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Identification of a variant associated with adult-type hypolactasia

Nature Genetics volume 30, pages 233–237 (2002)Cite this article

Abstract

Adult-type hypolactasia, also known as lactase non-persistence (lactose intolerance), is a common autosomal recessive condition resulting from the physiological decline in activity of the lactase-phlorizin hydrolase (LPH) in intestinal cells after weaning. LPH hydrolyzes lactose into glucose and galactose. Sequence analyses of the coding and promoter regions of LCT, the gene encoding LPH, has revealed no DNA variations correlating with lactase non-persistence1,2. An associated haplotype spanning LCT, as well as a distinct difference in the transcript levels of 'non-persistence' and 'persistence' alleles in heterozygotes, suggest that a cis-acting element contributes to the lactase non-persistence phenotype3,4. Using linkage disequilibrium (LD) and haplotype analysis of nine extended Finnish families, we restricted the locus to a 47-kb interval on 2q21. Sequence analysis of the complete region and subsequent association analyses revealed that a DNA variant, C/T−13910, roughly 14 kb upstream from the LCT locus, completely associates with biochemically verified lactase non-persistence in Finnish families and a sample set of 236 individuals from four different populations. A second variant, G/A−22018, 8 kb telomeric to C/T−13910, is also associated with the trait in 229 of 236 cases. Prevalence of the C/T−13910 variant in 1,047 DNA samples is consistent with the reported prevalence of adult-type hypolactasia in four different populations. That the variant (C/T−13910) occurs in distantly related populations indicates that it is very old.

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Figure 1: Finnish families with lactase non-persistence (hypolactasia).
Figure 2: Physical map of adult lactase non-persistence locus.
Figure 3: The 150-kb haplotypes constructed with seven microsatellite markers in 33 Finnish lactase persistence alleles.

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References

  1. Boll, W., Wagner, P. & Mantei, N. Structure of the chromosomal gene and cDNAs coding for lactase-phlorizin hydrolase in human with adult-type hypolactasia or persistence of lactase. Am. J. Hum. Genet. 48, 889–902 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Mantei, N. et al. Complete primary structure of human and rabbit lactase-phlorizin hydrolase: implications for biosynthesis, membrane anchoring and evolution of the enzyme. EMBO J. 7, 2705–2713 (1988).

    Article  CAS  Google Scholar 

  3. Wang, Y. et al. The lactase persistence/non-persistence polymorphism is controlled by a cis-acting element. Hum. Mol. Genet. 4, 657–662 (1995).

    Article  CAS  Google Scholar 

  4. Harvey, C.B., Pratt, W.S., Islam, I., Whitehouse, D.B. & Swallow, D.M. DNA polymorphisms in the lactase gene: linkage disequilibrium across the 70 kb region. Eur. J. Hum. Genet. 3, 27–41 (1995).

    Article  CAS  Google Scholar 

  5. Sahi, T., Isokoski, M., Jussila, J. & Launiala, K. Lactose malabsorption in Finnish children of school age. Acta Paediatr. Scand. 61, 11–16 (1972).

    Article  CAS  Google Scholar 

  6. Wang, Y. et al. The genetically programmed down-regulation of lactase in children. Gastroenterology 114,1230–1236 (1998).

    Article  CAS  Google Scholar 

  7. Sahi, T. Genetics and epidemiology of adult-type hypolactasia. Scam. J. Gastroenterol. Suppl. 202, 7–20 (1994).

    Article  CAS  Google Scholar 

  8. Harvey C.B. et al. Lactase haplotype frequencies in Caucasians: association with the lactase persistence/non persistence polymorphism. Ann. Hum. Genet. 62, 215–223 (1998).

    Article  CAS  Google Scholar 

  9. Harvey, C.B. et al. Characterization 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 Lett. 398, 135–140 (1996).

    Article  CAS  Google Scholar 

  10. Syvänen, A.-C. & Landegren, U. Detection of point mutations by solid-phase methods. Hum. Mutat. 3, 172–179 (1994).

    Article  Google Scholar 

  11. Cuddenec, Y., Delbrück, H. & Flatz, G. Distribution of the adult lactase phenotypes lactose absorber and malabsorber in a group of 131 Army recruits. Gastroenterol. Clin. Biol. 6, 776–779 (1982).

    CAS  PubMed  Google Scholar 

  12. McLellan, T., Jorde, L.B. & Skolnick, M.H. Genetic distance between the Utah Mormons and related populations. Am. J. Hum. Genet. 36, 836–857 (1984).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Järvelä, I. et al. Assignment of the locus for congenital lactase deficiency to 2q21, in the vicinity of but separate from the lactase-phlorizin hydrolase gene. Am. J. Hum. Genet. 63, 1078–1085 (1998).

    Article  Google Scholar 

  14. Clare, H. & Ruth, M. Phylogenetic analysis of the evolution of lactose digestion in adults. Hum. Biol. 69, 605–628 (1997).

    Google Scholar 

  15. McCracken, R.D. Lactase deficiency: an example of dietary evolution. Curr. Anthropol. 12, 479–517 (1971).

    Article  Google Scholar 

  16. Arola, H. et al. Diagnosis of hypolactasia and lactose malabsorption. Scand. J. Gastroenterol. Suppl. 202, 26–35 (1994).

    Article  CAS  Google Scholar 

  17. Sahi, T. The inheritance of selective adult-type lactose malabsorption. Scand. J. Gastroenterol. Suppl. 30, 1–73 (1974).

    CAS  PubMed  Google Scholar 

  18. Sulkanen, S. et al. Tissue transglutaminase autoantibody enzyme-linked immunosorbent assay in detecting celiac disease. Gastroenterology 115, 1322–1328 (1998).

    Article  CAS  Google Scholar 

  19. Sambrook, J., Fritsch, E.F. & Maniatis, T. Molecular Cloning: A Laboratory Manual 2nd edn (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, 1989).

    Google Scholar 

  20. Messer, M. & Dahlqvist, A. A one-step ultramicro method for the assay of intestinal disaccharidases. Anal. Biochem. 14, 376–392 (1966).

    Article  CAS  Google Scholar 

  21. Cottingham, R.W. Jr, Idury, R.M. & Schaffer, A.A. Faster sequential genetic linkage computations. Am. J. Hum. Genet. 53, 252–263 (1993).

    PubMed  PubMed Central  Google Scholar 

  22. Lathrop, G.M., Lalouel, J-M., Julier, C. & Ott, J. Strategies for multilocus linkage analysis in humans. Proc. Natl Acad. Sci. USA 81, 3443–3446 (1984).

    Article  CAS  Google Scholar 

  23. Göring, H.H.H. & Terwilliger, J.D. Linkage analysis in the presence of errors III: marker loci and their map as nuisance parameters. Am. J. Hum. Genet. 66, 1298–1309 (2000).

    Article  Google Scholar 

  24. Göring, H.H.H. & Terwilliger, J.D. Linkage analysis in the presence of errors IV: joint pseudomarker analysis of linkage and/or linkage disequilibrium on a mixture of pedigrees and singletons when mode of inheritance cannot be accurately specified. Am. J. Hum. Genet. 66, 1310–1327 (2000).

    Article  Google Scholar 

  25. Krugliak, L., Daly, M.J., Reeve-Daly, M.P. & Lander, E. Parametric and nonparametric linkage analysis: a unified multipoint approach. Am. J. Hum. Genet. 58, 1347–1363 (1996).

    Google Scholar 

  26. Ihalainen, J., Siitari, H., Laine, S., Syvanen, A.-C. & Palotie, A. Towards automatic detection of point mutations: use of scintillating microplates in solid-phase minisequencing. Biotechniques 16, 938–943 (1994).

    CAS  PubMed  Google Scholar 

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Acknowledgements

We are grateful to the families who participated in this study. We thank M. Levander for assistance with minisequencing. This work was supported by The Academy of Finland, The Paediatric Research Foundation (Ulla Hjelt Fond), The Sigrid Jusélius Foundation and Helsinki University Hospital Research Funding and The National Institutes of Health (grant to J.D.T.).

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Authors and Affiliations

  1. Department of Molecular Medicine, National Public Health Institute, Haartmaninkatu 8, PO Box 104, Helsinki, FIN-00251

    Nabil Sabri Enattah, Leena Peltonen & Irma Järvelä

  2. Department of Medical Genetics, University of Helsinki, Finland

    Nabil Sabri Enattah, Leena Peltonen & Irma Järvelä

  3. Department of Public Health, University of Helsinki,

    Timo Sahi

  4. Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland

    Erkki Savilahti

  5. Department of Psychiatry and Columbia Genome Center, Columbia University, New York, New York, USA

    Joseph D. Terwilliger

  6. Division of Medical Genetics, New York State Psychiatric Institute, New York, New York, USA

    Joseph D. Terwilliger

  7. Department of Human Genetics, UCLA School of Medicine, Los Angeles, California, USA

    Leena Peltonen

  8. HUCH-Laboratory Diagnostics, Laboratory of Molecular Genetics, Haartmanninkatu 2, PO Box 340, Helsinki, FIN-00290, Finland

    Irma Järvelä

Authors
  1. Nabil Sabri Enattah
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Correspondence to Leena Peltonen.

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Enattah, N., Sahi, T., Savilahti, E. et al. Identification of a variant associated with adult-type hypolactasia. Nat Genet 30, 233–237 (2002). https://doi.org/10.1038/ng826

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