The genetically programmed down-regulation of lactase in children

doi:10.1016/S0016-5085(98)70429-9

Gastroenterology

Volume 114, Issue 6, June 1998, Pages 1230-1236

https://doi.org/10.1016/S0016-5085(98)70429-9 Get rights and content

Abstract

Background & Aims: Intestinal lactase activity is high in all healthy human babies, but in adults a genetic polymorphism, which acts in cis to the lactase gene, determines high or low messenger RNA (mRNA) expression and activity (lactase persistence and nonpersistence, respectively). Our aim was to investigate the onset of expression of this polymorphism in children. Methods: Activities were analyzed in relation to age in normal biopsy specimens from a 20-year collection of diagnostic specimens. In a smaller set of 32 samples, aged 2–132 months, RNA was extracted for semiquantitative reverse-transcription polymerase chain reaction. Marker polymorphisms were used to determine the allelic origin of lactase mRNA transcripts. Results: Analysis of 866 children showed evidence that the lactase persistence/nonpersistence polymorphism began before 5 years of age. The 32 children tested had high lactase mRNA and activity. Six children aged 2–16 months showed equal expression of two alleles, 2 children aged 7 and 14 months showed slightly asymmetric expression, and 7 children aged 22–132 months showed very asymmetric expression, the second allele being undetectable in the 11-year-old, as previously seen in lactase-persistent heterozygote adults. Conclusions: Genetically programmed down-regulation of the lactase gene is detectable in children from the second year of life, although the onset and extent are somewhat variable.

GASTROENTEROLOGY 1998;114:1230-1236

Section snippets

Materials and methods

The patients were referred to Queen Elizabeth Hospital for Children in London for chronic intestinal symptoms and/or failure to thrive. Their ages ranged from 1 to 203 months. Biopsies of the small intestine were performed as part of their routine investigations with fully informed consent after an overnight fast, using a double-port pediatric capsule positioned at the duodenojejunal flexure. A sample was immediately frozen in liquid nitrogen and stored at −70°C for enzyme assay.

Retrospective review of lactase activities in histologically normal intestinal biopsy specimens

Over a 20-year period, a total of 1264 small intestinal biopsy specimens were assayed for lactase, sucrase, and maltase activities as one of the routine diagnostic tests on children with chronic intestinal symptoms and/or failure to thrive. In a retrospective review of the histology and enzyme activities of all these cases, it was possible to identify 866 samples from different individuals that were normal by two criteria: both normal histology and maltase activity of more than 10 U/g. (Maltase

Discussion

A large number of lactose tolerance studies on children of various variety of ages indicate that although all healthy babies have lactase activity, genetically determined lactose intolerance caused by lactase nonpersistence can develop at variable ages after the first year of life.2, 12 In a few studies, enzymatic activity has been measured directly.13, 14, 15, 16, 17 There has been some suggestion that the age of onset of lactose intolerance is different in different ethnic groups,¹ with

Acknowledgements

The authors thank Dr. A. Johnson, Institute of Child Health, London, for help with the disaccharidase data; Wendy Pratt for help with PCRs; Jan Henry for help with data analysis; Jeff Pinxteren for the use of his Phosphorimager; and Dr. L. Wong for samples.

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Lactose malabsorption is a very common condition due to intestinal lactase deficiency. Post weaning, a genetically programmed and irreversible reduction of lactase activity occurs in the majority of the world's population. Lactose malabsorption does not necessarily result in gastrointestinal symptoms, i.e. lactose intolerance, which occurs in approximately one third of those with lactase deficiency. In the absence of well-established guidelines, the common therapeutic approach tends to exclude milk and dairy products from the diet.
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Lactose intolerance (or lactase non-persistence) is a common autosomal recessive condition resulting from the physiological decline in activity of lactase-phlorizin hydrolase (LPH) in intestinal cells after weaning and has a significant impact on milk drinking behavior. The age of onset varies between populations and in some populations lactase activity persists at a high level throughout adult life (Sahi, 1994; Sahi, Isokoski, Jussila, & Launiala, 1972; Swallow, 2003; Wang et al., 1998). Although the sequence of the lactase gene (LCT, encoding LPH) had been known since 1991 (Boll, Wagner, & Mantei, 1991), the causative mechanism for lactase persistence remained elusive until 2002 when a linkage analysis of nine Finnish families with hypolactasia identified a variant upstream of the initiation codon of LCT (LCT-13910C > T) which demonstrated complete association with lactase persistence (Enattah et al., 2002).
Beverages make important contributions to nutritional intake and their role in health has received much attention. This review focuses on the genetic determinants of common beverage consumption and how research in this field is contributing insight to what and how much we consume and why this genetic knowledge matters from a research and public health perspective. The earliest efforts in gene-beverage behavior mapping involved genetic linkage and candidate gene analysis but these approaches have been largely replaced by genome-wide association studies (GWAS). GWAS have identified biologically plausible loci underlying alcohol and coffee drinking behavior. No GWAS has identified variants specifically associated with consumption of tea, juice, soda, wine, beer, milk or any other common beverage. Thus far, GWAS highlight an important behavior-reward component (as opposed to taste) to beverage consumption which may serve as a potential barrier to dietary interventions. Loci identified have been used in Mendelian randomization and gene × beverage interaction analysis of disease but results have been mixed. This research is necessary as it informs the clinical relevance of SNP-beverage associations and thus genotype-based personalized nutrition, which is gaining interest in the commercial and public health sectors.
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In individuals with LNP, lactase levels gradually fall to about 10–25% compared to those of young infants due to a decrease in mRNA [6, 18]. Several single nucleotide polymorphisms (SNP) have been identified in the promoter region of the lactase gene [25]. The most common polymorphism associated with lactase persistence in Caucasians is characterized by a C > T change at 13910 base pairs upstream of the lactase gene.
Lactose is the main carbohydrate in human and mammalian milk. Lactose requires enzymatic hydrolysis by lactase into D-glucose and D-galactose before it can be absorbed. Term infants express sufficient lactase to digest about one liter of breast milk daily. Physiological lactose malabsorption in infancy confers beneficial prebiotic effects, including the establishment of Bifidobacterium-rich fecal microbiota. In many populations, lactase levels decline after weaning (lactase non-persistence; LNP). LNP affects about 70% of the world’s population and is the physiological basis for primary lactose intolerance (LI). Persistence of lactase beyond infancy is linked to several single nucleotide polymorphisms in the lactase gene promoter region on chromosome 2. Primary LI generally does not manifest clinically before 5 years of age. LI in young children is typically caused by underlying gut conditions, such as viral gastroenteritis, giardiasis, cow’s milk enteropathy, celiac disease or Crohn’s disease. Therefore, LI in childhood is mostly transient and improves with resolution of the underlying pathology. There is ongoing confusion between LI and cow’s milk allergy (CMA) which still leads to misdiagnosis and inappropriate dietary management. In addition, perceived LI may cause unnecessary milk restriction and adverse nutritional outcomes. The treatment of LI involves the reduction, but not complete elimination, of lactose-containing foods. By contrast, breastfed infants with suspected CMA should undergo a trial of a strict cow’s milk protein-free maternal elimination diet. If the infant is not breastfed, an extensively hydrolyzed or amino acid-based formula and strict cow’s milk avoidance are the standard treatment for CMA. The majority of infants with CMA can tolerate lactose, except when an enteropathy with secondary lactase deficiency is present.
Country, regional, and global estimates for lactose malabsorption in adults: a systematic review and meta-analysis
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Because lactase persistence decreases with age, age is of importance when assessing lactose malabsorption.14 Studies of children indicate decreasing lactase activity with age, and lactose malabsorption is generally rare early in infancy, approaching adult levels around the age of 7–10 years.9,39–42 The occurence of lactose malabsorption generally increases with age and seems to increase more sharply in populations where the prevalence of lactose malabsorption is high.9
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None.
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^☆: Supported by a grant from the British Digestive Foundation (to C.B.H.).

^☆☆: Address requests for reprints to: Dallas M. Swallow, Ph.D., Medical Research Council Human Biochemical Genetics Unit, University College London, Wolfson House, 4 Stephenson Way, London NW12HE, England. e-mail: [email protected]; fax: (44) 171 387 3496.

^★: Dr. Wang's current affiliation is: Harvard Institute of Medicine, Boston, Massachusetts.

^★★: Dr. Harvey's current affiliation is: Unitat de Biologia Cellular i Molecular, Barcelona, Spain.

^♢: Drs. Wang, Harvey, and Hollox contributed equally to this study.

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Alimentary TractThe genetically programmed down-regulation of lactase in children☆,☆☆,★,★★,♢

Abstract

Section snippets

Materials and methods

Retrospective review of lactase activities in histologically normal intestinal biopsy specimens

Discussion

Acknowledgements

Gastroenterology

Am J Clin Nutr

Gastroenterology

Gastroenterology

Genetics of lactose digestion in humans

Adv Hum Genet

Progress report. Dietary lactose and the aetiology of human small-intestinal hypolactasia

Gut

Genetics of adult-type hypolactasia

The lactase persistence/non-persistence polymorphism is controlled by a cis-acting element

Hum Mol Genet

Structure of the chromosomal gene and cDNAs coding for lactase-phlorizin hydrolase in humans with adult-type hypolactasia or persistence of lactase

Am J Hum Genet

Studies on the expression of intestinal lactase in different individuals

Gut

Expression of intestinal mRNA transcripts during development: analysis by a semi-quantitative RNA PCR method

Pediatr Res

Microvillous surface area in secondary disaccharidase deficiency

Gut

Alimentary Tract
The genetically programmed down-regulation of lactase in children☆,☆☆,★,★★,♢