Genetics of lactose intolerance Päivi Onkamo adapted from materials by Heli Rasinperä & Kaija-Leena Kolho, from Department of Medical Genetics, University of Helsinki, and Lasten ja Nuorten sairaala, HUS
Lactose Lactase Glucose Galactose Lactose intolerance Adult-type hypolactasia • During the childhood, lactase activity declines to 10-15% of that in early childhood • > 50% of world population lactose intolerantics (18% of Finnish population) • Recessive inheritance (Sahi, 1974)
Water Water Lactose Small intestine Bacterial fermentation Acetic acid Lactic acid Large intestine Diarrhea Flatulence Lactose intolerance: phenotype and symptoms • The most typical enzyme deficiency in human populations • Causes typical symptoms of the deficiency, the lactose intolerance • Mainly diagnosed during childhood / early adulthood
Why population differences? • Milk from domestic cows has been a valuable food source for over 8,000 years, especially in lactose-tolerant human societies that exploit dairy breeds • Study of milk protein genetic diversity of domestic cattle and lactase persistence in humans showed highly concordant geographical distribution, indicating • Gene-culture coevolution driven by the advantages conferred by milk consumption: • The North-Central European population in neolithic times has been greatly dependent on milk, and thus the selection pressure for lactase persistence has been strong Beja-Pereira et al: Gene-culture coevolution between cattle milk protein genes and human lactase genes. Nat Genet 2003
Refinement of the adult-type hypolactasia locus RP11-329I10 NH0034L23 NH0318L13 D2S3017 D2S3016 D2S3013 D2S3015 D2S3014 D2S3018 D2S3011 D2S3012 LPH MCM6DARS (LPH=Lactase phlorizin hydrolase) Adult-type hypolactasia locus C/T-13910 G/A-22018 MCM6 exons D2S3013 D2S3014 0k 10k 20k 30k 40k 50k Enattah NS, Sahi T, Savilahti E, Terwilliger JD, Peltonen L, Järvelä I:Identification of a variant associated with adult-type hypolactasia.Nature Genetics 2002;30:233-7.
DNA variant C/T-13910 was found to be highly associated with lactase non-persistence:
Next, lactase mRNA was quantified in intestinal biopsy samples from 142 children with different genotypes regarding the SNP variant C/T-13910
Expression of the C/T-13910 genotypes • Heterozygotic genotype C/T had statistically significant difference in the amount of expressed LPH mRNA • =>DNA variant C/T-13910 roughly 14 kb upstream from the LCT locus participates in regulation of lactase production in the level of transcription • Lately, it has been shown that the expression of C-allele in C/T heterozygotes starts to decline in children >6 years of age, while the expression of T-allele persists (Rasinperä et al, A genetic test which can be used to diagnose adult-type hypolactasia in children. Gut 2004; 53:1571–1576)
Functional studies T-allele increases the promoter activity 4x compared to allele C Olds L et al, Hum Mol Genet 2003,12:2333-40 Troelsen J et al, Gastroenterology 2003;125:1686-94 Figure from Troelsen J, et al.
The genetic testing of C/T-13910 has rapidly gained footsite in diagnostics of abdominal problems. The previously predominated methods have been - only 80% reliable - tedious and expensive (when compared to a gene test) - false positive results in children even 30%