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Identification of a variant associated with adult-type hypolactasia


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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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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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).

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