Genetically defined adult-type hypolactasia and self-reported lactose intolerance as risk factors of osteoporosis in Finnish postmenopausal women.

OBJECTIVE: To study the relationships of molecularly defined lactose malabsorption (LM) and self-reported lactose intolerance (LI) to bone mineral density (BMD) and fractures among Finnish postmenopausal women. DESIGN: A cross-sectional study of two cohorts. SETTING: Helsinki University Central Hospital. SUBJECTS: One cohort was population-based and comprised 453 women, aged 62-78 (mean 69) y. Another comprised 52 women, aged 69-85 (mean 75) y, with osteoporotic fractures and 59 control women, aged 69-83 (mean 74) y, without osteoporosis. METHODS: A single nucleotide polymorphism of the lactase (LCT) gene at chromosome 2q21-22 was studied. It shows complete association with intestinal disaccharidase activity, with the genotype CC(-13 910) meaning adult-type hypolactasia (primary LM) and the genotypes CT(-13 910) and TT(-13 910) lactose absorption. BMD of the heel was measured by dual-energy X-ray absorptiometry (DXA). RESULTS: In the population-based cohort, 16.0% of women had self-reported LI but only 15.3% of them had the CC(-13 910) genotype. Calcium intake from dairy products (P = 0.10) and BMD, adjusted for age, weight, height, exercise, smoking, and estrogen use (P = 0.71) were similar for the genotypes. Women with self-reported LI had reduced calcium intake from dairy products (P < 0.0001) but they were more frequent users of calcium supplements than lactose-tolerants (P < 0.0001). Adjusted BMD was similar for lactose intolerant and tolerant women (P = 0.60). Of 104 women with previous fracture in the population-based cohort, 13.5% had the CC(-13 910) genotype, which did not differ from the prevalence of 19.3% among 347 women without fractures (P = 0.29). The frequency of the CC(-13 910) genotype (23.1%) for 52 women with established osteoporosis was similar as for 59 control women (15.3%) (P = 0.19). CONCLUSION: Molecularly defined LM and self-reported LI are not risk factors for osteoporosis, if calcium intake from diet and/or supplements remains sufficient. Our study confirms the poor correlation between self-reported LI and LM established by different techniques.

The C/C-13910 genotype of adult-type hypolactasia is associated with an increased risk of colorectal cancer in the Finnish population.

BACKGROUND AND AIMS: The role of nutrition in the pathogenesis of colorectal cancer is not fully understood. Milk products are an essential part of human nutrition in Western countries. Absorption of lactose, the main sugar of milk, is regulated by the activity of the lactase enzyme in the gut wall. The activity of lactase is genetically determined and is associated with a C/T single nucleotide polymorphism residing 13910 bp upstream of the lactase coding sequence. Here we have studied the relationship between the C/T(-13910) polymorphism and colorectal cancer in Finnish, British, and Spanish populations. PATIENTS AND METHODS: A total of 2766 subjects, including 963 Finnish, 283 British, and 163 Spanish subjects with colorectal cancer, and 773 Finnish, 363 British, and 221 Spanish control subjects, were genotyped for the C/T(-13910) variant by polymerase chain reaction minisequencing. RESULTS: The C/C(-13910) genotype, which is a robust molecular marker of low lactase activity (lactase non-persistence), was found to significantly associate with the risk of colorectal cancer (p = 0.015) in the Finnish subjects, with an odds ratio of 1.40 (95% confidence interval 1.07-1.85). No association was found with site, histology, or stage of the tumour. No significant risk was detected in the British or Spanish populations. CONCLUSION: Low lactase enzyme activity, defined by genotyping of the C/T(-13910) variant, may increase the risk of colorectal cancer. Further studies are warranted to investigate the role of milk and other dairy products in the pathogenesis of colon cancer in different populations.

A genetic test which can be used to diagnose adult-type hypolactasia in children.

BACKGROUND/AIMS: Adult-type hypolactasia (primary lactose malabsorption) affects most of world's human population and limits the use of fresh milk due to lactose intolerance. The diagnosis of adult-type hypolactasia has been difficult to establish because of unsatisfactory diagnostic methods. C/T(-13910) single nucleotide polymorphism residing 13910 base pairs from the 5' end of the lactase gene has been shown to be associated with lactase persistence. The aim of the study was to assess the applicability of the C/T(-13910) variant as a diagnostic test for adult-type hypolactasia during childhood. METHODS: Intestinal biopsies were obtained from 329 children and adolescents of African, Finnish, and other White origins aged 0.1-20 years undergoing upper gastrointestinal endoscopy because of abdominal complaints. The biopsies were assayed for lactase, sucrase, and maltase activity and genotyped for the C/T(-13910) variant using polymerase chain reaction minisequencing. RESULTS: The frequency of the C/C(-13910) genotype defining lactase non-persistence was well in agreement in this study with published figures for the prevalences of adult-type hypolactasia in Africans and Whites. The C/C(-13910) genotype was associated with very low lactase activity (<10 U/g protein) in the majority of children tested at 8 years of age and in every child older than 12 years of age giving a specificity of 100% and sensitivity of 93% for the genetic test. The decline of lactase activity was somewhat earlier in African compared with Finnish children with C/C(-13910) genotype (p<0.03). CONCLUSIONS: Genetic test of C/T(-13910) polymorphism can be used as a first stage screening test for adult-type hypolactasia.

Molecularly defined lactose malabsorption, peak bone mass and bone turnover rate in young finnish men.

Lactose malabsorption (LM; adult-type hypolactasia), an autosomal recessive condition, results from the down-regulation of the activity of lactase enzyme in the intestinal wall. In previous studies the effect of LM on bone mass, bone turnover rate, development of osteoporosis and osteoporotic fractures has remained controversial. We have recently identified a single nucleotide polymorphism (SNP), a C to T change residing 13910 base pairs upstream of the lactase (LCT) gene at chromosome 2q21-22, which shows complete association with lactase persistence, with the C/C-13910 genotype defining LM and the genotypes C/T-13910 and T/T-13910 lactase persistence. The present study was undertaken to examine the relationship of the C/T-13910 polymorphism to peak bone mass, bone turnover rate, and stress fractures among young Finnish men. The study population comprised 234 young men, aged 18.3 to 20.6 years, 184 men were recruits of the Finnish Army, and 50 were men of similar age who had postponed their military service for reasons not related to health. Bone mineral content (BMC), density (BMD), and scan area were measured in the lumbar spine and upper femur by dual-energy X-ray absorptiometry (DXA). Blood was sampled for genotyping of the C/T-13910 polymorphism and determination of serum 25-hydroxyvitamin D (25OHD), intact parathyroid hormone (iPTH), type I procollagen aminoterminal propeptide (PINP), and tartrate-resistant acid phosphatase 5b (TRACP5b). Second-void urine samples were collected for the determination of type I collagen aminoterminal telopeptide (NTX). The prevalence of the C/C-13910-genotype of these young adults did not differ significantly from the corresponding population prevalence of C/C-13910 (17.1% vs 18.1%) among Finnish blood donors. Fifteen recruits of the army experienced a stress fracture; 3 of them (20%) had the C/C-13910-genotype. Calcium intake was similar for the three genotypes as were the unadjusted BMCs, scan areas, and BMDs at different measurement sites. The adjustments for age, height, weight, smoking, alcohol consumption, and physical exercise in the multiple regression analysis did not reveal any significant relationships between the lactase genotypes and BMDs at lumbar (P = 0.16), femoral neck (P = 0.99) or total hip (P = 0.96) sites. Serum 25OHD, iPTH, and bone marker levels were similar for the C/C-13910 C/T-13910 and T/T-13910 genotypes. In summary, in young Finnish men, molecularly defined lactose malabsorption does not alter bone turnover rate and impair the acquisition of peak bone mass. Moreover, the C/C-13910 genotype does not seem to be a risk factor for stress fractures in army recruits.

Recurrent aphthous ulcers today: a review of the growing knowledge.

Recurrent aphthous ulcers represent a very common but poorly understood mucosal disorder. They occur in men and women of all ages, races and geographic regions. It is estimated that at least 1 in 5 individuals has at least once been afflicted with aphthous ulcers. The condition is classified as minor, major, and herpetiform on the basis of ulcer size and number. Attacks may be precipitated by local trauma, stress, food intake, drugs, hormonal changes and vitamin and trace element deficiencies. Local and systemic conditions, and genetic, immunological and microbial factors all may play a role in the pathogenesis of recurrent aphthous ulceration (RAU). However, to date, no principal cause has been discovered. Since the aetiology is unknown, diagnosis is entirely based on history and clinical criteria and no laboratory procedures exist to confirm the diagnosis. Although RAU may be a marker of an underlying systemic illness such as coeliac disease, or may present as one of the features of Behcet's disease, in most cases no additional body systems are affected, and patients remain otherwise fit and well. Different aetiologies and mechanisms might be operative in the aetiopathogenesis of aphthous ulceration, but pain, recurrence, self-limitation of the condition, and destruction of the epithelium seem to be the ultimate outcomes. There is no curative therapy to prevent the recurrence of ulcers, and all available treatment modalities can only reduce the frequency or severity of the lesions.

The genetic variant of lactase persistence C (-13910) T as a risk factor for type I and II diabetes in the Finnish population.

OBJECTIVE: Lactase persistence (LP), the ability to maintain a high lactase activity throughout life, has been suggested to be a possible risk factor for diabetes. Recently, a single nucleotide polymorphism C (-13910) T, residing 14 kb from the 5' end of the lactase (LCT) gene was shown to be associated with LP. Here we have studied the relationship between C (13910) T polymorphism and diabetes in the Finnish population. PATIENTS AND DESIGN: In all, 1455 patients with type I and 615 with type II diabetes and 446 nondiabetic controls in the Finnish population were genotyped for the C (-13910) T polymorphism by PCR minisequencing. RESULTS: No differences were detected in the LP genotype frequencies (CT&TT) between diabetic and nondiabetic subjects. CONCLUSIONS: We conclude that the C (-13910) T polymorphism associated with lifelong LP is not a risk factor for type I or type II diabetes in the Finnish population.

Transcriptional regulation of the lactase-phlorizin hydrolase gene by polymorphisms associated with adult-type hypolactasia.

BACKGROUND AND AIMS: The mechanism of the developmental downregulation of the lactase-phlorizin hydrolase (LPH) gene underlying adult-type hypolactasia is unknown. We have determined the functional significance of the recently identified two single nucleotide polymorphisms (SNPs), C/T(-13910) and G/A(-22018), associated with adult-type hypolactasia by studying LPH mRNA levels in intestinal biopsy samples with different genotypes. METHODS: Intestinal biopsy samples were taken from 52 patients with abdominal complaints. Hypolactasia was diagnosed by determining lactase and sucrase activities and calculating their ratio (L/S ratio). The functional effect of the C/T(-13910) and G/A(-22018) genotype on expression of LPH mRNA was demonstrated in patients heterozygous for the C/T(-13910) and G/A(-22018) polymorphism and an informative expressed SNP located in the coding region of the LPH mRNA. Reverse transcription-polymerase chain reaction followed by solid phase minisequencing was used for accessing the relative expression levels of the LPH alleles using informative SNPs located in exons 1, 2, 6, 10, 13, or 17 as markers. RESULTS: Statistically significant differences between the three different genotypes CC(-13910) GG(-22018), CT(-13910) GA(-22018), and TT(-13910) AA(-22018) and their respective L/S ratios were observed. Relative quantitation of the expressed LPH alleles showed that the persistent allele represented 92 (6)% (mean (SEM), range 78-99%; n=14) of the expressed LPH mRNA. The patient with the homozygous persistent TT(-13910) AA(-22018), as well as hypolactasic patients with CC(-13910) GG(-22018), showed equal expression of both alleles (47 (1)%; n=7). CONCLUSIONS: Expression of LPH mRNA in the intestinal mucosa in individuals with T(-13910) A(-22018) alleles is several times higher than that found in individuals with C(-13910), G(-22018) alleles. These findings suggest that the two SNPs, C/T(-13910) and G/A(-22018), associated with adult-type hypolactasia, are associated with the transcriptional regulation of the LPH gene. The presence of the T(-13910) A(-22018) allele also shows significant elevation of the L/S ratio.

Assignment of the locus for congenital lactase deficiency to 2q21, in the vicinity of but separate from the lactase-phlorizin hydrolase gene.

Congenital lactase deficiency (CLD) is an autosomal recessive, gastrointestinal disorder characterized by watery diarrhea starting during the first 1-10 d of life, in infants fed lactose-containing milks. Since 1966, 42 patients have been diagnosed in Finland. CLD is the most severe form of lactase deficiency, with an almost total lack of lactase-phlorizin hydrolase (LPH) activity on jejunal biopsy. In adult-type hypolactasia, the most common genetic enzyme deficiency in humans, this enzyme activity is reduced to 5%-10%. Although the activity of intestinal LPH has been found to be greatly reduced in both forms, the molecular pathogenesis of lactase deficiencies is unknown. On the basis of the initial candidate-gene approach, we assigned the CLD locus to an 8-cM interval on chromosome 2q21 in 19 Finnish families. At the closest marker locus, a specific allele 2 was present in 92% of disease alleles. On the basis of a genealogical study, the CLD mutation was found to be enriched in sparsely populated eastern and northern Finland, because of a founder effect. The results of both the genealogical study and the haplotype analysis indicate that one major mutation in a novel gene causes CLD in the Finnish population. Consequently, the critical region could be restricted further, to an approximately 350-kb interval, by ancient-haplotype and linkage-disequilibrium analyses. Surprisingly, the LPH gene was shown to lie outside the critical CLD region, excluding it as a causative gene for CLD. The LPH locus was found to reside >2 Mb from the critical CLD region.