Lactase persistence phenotype and genotype in Iranian Mazani-Shahmirzadi and Afghan Hazara ethnicities.

Lactase persistence is an autosomal dominant trait characterized by sustained expression of lactase gene throughout adulthood. This trait is mostly prevalent in populations with pastoral or agro-pastoral ancestry and allows lactase persistent individuals to benefit from milk nutrients. Several genetic variants have been identified to be responsible for lactase persistence in different populations and other genetic variants associated with lactase persistence are expected to be found. In this study, we aimed to investigate the lactase persistence phenotype and genotype in two isolated populations, the Iranian Mazani-Shahmirzadi and Afghan Hazaras living in Iran. For this purpose, we genotyped five single nucleotide polymorphisms -13.907C/G, -13.910C/T, -13.913T/C, -13.915T/G and -22.018A/G in 45 Mazanis from Shahmirzad and 50 Hazaras living in the suburb of Tehran. We also investigated lactase persistence by inquiring about digestive symptoms and measuring blood glucose levels after 50g lactose consumption. Our results show that 24.2% of Mazani-Shahmirzadis and 14% of Hazaras are lactase persistent based on blood glucose levels. Genotype investigation shows that only two SNPs, 13.910 C/T and 22.018 A/G display variation in the studied populations. The -13.910*T allele has a frequency of 7.7% in Mazani-Shahmirzadis and 12.7% in Hazaras. The frequency of -22.018*A was 16.6% in Mazani-Shahmirzadis and 17% in Hazaras. Importantly, we found a new genetic variant at -13.913 single nucleotide polymorphism which has not been previously reported. Given that the -13.913 single nucleotide polymorphism is within the enhancer Oct-1 binding site, the presence of this variant could affect lactase gene expression in adults. Further studies are required to elucidate the impact of this variant on LCT gene enhancer function.

Association of Lactase Persistence Genotypes (rs4988235) and Ethnicity with Dairy Intake in a Healthy U.S. Population.

Lactase persistence (LP) is a trait in which lactose can be digested throughout adulthood, while lactase non-persistence (LNP) can cause lactose intolerance and influence dairy consumption. One single nucleotide polymorphism (SNP ID: rs4988235) is often used as a predictor for dairy intake, since it is responsible for LP in people in European descent, and can occur in other ethnic groups. The objective of this study was to determine whether rs4988235 genotypes and ethnicity influence reported dairy consumption in the United States (U.S.). A food frequency questionnaire (FFQ) and multiple Automated Self-Administered 24-h recalls (ASA24®) were used to measure habitual and recent intake, respectively, of total dairy, cheese, cow's milk, plant-based alternative milk, and yogurt in a multi-ethnic U.S. cohort genotyped for rs4988235. Within Caucasian subjects, LP individuals reported consuming more recent total dairy and habitual total cow's milk intake. For subjects of all ethnicities, LP individuals consumed more cheese (FFQ p = 0.043, ASA24 p = 0.012) and recent total dairy (ASA24 p = 0.005). For both dietary assessments, Caucasians consumed more cheese than all non-Caucasians (FFQ p = 0.036, ASA24 p = 0.002) independent of genotype, as well as more recent intake of yogurt (ASA24 p = 0.042). LP subjects consumed more total cow's milk than LNP, but only when accounting for whether subjects were Caucasian or not (FFQ p = 0.015). Fluid milk and alternative plant-based milk consumption were not associated with genotypes or ethnicity. Our results show that both LP genotype and ethnicity influence the intake of some dairy products in a multi-ethnic U.S. cohort, but the ability of rs4988235 genotypes to predict intake may depend on ethnic background, the specific dairy product, and whether intake is reported on a habitual or recent basis. Therefore, ethnicity and the dietary assessment method should also be considered when determining the suitability of rs4988235 as a proxy for dairy intake.

Genetic and Oral Tests for the Diagnosis of Lactose Intolerance in Mixed-Ancestry Brazilians with Metabolic Syndrome.

BACKGROUND/AIMS: Metabolic syndrome (MetS) comprises a cluster of physiological and anthropometric abnormalities. MetS has been linked to lactose intolerance (LI). The aim of this study was to compare the sensitivity and specificity to detect LI using 2 different tests: (1) a genetic test and (2) an oral lactose tolerance test (OLTT). METHODS: Two hundred and fifty-four MetS patients, ≥20 years of age, of both genders, were recruited for this comparative study. Nine single nucleotide polymorphisms (SNPs) were selected for genetic investigation: rs182549and rs4988235(both considered "gold standard"); rs56064699; rs148142676; rs562211644; rs59533246; rs3754689; rs2278544,and rs10552864(as potential novel SNPs). Sensitivity and specificity, as well as positive and negative predictive values, were calculated for each genotype using WINPEPI version 11.65. Differences between positive and negative OLTT groups were considered statistically significant when p ≤ 0.05. RESULTS: Among the selected SNPs, only rs182549(p < 0.001) and rs4988235(p < 0.001) gave similar results compared to an OLTT. The sensitivity of both SNPs to detect LI was 87 and 86%, and specificity was 83 and 82.5%, respectively. CONCLUSION: Genetic tests using rs182549and rs4988235SNPs showed high agreement with OLTT. These genetic tests may be a good option to replace OLTT in MetS patients.

Lactose Intolerance (LCT-13910C>T) Genotype Is Associated with Plasma 25-Hydroxyvitamin D Concentrations in Caucasians: A Mendelian Randomization Study.

Background: The LCT-13910C>T gene variant is associated with lactose intolerance (LI) in different ethnic groups. Individuals with LI often limit or avoid dairy consumption, a major dietary source of vitamin D in North America, which may lead to inadequate vitamin D intake.Objective: The objective was to determine the prevalence of genotypes predictive of LI in different ethnic groups living in Canada and to determine whether the LCT genotype is associated with plasma 25(OH)D concentrations.Methods: Blood samples were drawn from a total of 1495 men and women aged 20-29 y from the Toronto Nutrigenomics and Health Study for genotyping and plasma 25(OH)D analysis. Intakes of dairy were assessed by using a 196-item food frequency questionnaire. The prevalence of LCT-13910C>T genotypes was compared by using χ2 analysis. Using a Mendelian randomization approach, we examined the association between LCT genotypes and 25(OH)D concentrations.Results: Approximately 32% of Caucasians, 99% of East Asians, 74% of South Asians, and 59% of those with other or mixed ethnicities had the CC genotype associated with LI. Compared with those with the TT genotype, those with the CC genotype had a lower mean ± SE total dairy intake (2.15 ± 0.09 compared with 2.67 ± 0.12 servings/d, P = 0.003), a lower skim-milk intake (0.20 ± 0.03 compared with 0.46 ± 0.06 servings/d, P = 0.0004), and a lower plasma 25(OH)D concentration (63 ± 1.9 compared with 75.8 ± 2.4 nmol/L, P < 0.0001). The CT and CC genotypes were associated with a 50% and a 2-fold increased risk, respectively, of a suboptimal plasma 25(OH)D concentration (<75 nmol/L).Conclusions: In Caucasians, the CC genotype that predicts LI is associated with a lower plasma 25(OH)D concentration, which is attributable at least in part to a lower intake of dairy, particularly skim milk. Increased risk of suboptimal concentrations of vitamin D was also observed among those with the CT genotype, suggesting an intermediate effect of the heterozygous genotype.

Systematic review and meta-analysis of lactose digestion, its impact on intolerance and nutritional effects of dairy food restriction in inflammatory bowel diseases.

BACKGROUND: Relationships between inflammatory bowel disease and lactose containing foods remain controversial and poorly defined regarding symptoms, nutritional outcomes, and epidemiologic associations for lactose maldigestion. METHODS: A literature review was performed using Pub Med, Cochrane library and individual references, to extract data on lactose maldigestion prevalence in inflammatory bowel diseases. A meta-analysis was done using selected articles, to determine odds ratios of maldigestion. Information was collected about symptoms, impact on pattern of dairy food consumption, as well as the effects of dairy foods on the course of inflammatory bowel diseases. RESULTS: A total of 1022 articles were evaluated, 35 articles were retained and 5 studies were added from review articles. Of these 17 were included in meta-analysis which showed overall increased lactose maldigestion in both diseases. However increased risk on sub analysis was only found in Crohn's in patients with small bowel involvement. Nine additional studies were reviewed for symptoms, with variable outcomes due to confounding between lactose intolerance and lactose maldigestion. Fourteen studies were evaluated for dairy food effects. There was a suggestion that dairy foods may protect against inflammatory bowel disease. Nutritional consequences of dairy restrictions might impact adversely on bone and colonic complications. CONCLUSIONS: Lactose maldigestion in inflammatory bowel disease is dependent on ethnic makeup of the population and usually not disease. No bias of increased disease prevalence was noted between lactase genotypes. Intolerance symptoms depend on several parameters besides lactose maldigestion. Dairy foods may decrease risks of inflammatory bowel disease. Dairy restrictions may adversely affect disease outcome.

Prevalence of lactose intolerance in Chile: a double-blind placebo study.

BACKGROUND AND STUDY AIMS: Lactase non-persistence (LNP), or primary hypolactasia, is a genetic condition that mediates lactose malabsorption and can cause lactose intolerance. Here we report the prevalence of lactose intolerance in a double-blind placebo study. METHODS: The LCT C>T-13910 variant was genotyped by RT-PCR in 121 volunteers and lactose malabsorption was assessed using the hydrogen breath test (HBT) after consuming 25 g of lactose. Lactose intolerance was assessed by scoring symptoms (SS) using a standardized questionnaire following challenge with a lactose solution or saccharose placebo. RESULTS: The LNP genotype was observed in 57% of the volunteers, among whom 87% were HBT⁺. In the HBT⁺ group the median SS was 9 and in the HBT⁻ group the median SS was 3 (p < 0.001). No difference was observed in the SS when both groups were challenged with the placebo. The most common symptoms included audible bowel sounds, abdominal pain and meteorism. In the ROC curve analysis, an SS ≥ 6 demonstrated 72% sensitivity and 81% specificity for predicting a positive HBT. To estimate prevalence, lactose intolerance was defined as the presence of an SS ≥ 6 points after subtracting the placebo effect and 34% of the study population met this definition. CONCLUSIONS: The LNP genotype was present in more than half of subjects evaluated and the observed prevalence of lactose intolerance was 34%.

Lactase persistence alleles reveal partial East African ancestry of southern African Khoe pastoralists.

The ability to digest milk into adulthood, lactase persistence (LP), as well as specific genetic variants associated with LP, is heterogeneously distributed in global populations. These variants were most likely targets of selection when some populations converted from hunter-gatherer to pastoralist or farming lifestyles. Specific LP polymorphisms are associated with particular geographic regions and populations; however, they have not been extensively studied in southern Africa. We investigate the LP-regulatory region in 267 individuals from 13 southern African populations (including descendants of hunter-gatherers, pastoralists, and agropastoralists), providing the first comprehensive study of the LP-regulatory region in a large group of southern Africans. The "East African" LP single-nucleotide polymorphism (SNP) (14010G>C) was found at high frequency (>20%) in a strict pastoralist Khoe population, the Nama of Namibia, suggesting a connection to East Africa, whereas the "European" LP SNP (13910C>T) was found in populations of mixed ancestry. Using genome-wide data from various African populations, we identify admixture (13%) in the Nama, from an Afro-Asiatic group dating to >1,300 years ago, with the remaining fraction of their genomes being from San hunter-gatherers. We also find evidence of selection around the LCT gene among Khoe-speaking groups, and the substantial frequency of the 14010C variant among the Nama is best explained by adaptation to digesting milk. These genome-local and genome-wide results support a model in which an East African group brought pastoralist practices to southern Africa and admixed with local hunter-gatherers to form the ancestors of Khoe people.

Reliable analysis of the single nucleotide polymorphism of lactase persistence LPH(-13910) C/T from saliva derived DNA: validation of a standardized saliva collection system.

BACKGROUND: The purpose of this study was to investigate the applicability of the Greiner Saliva Collection System (SCS) to obtain human genomic DNA for the analysis of single nucleotide polymorphisms (SNP) in the clinical routine laboratory. METHODS: Saliva and EDTA-blood were collected pair-wise from 112 participants. DNA was prepared by two automated procedures (MagNA Pure LC or MagNa Pure compact) and analyzed by UV-spectrophotometry and real-time PCR. RESULTS: Mean saliva derived DNA concentration was 52.7 ng/µL ± 36.4 (1000 µL, MagNA Pure LC) and 9.2 ng/µL ± 5.6 (200 µL, MagNA Pure compact) with A260/A280 ratios of 1.9 ± 0.1 and 2.1 ± 0.3 for MagNA Pure LC and MagNA Pure compact, respectively. SNP analysis for caucasian adult type lactase persistence showed a 100% success rate from saliva derived DNA and as reference from blood derived DNA. Matching genotypes were obtained in each sample pair. CONCLUSIONS: Saliva obtained with the standardized SCS yielded sufficient amounts of DNA in high purity and was found to represent a suitable and reliable source of human DNA for SNP analysis in the clinical routine laboratory.

Lactose intolerance and health disparities among African Americans and Hispanic Americans: an updated consensus statement.

Dairy foods contribute nine essential nutrients to the diet including calcium, potassium and vitamin D; nutrients identified by the 2010 Dietary Guidelines for Americans as being "of public health concern" within the U.S. population. Milk and milk product intake is associated with better diet quality and has been associated with a reduced risk of chronic diseases or conditions including hypertension, cardiovascular disease, metabolic syndrome, Type 2 Diabetes and osteoporosis. Some research also indicates dairy food intake may be linked to reduced body fat, when accompanied by energy-restriction. On average, both African Americans and Hispanic Americans consume less than the recommended levels of dairy foods, and perceived or actual lactose intolerance can be a primary reason for limiting or avoiding dairy intake. True lactose intolerance prevalence is not known because healthcare providers do not routinely measure for it, and no standardized assessment method exists. Avoiding dairy may lead to shortfalls of essential nutrients and increased susceptibility to chronic disease. This updated Consensus Statement aims to provide the most current information about lactose intolerance and health, with specific relevance to the African American and Hispanic American communities. Topics covered include diagnostic considerations, actual and recommended dairy food intake and levels of consumption of key dairy nutrients among African Americans and Hispanic Americans; prevalence of self-reported lactose intolerance among various racial/ethnic groups; the association between dairy food intake, lactose intolerance and chronic disease; and research-based management recommendations for those with lactose intolerance.

Several different lactase persistence associated alleles and high diversity of the lactase gene in the admixed Brazilian population.

Adult-type hypolactasia is a common phenotype caused by the lactase enzyme deficiency. The -13910 C>T polymorphism, located 14 Kb upstream of the lactase gene (LCT) in the MCM6 gene was associated with lactase persistence (LP) in Europeans. This polymorphism is rare in Africa but several other variants associated with lactase persistence were observed in Africans. The aims of this study were to identify polymorphisms in the MCM6 region associated with the lactase persistence phenotype and to determine the distribution of LCT gene haplotypes in 981 individuals from North, Northeast and South Brazil. These polymorphisms were genotyped by PCR based methods and sequencing. The -13779*C,-13910*T, -13937*A, -14010*C, -14011*T LP alleles previously described in the MCM6 gene region that acts as an enhancer for the LCT gene were identified in Brazilians. The most common LP allele was -13910*T. Its frequency was highly correlated with European ancestry in the Brazilian populations investigated. The -13910*T was higher (0.295) in southern Brazilians of European ancestry and lower (0.175) in the Northern admixed population. LCT haplotypes were derived from the 10 LCT SNPs genotyped. Overall twenty six haplotypes previously described were identified in the four Brazilian populations studied. The Multidimensional Scaling analysis showed that Belém, in the north, was closer to Amerindians. Northeastern and southern Afro-descendants were more related with Bantu-speaking South Africans whereas the Southern population with European ancestry grouped with Southern and Northern Europeans. This study shows a high variability considering the number of LCT haplotypes observed. Due to the highly admixed nature of the Brazilian populations, the diagnosis of hypolactasia in Brazil, based only in the investigation of the -13910*T allele is an oversimplification.

A study on genetic test of lactase persistence in relation to milk consumption in regional groups of India.

BACKGROUND: Lactase nonpersistence (LNP) is characterized by the decrease in lactase expression in the small intestine. Studies have shown that -13910 C>T and -22018 G>A single-nucleotide polymorphisms (SNPs) located upstream of the lactase gene are associated with an LNP/lactase persistence (LP) trait. OBJECTIVE: The current study evaluated the LP allelic frequency in 227 healthy Indian subjects consisting of North Indians, Maharashtrians, Gujaratis, Parsis, and South Indians, and for the first time assessed its relation with milk consumption pattern in Indian subjects. METHODS: The two SNPs were genotyped using the polymerase chain reaction and restriction fragment length polymorphism methods. The milk consumption pattern for the studied subjects was noted by questionnaire. RESULTS: The two SNPs were present in a strong linkage disequilibrium. LP prevalence varied in these Indian regional groups. The LP frequency was highest for North Indians and lowest for Parsis (p=0.03 CC vs. CT+TT, p=0.008 GG vs. GA+AA). South Indians had a lower LP frequency compared to North Indians (p=0.07 for each SNP). The milk consumption pattern varied in these Indian subgroups, with the Gujaratis exhibiting the highest milk intake and Parsis the lowest (p=0.04). CONCLUSION: Our study indicates that the milk intake in Indians might be influenced by their dietary habits in addition to their ancestral history. An overall correlation, however, between milk consumption and LP genotypes was not observed.

High lactose tolerance in North Europeans: a result of migration, not in situ milk consumption.

The main carbohydrate in milk is lactose, which must be hydrolyzed to glucose and galactose before the sugars can be digested. While 65% or more of the total human population are lactose intolerant, in some human populations lactase activity commonly persists into adulthood. Lactose tolerance is exceptionally widespread in Northern European countries such as Sweden and Finland, with tolerance levels of 74% and 82%, respectively. Theoretically, this may result either from a strong local selection pressure for lactose tolerance, or from immigration of lactose tolerant people to Northern Europe. We provide several lines of archaeological and historical evidence suggesting that the high lactose tolerance in North Europeans cannot be explained by selection from in situ milk consumption. First, fresh cow milk has not belonged to the traditional diet of Swedes or Finns until recent times. Second, not enough milk has been available for adult consumption. Cattle herding has been neither widespread nor productive enough in Northern Europe to have provided constant access to fresh milk. We suggest that the high prevalence of lactose tolerance in Finland in particular may be explained by immigration of people representing so-called Corded Ware Culture, an early culture representing agricultural development in Europe.

High prevalence of lactase non-persistence among indigenous nomadic Nenets, north-west Russia.

OBJECTIVES: The frequency of adult-type hypolactasia (lactase non-persistence) varies widely among different ethnic groups. The cultural historical hypothesis assumes a link between the occurrence of hypolactasia and the distribution of dairy farming. The nomadic Nenets have been reindeer herders for generations and have therefore not consumed any dairy products. The hypotheses here was that the prevalence of lactase non-persistence (-13910 C/C genotype) among Nenets people having four Nenets grandparents is high, while the prevalence among Nenets originating from ethnically mixed families is lower. STUDY DESIGN: The material was collected in four typical Nenets settlements in the Nenets Autonomous Okrug in Russia. One-third of the adult Nenets population were invited to answer a questionnaire and to donate buccal samples for genotyping by a doctor from the team of medical professionals who make rounds in this area. The total number of available participants was 177. METHODS: Genotyping was performed with the AbiPrism system. We used the method of concordance of grandparents' national origin to ascribe ethnicity. RESULTS: The prevalence of adult-type hypolactasia (-13910 C/C) among Nenets who had four Nenets grandparents was found to be 90%. The figures among others reporting three, two and one grandparent of Nenets origin were 72, 60 and 28%, respectively. CONCLUSION: The findings are in accord with the cultural historical hypothesis.

Comparison of lactase persistence polymorphism in ancient and present-day Hungarian populations.

The prevalence of adult-type hypolactasia varies ethnically and geographically among populations. A C/T-13910 single nucleotide polymorphism (SNP) upstream of the lactase gene is known to be associated with lactase non-persistence in Europeans. The aim of this study was to determine the prevalence of lactase persistent and non-persistent genotypes in current Hungarian-speaking populations and in ancient bone samples of classical conquerors and commoners from the 10th-11th centuries from the Carpathian basin; 181 present-day Hungarian, 65 present-day Sekler, and 23 ancient samples were successfully genotyped for the C/T-13910 SNP by the dCAPS PCR-RFLP method. Additional mitochondrial DNA testing was also carried out. In ancient Hungarians, the T-13910 allele was present only in 11% of the population, and exclusively in commoners of European mitochondrial haplogroups who may have been of pre-Hungarian indigenous ancestry. This is despite animal domestication and dairy products having been introduced into the Carpathian basin early in the Neolithic Age. This anomaly may be explained by the Hungarian use of fermented milk products, their greater consumption of ruminant meat than milk, cultural differences, or by their having other lactase-regulating genetic polymorphisms than C/T-13910. The low prevalence of lactase persistence provides additional information on the Asian origin of Hungarians. Present-day Hungarians have been assimilated with the surrounding European populations, since they do not differ significantly from the neighboring populations in their possession of mtDNA and C/T-13910 variants.

Multiple rare variants as a cause of a common phenotype: several different lactase persistence associated alleles in a single ethnic group.

Persistence of intestinal lactase into adulthood allows humans to use milk from other mammals as a source of food and water. This genetic trait has arisen by convergent evolution and the derived alleles of at least three different single nucleotide polymorphisms (-13910C>T, -13915T>G, -14010G>C) are associated with lactase persistence in different populations. Each allele occurs on an extended haplotype, consistent with positive directional selection. The SNPs are located in an 'enhancer' sequence in an intron of a neighboring gene (MCM6) and modulate lactase transcription in vitro. However, a number of lactase persistent individuals carry none of these alleles, but other low-frequency single nucleotide polymorphisms have been observed in the same region. Here we examine a cohort of 107 milk-drinking Somali camel-herders from Ethiopia. Eight polymorphic sites are identified in the enhancer. -13915*G and -13907*G (a previously reported candidate) are each significantly associated with lactase persistence. A new allele, -14009*G, has borderline association with lactase persistence, but loses significance after correction for multiple testing. Sequence diversity of the enhancer is significantly higher in the lactase persistent members of this and a second cohort compared with non-persistent members of the two groups (P = 7.7 x 10(-9) and 1.0 x 10(-3)). By comparing other loci, we show that this difference is not due to population sub-structure, demonstrating that increased diversity can accompany selection. This contrasts with the well-documented observation that positive selection decreases diversity by driving up the frequency of a single advantageous allele, and has implications for association studies.

Lactose intolerance and African Americans: implications for the consumption of appropriate intake levels of key nutrients.

Lactose intolerance is a complex condition that is complicated by cultural beliefs and perceptions about the consumption of dairy products. These attitudes about dairy may contribute to inadequate intake of key nutrients that may impact conditions that contribute to health disparities in African Americans. While a complex health problem, lactose intolerance is easy to treat. However, no treatment can improve the body's ability to produce lactase. Yet, symptoms can be controlled through dietary strategies. This position paper emphasizes the importance of using patient and provider-level strategies in order to reduce the risks to the health of African Americans that may accrue as a result of dairy nutrient deficiency. Evaluation and assessment of interventions tested is critical so that evidence-based approaches to addressing dairy nutrient deficiency and lactose Intolerance can be created. Lastly, it is essential for physicians to communicate key messages to their patients. Since dairy nutrients address important health concerns, the amelioration of lactose intolerance is an investment in health. Lactose intolerance is common, is easy to treat, and can be managed. It is possible to consume dairy even in the face of a history of maldigestion or lactose intolerant issues. Gradually increasing lactose in the diet--drinking small milk portions with food, eating yogurt, and consuming cheese--are effective strategies for managing lactose intolerance and meeting optimal dairy needs.

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.