The -13914G>A variant upstream of the lactase gene (LCT) is associated with lactase persistence/non-persistence.

BACKGROUND: Adult-type hypolactasia (lactase non-persistence) is a common cause of gastrointestinal symptoms. Several DNA sequence variants have been identified for the lactase-persistence/non-persistence (LP/LNP), the most common being the C to T residing -13910 bp upstream of the lactase gene (LCT). We have analysed sequence variants of LP/LNP in subjects originating from Northern Russia. METHODS: A total of 148 subjects with gastrointestinal complaints were genotyped covering about 400 bp around the -13910C/T variant using direct PCR-sequencing. All patients were interviewed about milk-related symptoms using the questionnaire. Disaccharidase activities were measured from intestinal biopsy specimens of the index person. RESULTS: The prevalence of the -13910C/C genotype among 148 patients was 28.4%. A G to A variant residing 13914 bp upstream from the LCT gene (-13914G>A) was identified in one participant carrying the -13910C/C genotype. In two biopsy specimens her lactase activity was above the generally accepted cut off level for adult-type hypolactasia, 10U/g protein. Three other family members also carried the -13914G>A genotype. Among eight family members five had the LNP genotype -13910C/C. CONCLUSION: A rare variant G to A residing 13914 bp upstream of the LCT gene was identified in a subject carrying the more frequent variant -13910C/C. The -13914G>A variant in heterozygous state was associated with increased lactase activity, suggesting that the increased lactase activity is most likely to be associated with the -13914G>A variant. Further studies need to be done to confirm the functional role of this variant.

Screening of DNA-variants in the properdin gene (CFP) in age-related macular degeneration (AMD).

Several variants in the complement cascade genes (complement factor H [CFH], C2, C3, CFB, and Serping1) have been reported to associate with age-related macular degeneration (AMD). Of these, a member of the complement alternative pathway, CFH, represents the highest risk. As properdin (P) is also an important protein in this pathway, we analysed whether variants in the properdin gene (CFP) at Xp11.4 are associated with AMD. Ten exons of CFP were sequenced in a total of 222 Finnish patients with AMD (150 sporadic cases and 72 familial cases). The controls were 86 age-matched non-AMD patients with no large drusen and no or minimal focal pigmentary abnormalities. A total of four single nucleotide polymorphisms (SNPs) were detected in CFP, three of them infrequent (in 5 patients and controls in total). The fourth SNP, rs1048118 in exon 10, was more frequent, but was not associated with AMD, either alone (p=0.33) or in conjunction with other risk factors. Thus, CFP does not seem to confer any risk for AMD.

Molecular genetics of human lactase deficiencies.

Lactase non-persistence (adult-type hypolactasia) is present in more than half of the human population and is caused by the down-regulation of lactase enzyme activity during childhood. Congenital lactase deficiency (CLD) is a rare severe gastrointestinal disorder of new-borns enriched in the Finnish population. Both lactase deficiencies are autosomal recessive traits and characterized by diminished expression of lactase activity in the intestine. Genetic variants underlying both forms have been identified. Here we review the current understanding of the molecular defects of human lactase deficiencies and their phenotype-genotype correlation, the implications on clinical practice, and the understanding of their function and role in human evolution.

Screening of variants for lactase persistence/non-persistence in populations from South Africa and Ghana.

BACKGROUND: Lactase non-persistence is a condition where lactase activity is decreased in the intestinal wall after weaning. In European derived populations a single nucleotide polymorphism (SNP) C/T-13910 residing 13.9 kb upstream from the lactase gene has been shown to define lactase activity, and several other single nucleotide polymorphisms (G/C-14010 T/G-13915, C/G-13907 and T/C-13913) in the same region have been identified in African and Middle East populations. RESULTS: The T-13910 allele most common in European populations was present in 21.8% mixed ancestry (N = 62) individuals and it was absent in the Xhosa (N = 109) and Ghana (N = 196) subjects. Five other substitutions were also found in the region covering the previously reported variants in African and Middle East populations. These included the G/C-14010 variant common in Kenyan and Tanzanian populations, which was present in 12.8% of Xhosa population and in 8.1% of mixed ancestry subjects. Two novel substitutions (C/T-14091 and A/C-14176) and one previously reported substitution G/A-13937 (rs4988234) were less common and present only in the Xhosa population. One novel substitution G/A-14107 was present in the Xhosa and Ghanaian populations. None of the other previously reported variants were identified. CONCLUSION: Identification of the G/C-14010 variant in the Xhosa population, further confirms their genetic relatedness to other nomadic populations members that belong to the Bantu linguistic group in Tanzania and Kenya. Further studies are needed to confirm the possible relationship of the novel substitutions to the lactase persistence trait.

[Congenital lactase deficiency--a more common disease than previously thought?]. / Synnynnäinen laktaasinpuute--arvioitua yleisempi sairaus?

Congenital lactase deficiency belongs to the Finnish Disease Heritage and is a recessively inherited diarrheal disease of the newborn, in which the activity of the lactase enzyme of the epithelial cells of the small intestine is very low ever since the birth. For the newborn infant, ingestion of lactose causes symptoms so severe that breastfeeding is not possible. Untreated disease leads to dehydration that usually requires hospitalization. Congenital lactase deficiency is caused by mutations in the gene coding for the lactase enzyme (LCT). Seven mutations in a total of 43 patients have been found in Finland so far.

Prevalence of lactase persistent/non-persistent genotypes and milk consumption in a young population in north-west Russia.

AIM: To estimate the prevalence of the lactase non-persistent genotype (C/C-13910) in a northern Russian population in accordance with ethnicity, and to evaluate self-reported milk consumption depending on lactase activity. METHODS: Blood samples for genotyping lactase activity, defining the C/T-13910 variant by polymerase chain reaction, and direct sequencing were taken from 231 medical students of Russian origin aged 17-26 years. We analyzed milk product consumption by questionnaire which was specially designed for the estimation of milk consumption and abdominal complaints. RESULTS: We found that the prevalence of the C/C-13190 genotype in the northern Russian population was 35.6%. The other genotypes nearby C/T-13910 and associated with lactase activity were not present in the study population. The consumption of milk among people with the non-persistent genotype tended to be lower than among the lactose tolerant subjects, but was not statistically significant. CONCLUSION: An investigation of the lactase persistent genotype in a northern Russian population has not been performed before. The genotype did not affect the consumption of milk products in this population which could be explained by low consumption of milk products among the entire study population.

Four novel mutations in the lactase gene (LCT) underlying congenital lactase deficiency (CLD).

BACKGROUND: Congenital lactase deficiency (CLD) is a severe gastrointestinal disorder of newborns. The diagnosis is challenging and based on clinical symptoms and low lactase activity in intestinal biopsy specimens. The disease is enriched in Finland but is also present in other parts of the world. Mutations encoding the lactase (LCT) gene have recently been shown to underlie CLD. The purpose of this study was to identify new mutations underlying CLD in patients with different ethnic origins, and to increase awareness of this disease so that the patients could be sought out and treated correctly. METHODS: Disaccharidase activities in intestinal biopsy specimens were assayed and the coding region of LCT was sequenced from five patients from Europe with clinical features compatible with CLD. In the analysis and prediction of mutations the following programs: ClustalW, Blosum62, PolyPhen, SIFT and Panther PSEC were used. RESULTS: Four novel mutations in the LCT gene were identified. A single nucleotide substitution leading to an amino acid change S688P in exon 7 and E1612X in exon 12 were present in a patient of Italian origin. Five base deletion V565fsX567 leading to a stop codon in exon 6 was found in one and a substitution R1587H in exon 12 from another Finnish patient. Both Finnish patients were heterozygous for the Finnish founder mutation Y1390X. The previously reported mutation G1363S was found in a homozygous state in two siblings of Turkish origin. CONCLUSION: This is the first report of CLD mutations in patients living outside Finland. It seems that disease is more common than previously thought. All mutations in the LCT gene lead to a similar phenotype despite the location and/or type of mutation.

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.

Lactase non-persistence and milk consumption in Estonia.

AIM: To define the frequency of the C/T-13910 variant associated with lactase persistence/non-persistence trait and to analyze the milk consumption of lactase non-persistent subjects in Estonia. METHODS: We genotyped 355 Estonians by polymerase chain reaction and direct sequencing. Milk consumption was analyzed by a questionnaire, specially developed to analyze milk consumption and abdominal complaints. RESULTS: The frequency of the genotype of the C/C-13910 (lactase non-persistence) was found to be 24.8% in native Estonians. No other single nucleotide polymorphisms covering the region of 400 bp adjacent to the C/T-13910 variant were found. Lactase non-persistence subjects were found to consume less milk than lactase persistence subjects. CONCLUSION: The frequency of lactase non-persistence defined by the C/C-13910 genotype confirms the results of the previous studies based on indirect methods of determining hypolactasia. Milk consumption of lactase non-persistence subjects is consistent with previously reported figures of adult-type hypolactasia in Estonia. However, lactase non-persistence does not prevent the intake of milk in many adults.