Haplotype Analysis Reveals a Possible Founder Effect of RET Mutation R114H for Hirschsprung's Disease in the Chinese Population

Background Hirschsprung's disease (HSCR) is a congenital disorder associated with the lack of intramural ganglion cells in the myenteric and sub-mucosal plexuses along varying segments of the gastrointestinal tract. The RET gene is the major gene implicated in this gastrointestinal disease. A highly recurrent mutation in RET (RETR114H) has recently been identified in ~6-7% of the Chinese HSCR patients which, to date, has not been found in Caucasian patients or controls nor in Chinese controls. Due to the high frequency of RETR114H in this population, we sought to investigate whether this mutation may be a founder HSCR mutation in the Chinese population. Methodology and Principal Findings To test whether all RETR114H were originated from a single mutational event, we predicted the approximate age of RETR114H by applying a Bayesian method to RET SNPs genotyped in 430 Chinese HSCR patients (of whom 25 individuals had the mutation) to be between 4-23 generations old depending on growth rate. We reasoned that if RETR114H was a founder mutation then those with the mutation would share a haplotype on which the mutation resides. Including SNPs spanning 509.31 kb across RET from a recently obtained 500 K genome-wide dataset for a subset of 181 patients (14 RETR114H patients), we applied haplotype estimation methods to determine whether there were any segments shared between patients with RETR114H that are not present in those without the mutation or controls. Analysis yielded a 250.2 kb (51 SNP) shared segment over the RET gene (and downstream) in only those patients with the mutation with no similar segments found among other patients. Conclusions This suggests that RETR114H is a founder mutation for HSCR in the Chinese population. © 2010 Cornes et al.published_or_final_versio

A “Crossomics” Study Analysing Variability of Different Components in Peripheral Blood of Healthy Caucasoid Individuals

Background: Different immunotherapy approaches for the treatment of cancer and autoimmune diseases are being developed and tested in clinical studies worldwide. Their resulting complex experimental data should be properly evaluated, therefore reliable normal healthy control baseline values are indispensable. Methodology/Principal Findings: To assess intra- and inter-individual variability of various biomarkers, peripheral blood of 16 age and gender equilibrated healthy volunteers was sampled on 3 different days within a period of one month. Complex "crossomics'' analyses of plasma metabolite profiles, antibody concentrations and lymphocyte subset counts as well as whole genome expression profiling in CD4(+)T and NK cells were performed. Some of the observed age, gender and BMI dependences are in agreement with the existing knowledge, like negative correlation between sex hormone levels and age or BMI related increase in lipids and soluble sugars. Thus we can assume that the distribution of all 39.743 analysed markers is well representing the normal Caucasoid population. All lymphocyte subsets, 20% of metabolites and less than 10% of genes, were identified as highly variable in our dataset. Conclusions/Significance: Our study shows that the intra- individual variability was at least two-fold lower compared to the inter-individual one at all investigated levels, showing the importance of personalised medicine approach from yet another perspective

Dietary iodine exposure and brain structures and cognition in older people. Exploratory analysis in the Lothian Birth Cohort 1936

Background: Iodine deficiency is one of the three key micronutrient deficiencies highlighted as major public health issues by the World Health Organisation. Iodine deficiency is known to cause brain structural alterations likely to affect cognition. However, it is not known whether or how different (lifelong) levels of exposure to dietary iodine influences brain health and cognitive functions. Methods: From 1091 participants initially enrolled in The Lothian Birth Cohort Study 1936, we obtained whole diet data from 882. Three years later, from 866 participants (mean age 72 yrs, SD ±0.8), we obtained cognitive information and ventricular, hippocampal and normal and abnormal tissue volumes from brain structural magnetic resonance imaging scans (n=700). We studied the brain structure and cognitive abilities of iodine-rich food avoiders/low consumers versus those with a high intake in iodine-rich foods (namely dairy and fish). Results: We identified individuals (n=189) with contrasting diets, i) belonging to the lowest quintiles for dairy and fish consumption, ii) milk avoiders, iii) belonging to the middle quintiles for dairy and fish consumption, and iv) belonging to the middle quintiles for dairy and fish consumption. Iodine intake was secured mostly though the diet (n=10 supplement users) and was sufficient for most (75.1%, median 193 μg/day). In individuals from these groups, brain lateral ventricular volume was positively associated with fat, energy and protein intake. The associations between iodine intake and brain ventricular volume and between consumption of fish products (including fish cakes and fish-containing pasties) and white matter hyperintensities (p=0.03) the latest being compounded by sodium, proteins and saturated fats, disappeared after type 1 error correction. Conclusion: In this large Scottish older cohort, the proportion of individuals reporting extreme (low vs. high)/medium iodine consumption is small. In these individuals, low iodine-rich food intake was associated with increased brain volume shrinkage, raising an important hypothesis worth being explored for designing appropriate guidelines

Genetic Variants of the FADS Gene Cluster and ELOVL Gene Family, Colostrums LC-PUFA Levels, Breastfeeding, and Child Cognition

Introduction: Breastfeeding effects on cognition are attributed to long-chain polyunsaturated fatty acids (LC-PUFAs), but controversy persists. Genetic variation in fatty acid desaturase (FADS) and elongase (ELOVL) enzymes has been overlooked when studying the effects of LC-PUFAs supply on cognition. We aimed to: 1) to determine whether maternal genetic variants in the FADS cluster and ELOVL genes contribute to differences in LC-PUFA levels in colostrum; 2) to analyze whether these maternal variants are related to child cognition; and 3) to assess whether children's variants modify breastfeeding effects on cognition. Methods: Data come from two population-based birth cohorts (n = 400 mother-child pairs from INMA-Sabadell; and n = 340 children from INMA-Menorca). LC-PUFAs were measured in 270 colostrum samples from INMA-Sabadell. Tag SNPs were genotyped both in mothers and children (13 in the FADS cluster, 6 in ELOVL2, and 7 in ELOVL5). Child cognition was assessed at 14 mo and 4 y using the Bayley Scales of Infant Development and the McCarthy Scales of Children"s Abilities, respectively. Results: Children of mothers carrying genetic variants associated with lower FADS1 activity (regulating AA and EPA synthesis), higher FADS2 activity (regulating DHA synthesis), and with higher EPA/AA and DHA/AA ratios in colostrum showed a significant advantage in cognition at 14 mo (3.5 to 5.3 points). Not being breastfed conferred an 8- to 9-point disadvantage in cognition among children GG homozygote for rs174468 (low FADS1 activity) but not among those with the A allele. Moreover, not being breastfed resulted in a disadvantage in cognition (5 to 8 points) among children CC homozygote for rs2397142 (low ELOVL5 activity), but not among those carrying the G allele. Conclusion: Genetically determined maternal supplies of LC-PUFAs during pregnancy and lactation appear to be crucial for child cognition. Breastfeeding effects on cognition are modified by child genetic variation in fatty acid desaturase and elongase enzymes

Bioavailability of fatty acids from krill oil, krill meal and fish oil in healthy subjects–a randomized, single-dose, cross-over trial

Background Krill contains two marine omega-3 polyunsaturated fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), mainly bound in phospholipids. Typical products from krill are krill oil and krill meal. Fish oils contain EPA and DHA predominantly bound in triglycerides. The difference in the chemical binding of EPA and DHA has been suggested to affect their bioavailability, but little is known on bioavailability of EPA and DHA in krill meal. This study was undertaken to compare the acute bioavailability of two krill products, krill oil and krill meal, with fish oil in healthy subjects. Methods A randomized, single-dose, single-blind, cross-over, active-reference trial was conducted in 15 subjects, who ingested krill oil, krill meal and fish oil, each containing approx. 1 700 mg EPA and DHA. Fatty acid compositions of plasma triglycerides and phospholipids were measured repeatedly for 72 hours. The primary efficacy analysis was based on the 72 hour incremental area under the curve (iAUC) of EPA and DHA in plasma phospholipid fatty acids. Results A larger iAUC for EPA and DHA in plasma phospholipid fatty acids was detected after krill oil (mean 89.08 ± 33.36% × h) than after krill meal (mean 44.97 ± 18.07% x h, p < 0.001) or after fish oil (mean 59.15 ± 22.22% × h, p=0.003). Mean iAUC’s after krill meal and after fish oil were not different. A large inter-individual variability in response was observed. Conclusion EPA and DHA in krill oil had a higher 72-hour bioavailability than in krill meal or fish oil. Our finding that bioavailabilities of EPA and DHA in krill meal and fish oil were not different argues against the interpretation that phospholipids are better absorbed than triglycerides. Longer-term studies using a parameter reflecting tissue fatty acid composition, like erythrocyte EPA plus DHA are needed