Genetics of lactose intolerance

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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

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Lactose intolerance

• Adult-type hypolactasia

• During the childhood, lactase activity declines
  to 10-15 of that in early childhood
• gt 50 of world population lactose intolerantics
  (18 of Finnish population)
• Recessive inheritance (Sahi, 1974)

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Lactase expression during different phases of
development

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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

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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
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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
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Refinement of the adult-type hypolactasia locus
RP11-329I10
NH0034L23
NH0318L13
D2S3016
D2S3017
D2S3013
D2S3015
D2S3014
D2S3018
D2S3011
D2S3012
LPH
MCM6
DARS
(LPHLactase phlorizin hydrolase)
Adult-type hypolactasia locus
C/T-13910
G/A-22018
MCM6 exons
D2S3013
D2S3014
0k
50k
10k
20k
30k
40k
Enattah NS, Sahi T, Savilahti E, Terwilliger JD,
Peltonen L, Järvelä I Identification of a
variant associated with adult-type hypolactasia.
Nature Genetics 200230233-7.
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DNA variant C/T-13910 was found to be highly
associated with lactase non-persistence
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• 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
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Expression of the C/T-13910 genotypes

• Heterozygotic genotype C/T had statistically
  significant difference in the amount of expressed
  LPH mRNA
• gtDNA 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 gt6 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 5315711576)

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Functional studies
T-allele increases the promoter activity 4x
compared to allele C Olds L et al, Hum Mol
Genet 2003,122333-40 Troelsen J et al,
Gastroenterology 20031251686-94
Figure from Troelsen J, et al.
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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
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