Project description: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.

Project description:BackgroundAdult lactase non-persistence (LNP) is due to low lactase expression, resulting in lactose malabsorption (LM). LNP is a genetic trait, but is typically determined by LM markers including breath H2, blood glucose, and urinary galactose after a lactose tolerance test. Known validity of these markers using milk is limited, despite being common practice. Compositional variation, such as β-casein variants, in milk may impact diagnostic efficacy. This study aimed to evaluate the diagnostic accuracy to detect LNP using these commonly measured LM markers after both lactose and milk challenges.MethodsFourty healthy young women were challenged with 50 g lactose then randomized for separate cross-over visits to ingest 750 mL milk (37.5 g lactose) as conventional (both A1 and A2 β-casein) and A1 β-casein-free (a2 Milk™) milk. Blood, breath and urine were collected prior to and up to 3 h following each challenge. The presence of C/T13910 and G/A22018 polymorphisms, determined by restriction fragment length polymorphism, was used as the diagnostic reference for LNP.ResultsGenetic testing identified 14 out of 40 subjects as having LNP (C/C13910 and G/G22018). All three LM markers (breath H2, plasma glucose and urinary galactose/creatinine) discriminated between lactase persistence (LP) and LNP following lactose challenge with an area under the receiver operating characteristic (ROC) curve (AUC) of 1.00, 0.75 and 0.73, respectively. Plasma glucose and urinary galactose/creatinine were unreliable (AUC < 0.70) after milk ingestion. The specificity of breath H2 remained high (100%) when milk was used, but sensitivity was reduced with conventional (92.9%) and a2 Milk™ (78.6%) compared to lactose (sensitivities adjusted for lactose content). The breath H2 optimal cut-off value was lower with a2 Milk™ (13 ppm) than conventional milk (21 ppm). Using existing literature cut-off values the sensitivity and specificity of breath H2 was greater than plasma glucose to detect LNP following lactose challenge whereas values obtained for urinary galactose/creatinine were lower than the existing literature cut-offs.ConclusionThis study showed accurate diagnosis of LNP by breath H2 irrespective of the substrate used, although the diagnostic threshold may vary depending on the lactose substrate or the composition of the milk.Trial registrationACTRN12616001694404 . Registered prospectively on December 9, 2016.

Project description:Abstract Objectives Lactase persistence (LP), a heritable trait in which lactose can be digested throughout adulthood, is often used to predict dairy intake. However, it is currently unknown how LP relates to daily lactose consumption in healthy US adults. The objective of the study was to estimate lactose from foods reported in the Automated Self-Administered 24-Hour Dietary Assessment Tool (ASA24) and to compare lactose and total dairy consumption in relation to LP genotypes. Methods ASA24 dietary data were collected from healthy Caucasians and Hispanics (n = 215) genotyped for the lactase persistence SNP ID: rs4988235. ASA24 outputs servings of dairy but not the nutrient lactose. Lactose was estimated by matching ASA24-reported foods to foods in the Nutrition Coordinating Center Food and Nutrient Database, which outputs lactose. Analysis of covariance was used to identify whether genotype influenced lactose and total dairy consumption with total energy intake and weight as covariates. Pairwise testing was conducted on the adjusted means using the Tukey adjustment to correct for multiple testing. Results Median lactose consumption for subjects with the AA genotype (homozygous LP) was 12.08 g (min: 0.91 g, max: 81.85 g), 10.05 g (min: 0.46 g, max: 45.82) for subjects with the AG genotype (heterozygous LP), and 8.97 g (min: 0.47, max: 38.96 g) for subjects with the GG genotype (homozygous lactase non-persistent). AA subjects consumed more lactose than GG subjects (P = 0.024). When stratifying by sex, there were no significant differences among genotypes in women, although GG women consumed the least amount of lactose compared to AA and AG women. AA men consumed more lactose than AG (P = 0.028) and GG men (P = 0.032). Subjects with the AA genotype consumed the most, and GG subjects the least amount of dairy. However, there were no significant differences in total dairy consumption among genotypes. Conclusions The median amount of lactose consumed daily by healthy adults is 9–12 g/day, with higher consumption by those with an LP genotype. Total dairy intake was not significantly influenced by genotype, highlighting the value in specifically estimating lactose consumption. Maximal lactose intake by lactase non-persisters exceeding 15 g/day suggests alternate routes of lactose catabolism. Funding Sources The California Dairy Research Foundation and the USDA-ARS.

Project description:BackgroundThe lactase enzyme allows lactose digestion in fresh milk. Its activity strongly decreases after the weaning phase in most humans, but persists at a high frequency in Europe and some nomadic populations. Two hypotheses are usually proposed to explain the particular distribution of the lactase persistence phenotype. The gene-culture coevolution hypothesis supposes a nutritional advantage of lactose digestion in pastoral populations. The calcium assimilation hypothesis suggests that carriers of the lactase persistence allele(s) (LCT*P) are favoured in high-latitude regions, where sunshine is insufficient to allow accurate vitamin-D synthesis. In this work, we test the validity of these two hypotheses on a large worldwide dataset of lactase persistence frequencies by using several complementary approaches.MethodologyWe first analyse the distribution of lactase persistence in various continents in relation to geographic variation, pastoralism levels, and the genetic patterns observed for other independent polymorphisms. Then we use computer simulations and a large database of archaeological dates for the introduction of domestication to explore the evolution of these frequencies in Europe according to different demographic scenarios and selection intensities.ConclusionsOur results show that gene-culture coevolution is a likely hypothesis in Africa as high LCT*P frequencies are preferentially found in pastoral populations. In Europe, we show that population history played an important role in the diffusion of lactase persistence over the continent. Moreover, selection pressure on lactase persistence has been very high in the North-western part of the continent, by contrast to the South-eastern part where genetic drift alone can explain the observed frequencies. This selection pressure increasing with latitude is highly compatible with the calcium assimilation hypothesis while the gene-culture coevolution hypothesis cannot be ruled out if a positively selected lactase gene was carried at the front of the expansion wave during the Neolithic transition in Europe.

Project description:Abstract Objectives Lactase persistence (LP) is a heritable trait in which lactose can be digested into adulthood. Lactase non-persisters (LNP) who consume lactose may experience microbial adaptations in response to the undigested lactose. The objective of this study was to determine the interaction between lactose consumption, LP genotype and gut microbiota in an observational cross-sectional study of healthy U.S. adults. Methods ASA24 dietary data and stool samples were collected from healthy U.S. adults genotyped for the lactase persistence SNP ID: rs4988235 (n = 280). Lactose was estimated by matching ASA24-reported foods to foods in the Nutrition Coordinating Center Food and Nutrient Database. The 16S rRNA V4/V5 region, amplified from bacterial DNA extracted from each frozen stool sample, was sequenced using Illumina MiSeq (300bp PE) and analyzed using Qiime 2 (v 2019.10). Bacterial sequence counts present at greater than 0.1% of the total data set were analyzed using DESeq2 and LEfSe. Taxa that were differentially abundant by both analyses at the family or genus level are reported here. Results On average 246 ng/uL (3.9 – 646.5ng/uL) DNA was obtained from each sample, yielding 21,470 sequences (10,122 – 56,837). LP genotypes were unevenly distributed by ethnicity and Clostridium (family Lachnospiraceae) was significantly enriched in Asian ethnicities. Therefore, only Caucasian and Hispanic participants were grouped as LP (AA or AG genotype) or LNP (GG genotype) for further analysis. The abundance of Roseburia and family Lachnospriaceae was higher in the upper (>12.4g), relative to lower (< 5.78g), tertile of lactose consumption in LNP adults, but not in LP. Conclusions Increased abundance of Roseburia, a microbe capable of utilizing lactose, in LNP individuals consuming >12.4 g lactose/day suggests that this genus may metabolize lactose in LNP adults. Funding Sources The California Dairy Research Foundation and the United States Department of Agriculture, Agricultural Research Service.

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Opinion: Increased calorie gain from lactose digestion could contribute to selection for lactase persistence.

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Opinion: Increased calorie gain from lactose digestion could contribute to selection for lactase persistence.

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