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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 intolerance
Adult-type hypolactasia
Lactose
-During the childhood, lactase activity
declines to 10-15% of that in early
childhood
- > 50% of world population lactose
intolerantics (18% of Finnish population)
Lactase
-Recessive inheritance (Sahi, 1974)
Glucose
Galactose
Lactase expression during different
phases of development
Lactose intolerance: phenotype and
symptoms



The most typical enzyme deficiency
in human populations
Small intestine
Causes typical symptoms of the
deficiency, the lactose intolerance
Mainly diagnosed during childhood /
early adulthood
Water
Water
Lactose
Bacterial fermentation
Lactic acid
Acetic acid
Large intestine
Diarrhea Flatulence
Lactose intolerance in different
populations
Population
Prevalence
Finnish
18%
Lapp
34 - 60%
Swedish-speaking Finnish
8%
Swedish
1% (9%)
Danish
2%
French
32 - 44%
Italian
50 - 72%
USA (Caucasian)
22%
USA (African-American)
65%
African (South of Sahara)
75 - 100%
Thai
97 - 100%
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
LPH
MCM6
(LPH=Lactase phlorizin hydrolase)
DARS
Adult-type hypolactasia locus
C/T-13910
G/A-22018
MCM6
exons
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
Genotype
Number
of persons
Lactase activity U/g
protein (average)
T/T
39
50.0
C/T
86
29.9
C/C
17
6.5
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 Callele 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%