Lactase Research Articles

Detecting and Measuring Selection from Gene Frequency Data

The recent advent of high-throughput sequencing and genotyping technologies makes it possible to produce, easily and cost effectively, large amounts of detailed data on the genotype composition of populations. Detecting locus-specific effects may help identify those genes that have been, or are currently, targeted by natural selection. How best to identify these selected regions, loci, or single nucleotides remains a challenging issue. Here, we introduce a new model-based method, called SelEstim, to distinguish putative selected polymorphisms from the background of neutral (or nearly neutral) ones and to estimate the intensity of selection at the former. The underlying population genetic model is a diffusion approximation for the distribution of allele frequency in a population subdivided into a number of demes that exchange migrants. We use a Markov chain Monte Carlo algorithm for sampling from the joint posterior distribution of the model parameters, in a hierarchical Bayesian framework. We present evidence from stochastic simulations, which demonstrates the good power of SelEstim to identify loci targeted by selection and to estimate the strength of selection acting on these loci, within each deme. We also reanalyze a subset of SNP data from the Stanford HGDP-CEPH Human Genome Diversity Cell Line Panel to illustrate the performance of SelEstim on real data. In agreement with previous studies, our analyses point to a very strong signal of positive selection upstream of the LCT gene, which encodes for the enzyme lactase-phlorizin hydrolase and is associated with adult-type hypolactasia. The geographical distribution of the strength of positive selection across the Old World matches the interpolated map of lactase persistence phenotype frequencies, with the strongest selection coefficients in Europe and in the Indus Valley.

Got Milk? Exploring the Evolutionary Connection between Milk Drinking, Lactose Digestion, and Sunlight

Milk,as thepopularslogangoes,doesabodygood.Itcontains essential nutrients including fat, protein, sugar, as well as calcium, other minerals, and vitamin D needed for bones. Most people in the world lose the ability to digest lactose, the main sugar in milk, shortly after weaning. For these people, drinking fresh milk can lead to unpleasant bloating, flatulence, and cramps. However, about one-third of people in the world— mostly those whose ancestors originate in Europe, the Middle East, Africa, and southern Asia—continue to produce the enzyme lactase, which is responsible for lactose digestion, throughout adulthood. This trait is called lactase persistence, and recent genetic evidence has shown that it evolved independently in different parts of the world over the last 10,000 years as ar esult of strong natural selection. Why lactase persistence has evolved under such strong natural selection remains something of a mystery. The most widely cited explanation is that in the absence of dietary sources for vitamin D and with insufficient sunlight to make vitamin D in the skin, early northern European farmers were at risk of bone disease. Milk is an excellent source of calcium and an adequate source of vitamin D. So, as this “calcium assimilation hypothesis” proposes, having the ability to drink fresh milk into adulthood could have led to a major survival advantage. In a new article in Molecular Biology and Evolution journal,

Direct Estimates of Natural Selection in Iberia Indicate Calcium Absorption Was Not the Only Driver of Lactase Persistence in Europe

Lactase persistence (LP) is a genetically determined trait whereby the enzyme lactase is expressed throughout adult life. Lactase is necessary for the digestion of lactose--the main carbohydrate in milk--and its production is downregulated after the weaning period in most humans and all other mammals studied. Several sources of evidence indicate that LP has evolved independently, in different parts of the world over the last 10,000 years, and has been subject to strong natural selection in dairying populations. In Europeans, LP is strongly associated with, and probably caused by, a single C to T mutation 13,910 bp upstream of the lactase (LCT) gene (-13,910*T). Despite a considerable body of research, the reasons why LP should provide such a strong selective advantage remain poorly understood. In this study, we examine one of the most widely cited hypotheses for selection on LP--that fresh milk consumption supplemented the poor vitamin D and calcium status of northern Europe's early farmers (the calcium assimilation hypothesis). We do this by testing for natural selection on -13,910*T using ancient DNA data from the skeletal remains of eight late Neolithic Iberian individuals, whom we would not expect to have poor vitamin D and calcium status because of relatively high incident UVB light levels. None of the eight samples successfully typed in the study had the derived T-allele. In addition, we reanalyze published data from French Neolithic remains to both test for population continuity and further examine the evolution of LP in the region. Using simulations that accommodate genetic drift, natural selection, uncertainty in calibrated radiocarbon dates, and sampling error, we find that natural selection is still required to explain the observed increase in allele frequency. We conclude that the calcium assimilation hypothesis is insufficient to explain the spread of LP in Europe.

Malabsorption et intolérance au lactose chez l’adulte

The milk sugar lactose is a disaccharide, which is hydrolyzed in the intestine by the brush border enzyme lactase in free glucose and galactose to be absorbed by the small bowel wall. Low lactase activity allows undigested lactose to reach the colon where the anaerobic activity of bacteria yields different products. These are principally short chain fatty acids, hydrogen, carbon dioxide and methane, responsible for symptoms mainly consisting in abdominal pain, bloating, flatulence and diarrhea. Lactase deficiency may be genetically mediated or acquired after weaning or secondary to diseases injuring the small bowel mucosa, such as celiac disease, enteritis or Crohn's disease. Lactose malabsorption is due to lactase deficiency and its clinical expression is lactose intolerance: in clinical practice, lactose malabsorption is diagnosed by the hydrogen breath test (HBT) that should be accompanied by the collection of intolerance symptoms possibly provoked by HBT. The treatment is lactose avoidance/reduction in the diet: this approach could be reserved to symptomatic patient (“intolerants”). Dietetic advice should aim to ensure nutritional adequacy of the diet and to avoid nutritional deficiencies, in particular due to a lower calcium intake.

Participation and Performance in INSTAND Multi-Analyte Molecular Genetics External Quality Assessment Schemes from 2006 to 2012

INSTAND e.V. has provided Molecular Genetics Multi-Analyte EQA schemes since 2006. EQA participation and performance were assessed from 2006 - 2012. From 2006 to 2012, the number of analytes in the Multi-Analyte EQA schemes rose from 17 to 53. Total number of results returned rose from 168 in January 2006 to 824 in August 2012. The overall error rate was 1.40 +/- 0.84% (mean +/- SD, N = 24 EQA dates). From 2006 to 2012, no analyte was reported 100% correctly. Individual participant performance was analysed for one common analyte, Lactase (LCT) T-13910C. From 2006 to 2012, 114 laboratories participated in this EQA. Of these, 10 laboratories (8.8%) reported at least one wrong result during the whole observation period. All laboratories reported correct results after their failure incident. In spite of the low overall error rate, EQA will continue to be important for Molecular Genetics.

Evaluation of Lactose in Milk and Dairy Products

Milk is an emulsion containing fat, protein, carbohydrate, vitamins, minerals and water. Lactose is the main carbohydrate presented in milk and dairy products. This sugar is composed by one unit of glucose and one of galactose. Metabolism of lactose depends on enzyme lactase which hydrolyzes this sugar. In some cases, lactase may be absent or an insufficient quantity in human body. Deficiency in lactase production causes numerous symptoms such as diarrhea; abdominal pain and bloating that characterize lactose intolerance. The aim of this work was to evaluate concentration of lactose in milk and dairy products to determine the effect of the processing and to calculate the quantity of each product which can be consumed without symptoms in lactose intolerant. Results obtained show lactose concentration of 4.42% w/v in Milk; 3.5% w/w in Minas cheese; 9.9%w/v in condensed milk and 4.76%w/v in yogurt. Portion innocous ranged from 60 to 170 mL depending on each product.

Scientific evidence about the role of yogurt and other fermented milks in the healthy diet for the Spanish population

Milk products contain proteins of high biologic value and digestibility; they also contain fat, carbohydrates, vitamins and minerals, specially calcium and phosphorus. Diversification of milk products consumption allows a high consumptiom of the above mentioned products, optimizing nutrient intake. In Spain, food consumption of milk products lower than the recommended amounts was observed in 20 to 40 % of the children and 30 to 45 % of the adults. Milk products represent 44 to 70 % of calcium intake in the Spanish population. Milk products consumption is positively associated with a high bone mineral density. More than 35 % of children and adults in Spain had calcium intakes below the national recommendations. Yogur contains less lactose than regular milk and fermenting milk bacteries express functioning lactase. Yogur intake is recommended to improve lactose digestion in individuals having lactose maldigestion. It seems reasonable to recommend yogur to improve calcium absorption, at least in post-menopausal women, and also for decreasing incidence and duration of infectious gastrointestinal disorders in children. Fermented milk products consumption, before, during and after medical eradication of Helicobacter Pylori, increases 5 to 10 % the effect of the specific drug therapy. Its consumption before, during and after antibiotic treatment, could also reduce the risk of diarrhea associated with the use of the above mentioned drugs. The Spanish Federation of Nutrition, Feeding and Dietetic Societies (FESNAD) recommend the following consumption of milk and milk products: Adults, 2-3 portions/day; school-age children, 2-3 portions/day; adolescents, 3-4 portions/day; pregnant and lactating women and during menopause, 3-4 portions/day; elderly, 2-4 portions/day. Considering yogur and fermented milk consumption show some advantages when compared with other milk products, we can recommend yogur within a daily and varied consumption of milk products.

Preparation of lactose-free pasteurized milk with a recombinant thermostable β-glucosidase from Pyrococcus furiosus

BackgroundLactose intolerance is a common health concern causing gastrointestinal symptoms and avoidance of dairy products by afflicted individuals. Since milk is a primary source of calcium and vitamin D, lactose intolerant individuals often obtain insufficient amounts of these nutrients which may lead to adverse health outcomes. Production of lactose-free milk can provide a solution to this problem, although it requires use of lactase from microbial sources and increases potential for contamination. Use of thermostable lactase enzymes can overcome this issue by functioning under pasteurization conditions.ResultsA thermostable β-glucosidase gene from Pyrococcus furiosus was cloned in frame with the Saccharomyces cerecisiae a-factor secretory signal and expressed in Pichia pastoris strain X-33. The recombinant enzyme was purified by a one-step method of weak anion exchange chromatography. The optimum temperature and pH for this β-glucosidase activity was 100°C and pH 6.0, respectively. The enzyme activity was not significantly inhibited by Ca2+. We tested the additive amount, hydrolysis time, and the influence of glucose on the enzyme during pasteurization and found that the enzyme possessed a high level of lactose hydrolysis in milk that was not obviously influenced by glucose.ConclusionsThe thermostablity of this recombinant β-glucosidase, combined with its neutral pH activity and favorable temperature activity optima, suggest that this enzyme is an ideal candidate for the hydrolysis of lactose in milk, and it would be suitable for application in low-lactose milk production during pasteurization.

Enzymatic activity preservation and protection through entrapment within degradable hydrogels

This work aims to develop a repeatable enzyme entrapment method that preserves activity within an amicable environment while resisting activity reduction in the presence of environmental challenges. Advances in such methods have wide potential use in biosensor applications. In this work β-galactosidase (lactase) enzyme was entrapped within hydrogel matrices of acrylamide (ACR) crosslinked with N,N'-methylenebisacrylamide (BIS, non-degradable) or poly(ethylene glycol) diacrylate (PEGDA, degradable) to create "biogels." Diffusivity studies of control, enzyme free, hydrogel constructs showed near-Fickian swelling behavior in PBS regardless of crosslinker type or density. As expected, the swelling rate, Ks , decreased when increasing the crosslink density from 78.6 to 14.7 min⁻¹ over a range of 1-20 mol% PEGDA indicating that diffusivity into the matrix is dependent on crosslink density. Fabricated biogels were evaluated for maintained enzyme activity in the 7 and 8 pH range. PEGDA crosslinked gels consistently showed improved enzymatic activity retention as compared to BIS crosslinked gels. As PEGDA crosslink density increased from 5 to 10 mol%, enzymatic activity retention post-initial entrapment increased. Higher PEGDA crosslink densities between 15% and 40% decreased enzymatic activity due to assumed steric hindrance of the entrapped enzyme and also decreased substrate and product diffusion. Increased enzymatic stability was observed in 40 mol% PEGDA crosslinked gels. The biogels were pH challenged to 8.0 and stability, measured as retention of activity, was observed to be 91%. Free, non-entrapped, solution based enzyme conversion only retained 23% activity under the same pH challenge conditions. No significant loss of active enzyme was determined to elute out of the biogels during storage in PBS or during biogel wash and recycling. This entrapment method illustrates the potential to sterically hinder and diffusively impede enzymes from performing their function. Degradation of the network crosslinks can then potentially enable the reactivation of the enzyme at a site and time dictated by the user.

Brief communication: Effect of nomadic subsistence practices on lactase persistence associated genetic variation in Kuwait

Lactase persistence (LP)-the ability to digest lactose in adulthood-is paradigmatic of Holocenic dietary change affecting the evolutionary trajectory of specific populations. Kuwait represents one location of high LP where the variation in associated genomic regions has not been examined. Here, we present new sequence data from a 427 bp amplicon 14 kb upstream of the LCT (lactase) gene for two Bedouin tribal populations, the Ajman and Mutran. We estimate the frequency of known LP associated alleles and discuss the impact of nomadic-pastoralism on the associated genetic variation. We observe high frequency (56% on average) of the -13,915*G allele in both tribes, which is consistent with the high prevalence of LP in Kuwait. Whilst LP associated alleles occur in Kuwait at a similar frequency to other regional populations, we suggest that the -13,915*G allele frequency among the Kuwaiti Bedouin may be higher than among non-Bedouin Kuwaitis, possibly due to greater historical reliance on milk consumption or genetic drift.

THE ROLE OF LACTASE INSUFFICIENCY AND INTESTINAL MICROFLORA IN DEVELOPMENT OF GASTROINTESTINAL DYSFUNCTIONS IN INFANTS AGED 0–6 MONTHS OLD

Aim: to determine the role of lactase insufficiency (LI) and microbial imbalance (MI) in functional disorders of the gastrointestinal dysfunctions (GIF) in infants. Patients and methods: 102 children from the observed population of 268 infants aged 0–6 month old were examined more thoroughly. They were divided into 2 groups: control group of healthy children (n = 40) and 62 patients corresponding the Rome criteria III on GIF in children (study group). Results: regurgitation and intestinal colic predominated among GIF, in 71% of cases they were associated. LI was found in 37% of children with GIF У 37%.Clinical manifestations of GIF were similar both in patients with and without LI. In all children with LI and in 85% of children without LI there was complicated pregnancy history. Intestinal microbiocenosis imbalance (increased amount of conditionally pathogenic flora) was found in all children with GIF, however the results of cultural investigation of faeces and polymerase chain reaction did not coincide with each other. Calprotectin concentration was increased in all children with GIF, especially in LI (522,21 ± 27,84 mcg/g). Treatment management depended on feeding type and presence of LI: in cases of LI patients were administered β-galactosidase, in infants without LI probiotic strains included into milk formulas or drugs were used. In all cases clinical improvement, decrease of calprotectin concentration and improvement of microbiological signs were observed. Conclusions: transitory LI was found more than in 1/3 of the patients with GIF symptoms, moreover the clinical manifestations are similar, which requires additional examination. The optimal diagnostic test is lactose hydrogen breath test. All children with GIF have intestinal microbiocenosis imbalance and symptoms of mild intestinal inflammation. Correction of GIF should be performed in accordance with LI. Lactase enzyme effectively eliminates both LI symptoms and inflammation signs.

Influence of inulin on chemical, sensorial and survival of L. Acidophilus in symbiotic frozen yogurt with reduced-lactose:

<p>Recently, the dairy industry has given special attention to development of products containing low lactose content, to meet the needs of consumers intolerant to this sugar type. This study aimed to evaluate the effects of adding inulin on chemical, sensory and survival of probiotics in symbiotic frozen yogurt with reduced lactose content during the storage period. The hydrolysis degree achieved using 0.8 g of lactase per liter milk was about 97.54%, being below the limit quantification (0.5%) and being considered as a food for special purposes. Based on the results obtained, it can be concluded that the enzyme lactase effectively reduced the lactose content in frozen developed, not by changing the physicochemical and viability of probiotic culture. The addition of inulin caused a significant change (p<0.05) in sensory attributes evaluated and promoted the growth of <em>L. acidophilus</em>, showing that this type of edible ice cream is a good option for the dairy market, catering lactose intolerant consumers.</p><p> </p><p>DOI: http://dx.doi.org/10.14685/rebrapa.v3i1.90</p>

Association Between Polymorphisms of VDR, COL1A1, and LCT Genes and Bone Mineral Density in Belarusian Women With Severe Postmenopausal Osteoporosis

BACKGROUND AND OBJECTIVE. Variation of osteoporosis in the population is the result of an interaction between the genotype and the environment, and the genetic causes of osteoporosis are being widely investigated. The aim of this study was to analyze the association between the polymorphisms of the vitamin D receptor (VDR), type I collagen (COL1A1), and lactase (LCT) genes and severe postmenopausal osteoporosis as well as bone mineral density (BMD). MATERIAL AND METHODS. A total of 54 women with severe postmenopausal osteoporosis and 77 controls (mean age, 58.3 years [SD, 6.2] and 56.7 years [SD, 7.42], respectively) were included into the study. The subjects were recruited at the City Center for Osteoporosis Prevention (Minsk, Belarus). Dual-energy x-ray absorptiometry was used to measure bone mineral density at the lumbar spine and the femoral neck. Severe osteoporosis was diagnosed in the women with the clinical diagnosis of postmenopausal osteoporosis and at least 1 fragility fracture. The control group included women without osteoporosis. Polymorphic sites in osteoporosis predisposition genes (ApaI, BsmI, TaqI, and Cdx2 of the VDR gene, G2046T of the COL1A1 gene, and T-13910C of the LCT gene) were determined using the polymerase chain reaction on the deoxyribonucleic acid isolated from dried bloodspots. RESULTS. The data showed that the ApaI and BsmI polymorphisms of the VDR gene and T- 13910C of the LCT gene were associated with severe postmenopausal osteoporosis in the analyzed Belarusian women (P<0.01). A statistically significant positive correlation between the VDR risk genotypes ApaI and TaqI and bone mineral density was found (P<0.05). CONCLUSIONS. The findings of this study suggest that at least the ApaI and BsmI polymorphisms of the VDR gene and T-13910C of the LCT gene are associated with the risk of postmenopausal osteoporosis in our sample of the Belarusian women.

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

Childhood obesity is a worldwide health concern with a multifaceted and sometimes confounding etiology. Dairy products have been implicated as both pro- and 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, 7-12years 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.

No association of LCT-13910 single nucleotide polymorphism with gastroenteritis in Korean children

Zinc and lactase deficiency are closely associated with the severity of gastroenteritis in children. Absorption of lactose is dependent on lactase and enhances the absorption of zinc. In the present study, we analyzed the association of the lactase (LCT)-13910 polymorphism and serum zinc levels with the severity of gastroenteritis in Korean children. 133 gastroenteritis patients and 476 healthy controls were examined for their LCT-13910 genotype using a polymerase chain reaction-restriction fragment length polymorphism. We also analyzed serum zinc levels in 111 pediatric patients and compared their severity of gastroenteritis. For the LCT-13910 genotype, all of 133 gastroenteritis patients and 476 healthy children had only the C/C genotype, which is associated with lactase deficiency. In addition, 111 pediatric patients showed no deficit of serum zinc and no association with severity of gastroenteritis. These results suggested that LCT-13910 polymorphism and zinc deficit may not be risk factors and that zinc administration may not be needed in Korean pediatric patients with gastroenteritis.

Neolithic pots and potters in Europe: the end of ‘demic diffusion’ migratory model

In this paper we discuss the inventions and re-inventions of ceramic technology and pot- tery dispersals in foraging and farming contexts in Eurasia. We focus on narratives that operate with- in interpretative paradigms that suggest movements of unidirectional colonisation and ‘demic’ diffusion, and a correlation between pottery and human DNA haplogroup distributions in Europe in the Initial Neolithic. In addition, we present the results of ancient, Mesolithic and Neolithic mitochon- drial DNA analyses, which suggest variations in population trajectories in prehistoric Europe. We comment on a hypothesis presented recently on the correlation between the distribution of the lactase (LCT) gene –13 910*T in the modern population of Europe, which has been shown to be associated with lactase persistence and dairying, and the Neolithic transition to farming in Central Europe.

Severe lactose intolerance in a patient with coronary artery disease and ischemic cardiomyopathy

A 72-year-old man with severe lactose intolerance was admitted for non-ST-segment elevation myocardial infarction. The coronary angiogram revealed occlusion of the distal third of the first diagonal artery and several non-significant lesions. The pre-discharge echocardiogram revealed moderate left ventricular systolic dysfunction. Discharged on dual antiplatelet therapy, rosuvastatin, perindopril and carvedilol, he was repeatedly readmitted in the following days for abdominal pain/bloating, diarrhea and nausea despite avoiding food products containing lactose. To date, there has been no comprehensive study on the relationship between lactose intolerance and coronary disease, nor has its impact on therapeutics been appropriately addressed. Intolerance to lactose-containing prescription medicines is an extremely rare phenomenon and few strategies are available to overcome this condition, as it has received little attention from the scientific community. Commercial forms of the lactase enzyme and probiotics can limit symptom severity, but different routes of administration, different brands of the same medicine or completely different medicines may be necessary. Some measures were proposed to our patient and, soon afterwards, he was completely asymptomatic in both gastrointestinal and cardiovascular terms.

Severe lactose intolerance in a patient with coronary artery disease and ischemic cardiomyopathy

A 72-year-old man with severe lactose intolerance was admitted for non-ST-segment elevation myocardial infarction. The coronary angiogram revealed occlusion of the distal third of the first diagonal artery and several non-significant lesions. The pre-discharge echocardiogram revealed moderate left ventricular systolic dysfunction. Discharged on dual antiplatelet therapy, rosuvastatin, perindopril and carvedilol, he was repeatedly readmitted in the following days for abdominal pain/bloating, diarrhea and nausea despite avoiding food products containing lactose. To date, there has been no comprehensive study on the relationship between lactose intolerance and coronary disease, nor has its impact on therapeutics been appropriately addressed. Intolerance to lactose-containing prescription medicines is an extremely rare phenomenon and few strategies are available to overcome this condition, as it has received little attention from the scientific community. Commercial forms of the lactase enzyme and probiotics can limit symptom severity, but different routes of administration, different brands of the same medicine or completely different medicines may be necessary. Some measures were proposed to our patient and, soon afterwards, he was completely asymptomatic in both gastrointestinal and cardiovascular terms.

Genetic variation in the lactase gene, dairy product intake and risk for prostate cancer in the European prospective investigation into cancer and nutrition

High dairy protein intake has been found to be associated with increased prostate cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC). To further examine this possible relationship, we investigated the hypothesis that a genetic polymorphism in the lactase (LCT) gene might be associated with elevated dairy product intake and increased prostate cancer risk in a case–control study nested in EPIC. The C/T-13910 lactase variant (rs4988235) was genotyped in 630 men with prostate cancer and 873 matched control participants. Dairy product consumption was assessed by diet questionnaire. Odds ratios (ORs) for prostate cancer in relation to lactase genotype were estimated by conditional logistic regression. Lactase genotype frequency varied significantly between countries, with frequencies of the T (lactase persistence) allele ranging from 7% in Greece to 79% in Denmark. Intake of milk and total dairy products varied significantly by lactase genotype after adjustment for recruitment center; adjusted mean intakes of milk were 44.4, 69.8 and 82.3 g/day among men with CC, CT and TT genotypes, respectively. The lactase variant was not significantly associated with prostate cancer risk, both in our data (adjusted OR for TT vs. CC homozygotes: 1.10, 95% CI: 0.76–1.59) and in a meta-analysis of all the published data (combined OR for T allele carriers vs. CC homozygotes: 1.12, 0.96–1.32). These findings show that while variation in the lactase gene is associated with milk intake in men, the lactase polymorphism does not have a large effect on prostate cancer risk.What's new?High dairy protein intake has previously been found to be associated with increased prostate cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC). The current study was nested in EPIC, and results from this first Europe-wide study suggest that while the C/T13910 lactase polymorphism is associated with milk intake, the variant has no large effect on prostate cancer risk. The data illustrate the challenges of applying mendelian randomisation to explore the relationship between dairy product consumption and cancer risk. Very large studies with both genetic and dietary data are thus needed for investigations using genetic proxies of nutritional exposures.

Lactase persistence and lipid pathway selection in the Maasai.

The Maasai are a pastoral people in Kenya and Tanzania, whose traditional diet of milk, blood and meat is rich in lactose, fat and cholesterol. In spite of this, they have low levels of blood cholesterol, and seldom suffer from gallstones or cardiac diseases. Field studies in the 1970s suggested that the Maasai have a genetic adaptation for cholesterol homeostasis. Analysis of HapMap 3 data using Fixation Index (Fst) and two metrics of haplotype diversity: the integrated Haplotype Score (iHS) and the Cross Population Extended Haplotype Homozygosity (XP-EHH), identified genomic regions and single nucleotide polymorphisms (SNPs) as strong candidates for recent selection for lactase persistence and cholesterol regulation in 143–156 founder individuals from the Maasai population in Kinyawa, Kenya (MKK). The non-synonmous SNP with the highest genome-wide Fst was the TC polymorphism at rs2241883 in Fatty Acid Binding Protein 1(FABP1), known to reduce low density lipoprotein and tri-glyceride levels in Europeans. The strongest signal identified by all three metrics was a 1.7 Mb region on Chr2q21. This region contains the genes LCT (Lactase) and MCM6 (Minichromosome Maintenance Complex Component) involved in lactase persistence, and the gene Rab3GAP1 (Rab3 GTPase-activating Protein Catalytic Subunit), which contains polymorphisms associated with total cholesterol levels in a genome-wide association study of >100,000 individuals of European ancestry. Sanger sequencing of DNA from six MKK samples showed that the GC-14010 polymorphism in the MCM6 gene, known to be associated with lactase persistence in Africans, is segregating in MKK at high frequency (∼58%). The Cytochrome P450 Family 3 Subfamily A (CYP3A) cluster of genes, involved in cholesterol metabolism, was identified by Fst and iHS as candidate loci under selection. Overall, our study identified several specific genomic regions under selection in the Maasai which contain polymorphisms in genes associated with lactase persistence and cholesterol regulation.