, Hirschhorn JN (2004) Genetic signatures of strong recent positive selection at the lactase gene. Am J Hum Genet 74:1111-1120
9. Bloom G, Sherman PW (2005) Dairying barriers affect the distribution of lactose malabsorption. Evol Human Behav 26:301-312
10. Boll W, Wagner P, Mantei N (1991) Structure of the chromosomal gene and CDNAs coding for lactase-phlorizin hydrolase in humans with adult-type hypolactasia or persistence of lactase. Am J Hum Genet 48:889-902
11. Bosse T, Piaseckyj CM, Burghard E, Fialkovich JJ, Rajagopal S, Pu WT, Krasinski SD (2006a) Gata4 is essential for the maintenance of jejunal-ileal identities in the adult mouse small intestine. Mol Cell Biol 26:9060-9070
12. Bosse T, van Wering HM, Gielen M, Dowling LN, Fialkovich JJ, Piaseckyj CM, Gonzalez FJ, Akiyama TE, Montgomery RK, Grand RJ, Krasinski SD (2006b) Hepatocyte nuclear factor-1alpha is required for expression but dispensable for histone acetylation of the lactase-phlorizin hydrolase gene in vivo. Am J Physiol Gastrointest Liver Physiol 290:G1016-G1024
13. Bosse T, Fialkovich JJ, Piaseckyj CM, Beuling E, Broekman H, Grand RJ, Montgomery RK, Krasinski SD (2007) Gata4 and Hnf1alpha are partially required for the expression of specific intestinal genes during development. Am J Physiol Gastrointest Liver Physiol 292:G1302-G1314
14. Briet F, Pochart P, Marteau P, Flourie B, Arrigoni E, Rambaud JC (1997) Improved clinical tolerance to chronic lactose ingestion in subjects with lactose intolerance: A placebo effect? Gut 41:632-635
15. Buller HA, Kothe MJC, Goldman DA, Grubman SA, Sasak WV, Matsudaira PT, Montgomery RK, Grand RJ (1990) Coordinate expression of lactase-phlorizin hydrolase mRNA and enzyme levels in rat intestine during development. J Biol Chem 265:6978-6983
16. Burger J, Kirchner M, Bramanti B, Haak W, Thomas MG (2007) Absence of the lactase-persistence-associated allele in early Neolithic Europeans. Proc Natl Acad Sci USA 104:3736-3741
17. Campbell AK, Matthews SB (2005) Darwin's illness revealed. Postgrad Med J 81:248-251
18. Coelho M, Luiselli D, Bertorelle G, Lopes AI, Seixas S, stro-Bisol G, Rocha J (2005) Microsatellite variation and evolution of human lactase persistence. Hum Genet 117:329-339
19. Cook GC, al-Torki MT (1975) High intestinal lactase concentrations in adult Arabs in Saudi Arabia. Br Med J 3:135-136
20. Crittenden RG, Bennett LE (2005) Cow's milk allergy: A complex disorder. J Am Coll Nutr 24:582S-591S
21. Dahlqvist A, Hammond B, Crane R, Dunphy J, Littman A (1963) Intestinal lactase deficiency and lactose intolerance in adults: Preliminary report. Gastroenterology 45:488-491
22. Dissanyake AS, El-Munshid HA, Al-Qurain A (1990) Prevalence of primary adult lactose malabsorption in the eastern province of Saudi Arabia. Ann Saudi Med 10:598-601
23. Enattah NS, Sahi T, Savilahti E, Terwilliger JD, Peltonen L, Jarvela I (2002) Identification of a variant associated with adult-type hypolactasia. Nat Genet 30:233-237
24. Enattah NS, Forsblom C, Rasinpera H, Tuomi T, Groop PH, Jarvela I (2004) The genetic variant of lactase persistence C (-13910) T as a risk factor for type I and II diabetes in the Finnish population. Eur J Clin Nutr 58:1319-1322
25. Enattah N, Pekkarinen T, Valimaki MJ, Loyttyniemi E, Jarvela I (2005a) Genetically defined adult-type hypolactasia and self-reported lactose intolerance as risk factors of osteoporosis in Finnish postmenopausal women. Eur J Clin Nutr 59:1105-1111
26. Enattah NS, Sulkava R, Halonen P, Kontula K, Jarvela I (2005b) Genetic variant of lactase-persistent C/T-13910 is associated with bone fractures in very old age. J Am Geriatr Soc 53:79-82
27. Enattah NS, Trudeau A, Pimenoff V, Maiuri L, Auricchio S, Greco L, Rossi M, Lentze M, Seo JK, Rahgozar S, Khalil I, Alifrangis M, Natah S, Groop L, Shaat N, Kozlov A, Verschubskaya G, Comas D, Bulayeva K, Mehdi SQ, Terwilliger JD, Sahi T, Savilahti E, Perola M, Sajantila A, Jarvela I, Peltonen L (2007) Evidence of still-ongoing convergence evolution of the lactase persistence T-13910 alleles in humans. Am J Hum Genet 81:615-625
28. Enattah NS, Jensen TG, Nielsen M, Lewinski R, Kuokkanen M, Rasinpera H, El-Shanti H, Seo JK, Alifrangis M, Khalil IF, Natah A, Ali A, Natah S, Comas D, Mehdi SQ, Groop L, Vestergaard EM, Imtiaz F, Rashed MS, Meyer B, Troelsen J, Peltonen L (2008) Independent introduction of two lactase-persistence alleles into human populations reflects different history of adaptation to milk culture. Am J Hum Genet 82:57-72
29. Escher JC, de Koning ND, van Engen CG, Arora S, Buller HA, Montgomery RK, Grand RJ (1992) Molecular basis of lactase levels in adult humans. J Clin Invest 89:480-483
30. Fang R, Santiago NA, Olds LC, Sibley E (2000) The homeodomain protein Cdx2 regulates lactase gene promoter activity during enterocyte differentiation. Gastroenterology 118:115-127
31. Fang R, Olds LC, Santiago NA, Sibley E (2001) GATA family transcription factors activate lactase gene promoter in intestinal Caco-2 cells. Am J Physiol Gastrointest Liver Physiol 280:G58-G67
32. Ferguson A, Maxwell J (1967) Genetic aetiology of lactose intolerance. Lancet 2:188-190
33. Flatz G (1984) Gene dosage effect on intestinal lactase activity demonstrated in vivo. Am J Hum Genet 36:306-310
34. Flatz G (1987) Genetics of lactose digestion in humans. In: Harris H, Hirschhorn K (eds) Advances in human genetics, vol 16. Plenum Press, New York, pp 1-77
35. Flatz G, Rotthauwe HW (1973) Lactose nutrition and natural selection. Lancet 2:76-77
36. Gueguen L, Pointillart A (2000) The bioavailability of dietary calcium. J Am Coll Nutr 19:119S-136S
37. HapMap Consortium (2003) The International HapMap Project. Nature 426:789-796
38. Harju M (2003) Chromatographic and enzymatic removal of lactose from milk, IDF World Dairy Summit, Bruges, BELGIQUE (09/2003) 2004, no 389, pp 4-8
39. Harvey CB, Pratt WS, Islam I, Whitehouse DB, Swallow DM (1995) DNA polymorphisms in the lactase gene. Linkage disequilibrium across the 70-kb region. Eur J Hum Genet 3:27-41
40. Harvey CB, Hollox EJ, Poulter M, Wang Y, Rossi M, Auricchio S, Iqbal TH, Cooper BT, Barton R, Sarner M, Korpela R, Swallow DM (1998) Lactase haplotype frequencies in Caucasians: Association with the lactase persistence/non-persistence polymorphism. Ann Hum Genet 62(Pt 3):215-223
41. Hauri HP, Sterchi EE, Bienz D, Fransen JA, Marxer A (1985) Expression and intracellular transport of microvillus membrane hydrolases in human intestinal epithelial cells. J Cell Biol 101:838-851
42. Hertzler SR, Savaiano DA (1996) Colonic adaptation to daily lactose feeding in lactose maldigesters reduces lactose intolerance. Am J Clin Nutr 64:232-236
43. Hertzler SR, Savaiano DA, Levitt MD (1997) Fecal hydrogen production and consumption measurements - response to daily lactose ingestion by lactose maldigesters. Dig Dis Sci 42:348-353
44. Ho MW, Povey S, Swallow DM (1982) Lactase polymorphism in adult British natives: Estimating allele frequencies by enzyme assays in autopsy samples. Am J Hum Genet 34:650-657
45. Hogenauer C, Hammer HF, Mellitzer K, Renner W, Krejs GJ, Toplak H (2005) Evaluation of a new DNA test compared with the lactose hydrogen breath test for the diagnosis of lactase non-persistence. Eur J Gastroenterol Hepatol 17:371-376
46. Holden C, Mace R (1997) Phylogenetic analysis of the evolution of lactose digestion in adults. Hum Biol 69:605-628
47. Hollox EJ, Poulter M, Wang Y, Krause A, Swallow DM (1999) Common polymorphism in a highly variable region upstream of the human lactase gene affects DNA-protein interactions. Eur J Hum Genet 7:791-800
48. Hollox EJ, Poulter M, Zvarik M, Ferak V, Krause A, Jenkins T, Saha N, Kozlov AI, Swallow DM (2001) Lactase haplotype diversity in the Old World. Am J Hum Genet 68:160-172
49. Imtiaz F, Savilahti E, Sarnesto A, Trabzuni D, Al-Kahtani K, Kagevi I, Rashed MS, Meyer BF, Jarvela I (2007) The T/G 13915 variant upstream of the lactase gene (LCT) is the founder allele of lactase persistence in an urban Saudi population. J Med Genet 44:e89
50. Ingram CJE (2008) The evolutionary genetics of lactase persistence in Africa and the Middle East. Ph.D. thesis University of London
51. Ingram CJE, Elamin MF, Mulcare CA, Weale ME, Tarekegn A, Raga TO, Bekele E, Elamin FM, Thomas MG, Bradman N, Swallow DM (2007) A novel polymorphism associated with lactose tolerance in Africa: Multiple causes for lactase persistence? Hum Genet 120:779-788
52. Jacob R, Brewer C, Fransen JA, Naim HY (1994) Transport, function, and sorting of lactase-phlorizin hydrolase in Madin-Darby canine kidney cells. J Biol Chem 269:2712-2721
53. Jacob R, Bulleid NJ, Naim HY (1995) Folding of human intestinal lactase-phlorizin hydrolase. J Biol Chem 270:18678-18684
54. Jacob R, Radebach I, Wuthrich M, Grunberg J, Sterchi EE, Naim HY (1996) Maturation of human intestinal lactase-phlorizin hydrolase: Generation of the brush border form of the enzyme involves at least two proteolytic cleavage steps. Eur J Biochem 236:789-795
55. Jacob R, Peters K, Naim HY (2002) The prosequence of human lactase-phlorizin hydrolase modulates the folding of the mature enzyme. J Biol Chem 277:8217-8225
56. Kerber M, Oberkanins C, Kriegshauser G, Kollerits B, senbach-Glaninger A, Fuchs D, Ledochowski M (2007) Hydrogen breath testing versus LCT genotyping for the diagnosis of lactose intolerance: A matter of age? Clin Chim Acta 383:91-96
57. Krasinski SD, van Wering HM, Tannemaat MR, Grand RJ (2001) Differential activation of intestinal gene promoters: Functional interactions between GATA-5 and HNF-1 alpha. Am J Physiol Gastrointest Liver Physiol 281:G69-G84
58. Lacey SW, Naim HY, Magness RR, Gething M-J, Sambrook JF (1994) Expression of lactase-phlorizin hydrolase in sheep is regulated at the RNA level. Biochem J 302:929-935
59. Larsson SC, Orsini N, Wolk A (2006) Milk, milk products and lactose intake and ovarian cancer risk: A meta-analysis of epidemiological studies. Int J Cancer 118:431-441
60. Lee SY, Wang Z, Lin CK, Contag CH, Olds LC, Cooper AD, Sibley E (2002) Regulation of intestine-specific spatiotemporal expression by the rat lactase promoter. J Biol Chem 277:13099-13105
61. Lewinsky RH, Jensen TG, Moller J, Stensballe A, Olsen J, Troelsen JT (2005) T-13910 DNA variant associated with lactase persistence interacts with Oct-1 and stimulates lactase promoter activity in vitro. Hum Mol Genet 14:3945-3953
62. Lloyd M, Mevissen G, Fischer M, Olsen W, Goodspeed D, Genini M, Boll W, Semenza G, Mantei N (1992) Regulation of intestinal lactase in adult hypolactasia. J Clin Invest 89:524-529
63. Maiuri L, Raia V, Potter J, Swallow DM, Ho MW, Fiocca R, Finzi G, Cornaggia M, Capella C, Quaroni A, Auricchio S (1991) Mosaic pattern of lactase expression in villous enterocytes in human adult-type hypolactasia. Gastroenterology 100:359-369
64. Maiuri L, Rossi M, Raia V, Garipoli V, Hughes LA, Swallow D, Noren O, Sjostrom H, Auricchio S (1994) Mosaic regulation of lactase in human adult-type hypolactasia. Gastroenterology 107:54-60
65. Matthews SB, Waud JP, Roberts AG, Campbell AK (2005) Systemic lactose intolerance: A new perspective on an old problem. Postgrad Med J 81:167-173
66. McCracken RD (1971) Lactase deficiency - example of dietary evolution. Curr Anthropol 12:479
67. Meloni T, Colombo C, Ruggiu G, Dessena M, Meloni GF (1998) Primary lactase deficiency and past malarial endemicity in Sardinia. Ital J Gastroenterol Hepatol 30:490-493
68. Meloni GF, Colombo C, La VC, Ruggiu G, Mannazzu MC, Ambrosini G, Cherchi PL (1999) Lactose absorption in patients with ovarian cancer. Am J Epidemiol 150:183-186
69. Meloni GF, Colombo C, La VC, Pacifico A, Tomasi P, Ogana A, Marinaro AM, Meloni T (2001) High prevalence of lactose absorbers in Northern Sardinian patients with type 1 and type 2 diabetes mellitus. Am J Clin Nutr 73:582-585
70. Metneki J, Cziezel A, Flatz SD, Flatz G (1984) A study of lactose absorption capacity in twins. Hum Genet 67:296-300
71. Mitchelmore C, Troelsen JT, Spodsberg N, Sjostrom H, Noren O (2000) Interaction between the homeodomain proteins Cdx2 and HNF1alpha mediates expression of the lactase-phlorizin hydrolase gene. Biochem J 346(Pt 2):529-535
72. Mulcare (2006) The evolution of the lactase persistence phenotype. Ph.D. thesis University of London, London, UK
73. Mulcare CA, Weale ME, Jones AL, Connell B, Zeitlyn D, Tarekegn A, Swallow DM, Bradman N, Thomas MG (2004) The T allele of a single-nucleotide polymorphism 13.9 kb upstream of the lactase gene (LCT) (C-13.9kbT) does not predict or cause the lactase-persistence phenotype in Africans. Am J Hum Genet 74:1102-1110
74. Naim HY, Lentze MJ (1992) Impact of O -glycosylation on the function of human intestinal lactase-phlorizin hydrolase. Characterization of glycoforms varying in enzyme activity and localization of O -glycoside addition. J Biol Chem 267:25494-25504
75. Newcomer AD, McGill DB, Thomas PJ, Hofmann AF (1975) Prospective comparison of indirect methods for detecting lactase deficiency. N Engl J Med 293:1232-1236
76. Obermayer-Pietsch BM, Bonelli CM, Walter DE, Kuhn RJ, Fahrleitner-Pammer A, Berghold A, Goessler W, Stepan V, Dobnig H, Leb G, Renner W (2004) Genetic predisposition for adult lactose intolerance and relation to diet, bone density, and bone fractures. J Bone Miner Res 19:42-47
77. Olds LC, Sibley E (2003) Lactase persistence DNA variant enhances lactase promoter activity in vitro: Functional role as a cis regulatory element. Hum Mol Genet 12:2333-2340
78. Peuhkuri (2000) Lactose, lactase, and bowel disorders, Ph.D. thesis, University of Helsinki, Finland
79. Peuhkuri K, Vapaatalo H, Korpela R, Teuri U (2000) Lactose intolerance - a confusing clinical diagnosis. Am J Clin Nutr 71:600-602
80. Poulter M, Hollox E, Harvey CB, Mulcare C, Peuhkuri K, Kajander K, Sarner M, Korpela R, Swallow DM (2003) The causal element for the lactase persistence/non-persistence polymorphism is located in a 1 Mb region of linkage disequilibrium in Europeans. Ann Hum Genet 67:298-311
81. Rasinpera H, Savilahti E, Enattah NS, Kuokkanen M, Totterman N, Lindahl H, Jarvela I, Kolho KL (2004) A genetic test which can be used to diagnose adult-type hypolactasia in children. Gut 53:1571-1576
82. Sabeti PC, Schaffner SF, Fry B, Lohmueller J, Varilly P, Shamovsky O, Palma A, Mikkelsen TS, Altshuler D, Lander ES (2006) Positive natural selection in the human lineage. Science 312:1614-1620
83. Sahi T (1974) The inheritance of selective adult-type lactose malabsorption. Scand J Gastroenterol 9:1-73
84. Saltzman JR, Russell RM, Golner B, Barakat S, Dallal GE, Goldin BR (1999) A randomized trial of Lactobacillus acidophilus BG2FO4 to treat lactose intolerance. Am J Clin Nutr 69:140-146
85. Scrimshaw NS, Murray EB (1988) The acceptability of milk and milk products in populations with a high prevalence of lactose intolerance. Am J Clin Nutr 48:1079-1159
86. Sebastio G, Villa M, Sartorio R, Guzzetta V, Poggi V, Auricchio S, Boll W, Mantei N, Semenza G (1989) Control of lactase in human adult-type hypolactasia and in weaning rabbits and rats. Am J Hum Genet 45:489-497
87. Simoons FJ (1970) Primary lactose intolerance and the milking habit: A problem in biological and cultural interrelations, II. A culture historical hypothesis. Am J Dig Dis 15:695-710
88. Simoons FJ (1978) The geographic hypothesis and lactose malabsorption - a weighing of the evidence. Dig Dis 23:963-980
89. Snook CR, Mahmoud JN, Chang WP (1976) Lactose tolerance in adult Jordanian Arabs. Trop Geogr Med 28:333-335
90. Spodsberg N, Troelsen JT, Carlsson P, Enerback S, Sjostrom H, Noren O (1999) Transcriptional regulation of pig lactase-phlorizin hydrolase. Involvement of HNF-1 and FREACs. Gastroenterology 116:842-854
91. Sterchi E, Mills P, Fransen J, Hauri H, Lentze M, Naim H, Ginsel L, Bond J (1990) Biogenesis of intestinal lactase-phlorizin hydrolase in adults with lactose intolerance. Evidence for reduced biosynthesis and slowed-down maturation in enterocytes. J Clin Invest 86:1329-1337
92. Suarez FL, Savaiano D, Arbisi P, Levitt MD (1997) Tolerance to the daily ingestion of two cups of milk by individuals claiming lactose intolerance. Am J Clin Nutr 65:1502-1506
93. Swallow DM (2006) DNA test for hypolactasia premature. Gut 55:131-132
94. Swallow DM, Hollox EJ (2000) The genetic polymorphism of intestinal lactase activity in adult humans. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic and molecular basis of inherited disease. McGraw-Hill, New York, pp 1651-1662
95. Tag CG, Schifflers MC, Mohnen M, Gressner AM, Weiskirchen R (2007) A novel proximal -13914G > A base replacement in the vicinity of the common-13910T/C lactase gene variation results in an atypical LightCycler melting curve in testing with the MutaREAL lactase test. Clin Chem 53:146-148
96. Tag CG, Oberkanins C, Kriegshauser G, Ingram CJ, Swallow DM, Gressner AM, Ledochowski M, Weiskirchen R (2008) Evaluation of a novel reverse-hybridization StripAssay for typing DNA variants useful in diagnosis of adult-type hypolactasia. Clin Chim Acta 392:58-62
97. Thacher TD, Fischer PR, Pettifor JM, Lawson JO, Isichei CO, Reading JC, Chan GM (1999) A comparison of calcium, vitamin D, or both for nutritional rickets in Nigerian children. N Engl J Med 341:563-568
98. Tishkoff SA, Reed FA, Ranciaro A, Voight BF, Babbitt CC, Silverman JS, Powell K, Mortensen HM, Hirbo JB, Osman M, Ibrahim M, Omar SA, Lema G, Nyambo TB, Ghori J, Bumpstead S, Pritchard JK, Wray GA, Deloukas P (2007) Convergent adaptation of human lactase persistence in Africa and Europe. Nat Genet 39:31-40
99. Troelsen JT, Mehlum A, Olsen J, Spodsberg N, Hansen GH, Prydz H, Noren O, Sjostrom H (1994) 1 kb of the lactase-phlorhizin hydrolase promoter directs post-weaning decline and small intestinal-specific expression in transgenic mice. FEBS Lett 342:291-296
100. Troelsen JT, Mitchelmore C, Spodsberg N, Jensen AM, Noren O, Sjostrom H (1997) Regulation of lactase-phlorizin hydrolase gene expression by the caudal-related homoeodomain protein Cdx-2. Biochem J 322(Pt 3):833-838
101. Troelsen JT, Olsen J, Moller J, Sjostrom H (2003) An upstream polymorphism associated with lactase persistence has increased enhancer activity. Gastroenterology 125:1686-1694
102. van Wering HM, Bosse T, Musters A, de Jong E, de Jong N, Hogen Esch CE, Boudreau F, Swain GP, Dowling LN, Montgomery RK, Grand RJ, Krasinski SD (2004) Complex regulation of the lactase-phlorizin hydrolase promoter by GATA-4. Am J Physiol Gastrointest Liver Physiol 287(4):G899-909
103. Vesa TH, Marteau P, Korpela R (2000) Lactose intolerance. J Am Coll Nutr 19:165S-175S
104. Villako K, Maaroos H (1994) Clinical picture of hypolactasia and lactose intolerance. Scand J Gastroenterol Suppl 202:36-54
105. Wang Y, Harvey CB, Pratt WS, Sams VR, Sarner M, Rossi M, Auricchio S, Swallow DM (1995) The lactase persistence/non-persistence polymorphism is controlled by a cis-acting element. Hum Mol Genet 4:657-662
106. Wang Z, Maravelias C, Sibley E (2006) Lactase gene promoter fragments mediate differential spatial and temporal expression patterns in transgenic mice. DNA Cell Biol 25:215-222
107. Weiskirchen, Tag CG, Mengsteab S, Gressner AM, Ingram CJE, Swallow DM (2007) Pitfalls in LightCycler Diagnosis of the single-nucleotide polymorphism 13.9 kb upstream of the lactase gene that is associated with adult-type hypolactasia
108. Witte J, Lloyd M, Lorenzsonn V, Korsmo H, Olsen W (1990) The biosynthetic basis of adult lactase deficiency. J Clin Invest 86:1338-1342