Can primary hypolactasia manifest itself after the age of 20 years? A two-decade follow-up study.

OBJECTIVE: The age at manifestation of primary hypolactasia varies between ethnic groups. Many people report experiencing the first symptoms of lactose intolerance at adult age. The purpose of this study was to investigate whether primary hypolactasia can appear after the age of 20 among the Finnish population and to investigate the outcome of different diagnostic methods of lactose maldigestion. MATERIAL AND METHODS: Lactose digestion status was assessed by the lactose tolerance test with ethanol (LTTE) in 42 subjects (38-71 years) who reported having gastrointestinal symptoms after the ingestion of 20 g or less of lactose and who were diagnosed as lactose digesters in earlier studies. Thirteen of the study subjects underwent upper gastrointestinal endoscopy, and 35 gave a blood sample for DNA analysis. RESULTS: Only one of the 42 subjects studied had the genotype C/C(-13910) indicating hypolactasia. Lactase activity was higher in those with the genotype T/T (69.2 U/g protein) than in those with the heterozygous genotype C/T (36.3 U/g protein) (p=0.017). CONCLUSIONS: Although primary hypolactasia normally appears before the age of 20 years, the decline in lactase activity may on rare occasions continue after that age. Genotyping of the C/T(-13910) variant was found to be a reliable diagnostic approach in defining the lactase persistence/non-persistence status of the study subjects.

Independent introduction of two lactase-persistence alleles into human populations reflects different history of adaptation to milk culture.

The T(-13910) variant located in the enhancer element of the lactase (LCT) gene correlates perfectly with lactase persistence (LP) in Eurasian populations whereas the variant is almost nonexistent among Sub-Saharan African populations, showing high prevalence of LP. Here, we report identification of two new mutations among Saudis, also known for the high prevalence of LP. We confirmed the absence of the European T(-13910) and established two new mutations found as a compound allele: T/G(-13915) within the -13910 enhancer region and a synonymous SNP in the exon 17 of the MCM6 gene T/C(-3712), -3712 bp from the LCT gene. The compound allele is driven to a high prevalence among Middle East population(s). Our functional analyses in vitro showed that both SNPs of the compound allele, located 10 kb apart, are required for the enhancer effect, most probably mediated through the binding of the hepatic nuclear factor 1 alpha (HNF1 alpha). High selection coefficient (s) approximately 0.04 for LP phenotype was found for both T(-13910) and the compound allele. The European T(-13910) and the earlier identified East African G(-13907) LP allele share the same ancestral background and most likely the same history, probably related to the same cattle domestication event. In contrast, the compound Arab allele shows a different, highly divergent ancestral haplotype, suggesting that these two major global LP alleles have arisen independently, the latter perhaps in response to camel milk consumption. These results support the convergent evolution of the LP in diverse populations, most probably reflecting different histories of adaptation to milk culture.

Lactase persistence, dietary intake of milk, and the risk for prostate cancer in Sweden and Finland.

Prostate carcinoma is the most common cancer in men. Its primary pathogenesis is mostly unknown. Dairy products containing lactose have been suggested to be risk factors for prostate cancer. Digestion of lactose is dependent on lactase activity in the intestinal wall. A single nucleotide polymorphism C to T residing 13,910 bp upstream of the lactase gene has been shown to associate with the developmental down-regulation of lactase activity underlying persistence/nonpersistence trait. To find out whether lactase persistence is related to the risk for prostate cancer, we genotyped 1,229 Finnish and 2,924 Swedish patients and their 473 Finnish and 1,842 Swedish controls using solid-phase minisequencing. To explore if dairy products have an association with prostate cancer, we analyzed the milk consumption in the Swedish study consisting of 1,499 prostate cancer patients and 1,130 controls (Cancer Prostate in Sweden I study) using a questionnaire. Only the consumption of low-fat milk was found to be associated with increased risk of prostate cancer [odds ratio (OR), 1.73; 95% confidence interval (95% CI), 1.16-2.39]. A statistically significantly higher (P < 0.01) lactose intake was observed among subjects with high lactase activity (C/T and T/T genotypes) compared with those with low lactase activity (C/C genotype). Lactase persistence did not associate with increased risk for prostate carcinoma in the Finnish (OR, 1.11; 95% CI, 0.83-1.47; P = 0.488) or in the Swedish populations (OR, 1.16; 95% CI, 0.91-1.46; P = 0.23). In conclusion, lactase persistence/nonpersistence contains no risk for prostate cancer. Analysis of different milk products showed some evidence for low-fat milk as a potential risk factor for prostate cancer.

Molecularly defined adult-type hypolactasia among working age people with reference to milk consumption and gastrointestinal symptoms.

AIM: To study milk consumption and subjective milk-related symptoms in adults genotyped for adult-type hypolactasia. METHODS: A total of 1900 Finnish adults were genotyped for the C/T(-13910) variant of adult-type hypolactasia and filled in a structured questionnaire concerning milk consumption and gastrointestinal problems. RESULTS: The C/C(-13910) genotype of adult-type hypolactasia was present in 18% of the study population. The prevalence of the C/C(-13910) genotype was higher among subjects who were undergoing investigations because of abdominal symptoms (24%, P < 0.05). Those with the C/C(-13910) genotype drank less milk than subjects with either the C/T(-13910) or the T/T(-13910) genotype of lactase persistence (18% vs 38%; 18% vs 36%, P < 0.01). Subjects with the C/C(-13910) genotype had experienced more gastrointestinal symptoms (84%) during the preceding three-month period than those with the C/T(-13910) (79%, P < 0.05) or the T/T(-13910) genotype (78 %, P < 0.05). Only 9% (29/338) of the subjects with the C/C(-13910) genotype consumed milk and reported no symptoms from it. CONCLUSION: Gastrointestinal symptoms are more common among adults with the C/C(-13910) genotype of adult-type hypolactasia than in those with genotypes of lactase persistence.

Molecularly defined adult-type hypolactasia in school-aged children with a previous history of cow's milk allergy.

AIM: To assess the role of lactase non-persistence/persistence in school-aged children and their milk-related symptoms. METHODS: The genotypes for the C/T(-13910) variant associated with lactase non-persistence/ persistence were determined using PCR-minisequencing in a group of 172 children with a mean age of 8.6 years (SE = 0.02, 93 boys) participating in a follow-up study for cow's milk allergy. The parents were asked to assess their children's milk consumption and abdominal symptoms. RESULTS: The presence of allergy to cow's milk was not associated with the C/C(-13910) genotype related with a decline of lactase enzyme activity during childhood (lactase non-persistence). The frequency of the C/C(-13910) genotype (16%) was similar to published figures for the prevalence of adult-type hypolactasia in Finland. The majority of the children (90%) in this series consumed milk but 26% of their families suspected that their children had milk-related symptoms. Forty-eight percent of the children with the C/C(-13910) genotype did not drink milk at all or consumed a low lactose containing diet prior to the genotyping (P < 0.004 when compared to the other genotypes). CONCLUSION: Analysis of the C/T(-13910) polymorphism is an easy and reliable method for excluding adult-type hypolactasia in children with milk-related symptoms. Genotyping for this variant can be used to advise diets for children with a previous history of cow's milk allergy.

Lactase persistence and ovarian carcinoma risk in Finland, Poland and Sweden.

Ovarian carcinoma is the fourth most common cause of cancer death in women. The cause and pathogenesis of this disease has remained obscure. Galactose, the hydrolyzing product of the milk sugar lactose, has been hypothesized to be toxic to ovarian epithelial cells and consumption of dairy products and lactase persistence has been suggested to be a risk factor for ovarian carcinoma. In adults, downregulation of lactase depends on a variant C/T-13910 at the 5' end of the lactase gene. To explore whether lactase persistence is related to the risk of ovarian carcinoma we determined the C/T-13910 genotype in a cohort of 782 women with ovarian carcinoma. The C/T-13910 genotype was defined by solid phase minisequencing from 327 Finnish, 303 Polish, 152 Swedish patients and 938 Finnish, 296 Polish and 97 Swedish healthy individuals served as controls. Lactase persistence did not associate significantly with increased risk for ovarian carcinoma in the Finnish (odds ratio [OR]=0.77, 95% confidence interval [CI]=0.57-1.05, p=0.097), in the Polish (OR=0.95, 95% CI=0.68-1.33, p=0.75), or in the Swedish populations (OR=1.63, 95% CI=0.65-4.08, p=0.29). Our results do not support the hypothesis that lactase persistence increases the ovarian carcinoma risk. On the contrary, lactase persistence may decrease the ovarian carcinoma risk at least in the Finnish population.