The genetically programmed down-regulation of lactase in children

Wang, Yangxi; Harvey, Clare B.; Hollox, Edward J.; Phillips, Alan D.; Poulter, Mark; Clay, Peter; Walker-Smith, J A; Swallow, Dallas M.

doi:10.1016/s0016-5085(98)70429-9

Cited by 121 publications

(83 citation statements)

References 19 publications

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“…The C allele and A allele are associated with the B haplotype. Details of technique and controls can be found in Wang et al (1998). tion. In contrast, the one additional exception with the GA-22 kb SNP tends to support the notion that this is not the causal change.…”

Section: Discussionmentioning

confidence: 99%

The Causal Element for the Lactase Persistence/ non‐persistence Polymorphism is Located in a 1 Mb Region of Linkage Disequilibrium in Europeans

Poulter

Hollox

Harvey

et al. 2003

Annals of Human Genetics

112

121

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SummaryExpression of lactase in the intestine persists into adult life in some people and not others, and this is due to a cisacting regulatory polymorphism. Previous data indicated that a mutation leading to lactase persistence had occurred on the background of a 60 kb 11-site LCT haplotype known as A (Hollox et al. 2001). Recent studies reported a 100% correlation of lactase persistence with the presence of the T allele at a CT SNP at − 14 kb from LCT, in individuals of Finnish origin, suggesting that this SNP may be causal of the lactase persistence polymorphism, and also reported a very tight association with a second SNP (GA -22 kb) (Enattah et al. 2002). Here we report the existence of a one megabase stretch of linkage disequilibrium in the region of LCT and show that the -14 kb T allele and the -22 kb A allele both occur on the background of a very extended A haplotype. In a series of Finnish individuals we found a strong correlation (40/41 people) with lactose digestion and the presence of the T allele. The T allele was present in all 36 lactase persistent individuals from the UK (phenotyped by enzyme assay) studied, 31/36 of whom were of Northern European ancestry, but not in 11 non-persistent individuals who were mainly of non-UK ancestry. However, the CT heterozygotes did not show intermediate lactase enzyme activity, unlike those previously phenotyped by determining allelic transcript expression. Furthermore the one lactase persistent homozygote identified by having equally high expression of A and B haplotype transcripts, was heterozygous for CT at the − 14 kb site. SNP analysis across the 1 megabase region in this person showed no evidence of recombination on either chromosome between the -14 kb SNP and LCT. The combined data shows that although the -14 kb CT SNP is an excellent candidate for the cause of the lactase persistence polymorphism, linkage disequilibrium extends far beyond the region searched so far. In addition, the CT SNP does not, on its own, explain all the variation in expression of LCT, suggesting the possibility of genetic heterogeneity. *

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Section: Discussionmentioning

confidence: 99%

The Causal Element for the Lactase Persistence/ non‐persistence Polymorphism is Located in a 1 Mb Region of Linkage Disequilibrium in Europeans

Poulter

Hollox

Harvey

et al. 2003

Annals of Human Genetics

112

121

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“…This SNP is variable for either cytosine (C) or thymine (T) and is located within intron 13 of the MCM6 gene on chromosome 2 (Wang et al 1995(Wang et al , 1998. The ''C'' variant functions as a cis-element down-regulator by coding for a binding motif that affects an AP2 site on the lactase gene promoter causing delayed transcription and decreased lactase production.…”

Section: Introductionmentioning

confidence: 99%

Associations of the lactase persistence allele and lactose intake with body composition among multiethnic children

et al. 2013

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Childhood obesity is a worldwide health concern with a multifaceted and sometimes confounding etiology. Dairy products have been implicated as both proand anti-obesogenic, perhaps due to the confounding relationship between dairy, lactose consumption, and potential genetic predisposition. We aimed to understand how lactase persistence influenced obesity-related traits by observing the relationships among lactose consumption, a single nucleotide polymorphism (SNP) near the lactase (LCT) gene and body composition parameters in a sample of multiethnic children (n = 296, 7-12 years old). We hypothesized that individuals with the lactase persistence (LP) allele of the LCT SNP (rs4988235) would exhibit a greater degree of adiposity and that this relationship would be mediated by lactose consumption. Body composition variables were measured using dual X-ray absorptiometry and a registered dietitian assessed dietary intake of lactose. Statistical models were adjusted for sex, age, pubertal stage, ethnic group, genetic admixture, socio-economic status, and total energy intake. Our findings indicate a positive, significant association between the LP allele and body mass index (p = 0.034), fat mass index (FMI) (p = 0.043), and waist circumference (p = 0.008), with associations being stronger in males than in females. Our results also reveal that lactose consumption is positively and nearly significantly associated with FMI.

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“…It is a very common condition, reaching 70% in southern Italy (Gudmand-Hoyer, 1994). High concentrations of lactase are physiologically present in neonates; nevertheless, postweaning, a genetically programmed and irreversible reduction of its activity occurs in the majority of the world's population (Wang et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Effect of exogenous β-galactosidase in patients with lactose malabsorption and intolerance: a crossover double-blind placebo-controlled study

et al. 2005

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Objective: To evaluate the efficacy of the addition to milk, 5 min and 10 h before its consumption, of a lactase obtained from Kluyveromyces lactis in lactose malabsorbers with intolerance. Design: Double-blind, placebo-controlled, crossover study. Setting: University Hospital. Subjects: In total, 11 male and 19 female (aged from 18 to 65 y, mean age 43.3 y) lactose malabsorbers with intolerance participated. Interventions: Each patient underwent three H 2 breath tests, in a random order. We used 400 ml of cow's semiskimmed milk as substrate and a b-galactosidase obtained from K. lactis. The test A was carried out adding to the milk the enzyme (3000 UI), 10 h before its consumption; the test B was performed adding the b-galactosidase (6000 UI) 5 min before milk ingestion and the test C was made using placebo. We evaluated the maximum breath H 2 concentration, the cumulative H 2 excretion and a clinical score based on intolerance symptoms (bloating, abdominal pain, flatulence and diarrhoea). Results: Our study showed a significant reduction of the mean maximum H 2 concentration after both test A (12.0777.8 p.p.m.) and test B (13.9777.99 p.p.m.) compared with test C (51.46716.12 p.p.m.) (ANOVA F ¼ 54.33, Po0.001). Similarly, there was a significant reduction of the mean cumulative H 2 excretion after both test A (142871156 p.p.m.) and test B (17617966 p.p.m.) compared with test C (579572707 p.p.m.) (ANOVA F ¼ 31.46, Po0.001). We also observed a significant reduction of the mean clinical score after both test A (0.3670.55) and test B (0.9670.85) compared with test C (3.770.79) (ANOVA F ¼ 106.81, Po0.001). Moreover, with regard to the mean clinical score, there was a significant reduction after test A with respect to test B (Bonferroni's P ¼ 0.03). Conclusions: Our study shows that in lactose malabsorbers with intolerance, the lactase obtained from K. lactis can represent a valid therapeutic strategy, with objective and subjective efficacy and without side effects.

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The genetically programmed down-regulation of lactase in children

Cited by 121 publications

References 19 publications

The Causal Element for the Lactase Persistence/ non‐persistence Polymorphism is Located in a 1 Mb Region of Linkage Disequilibrium in Europeans

The Causal Element for the Lactase Persistence/ non‐persistence Polymorphism is Located in a 1 Mb Region of Linkage Disequilibrium in Europeans

Associations of the lactase persistence allele and lactose intake with body composition among multiethnic children

Effect of exogenous β-galactosidase in patients with lactose malabsorption and intolerance: a crossover double-blind placebo-controlled study

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