Acute Effects of Single Doses of Bonito Fish Peptides and Vitamin D on Whole Blood Gene Expression Levels: A Randomized Controlled Trial.

Fish contains high quality proteins and essential nutrients including 25-hydroxyvitamin D (25(OH)D). Fish peptide consumption can lower cardiovascular disease (CVD) risk factors, and studies have shown an association between 25(OH)D deficiency, CVD and CVD risk factors, such as diabetes. This study investigated acute effects of a single dose of cholecalciferol (VitD3), bonito fish peptide hydrolysate (BPH), or a combination of both on CVD risk factors and whole blood gene expression levels. A randomized, crossover, placebo controlled trial was conducted in 22 adults. They ingested, in random order and at 7-day intervals, 1000 IU of VitD3, 3 g of BPH, a combination of both, or a placebo. A 180 min oral glucose tolerance test was performed. Differences in whole-genome expression levels after versus before each supplementation were computed for 18 subjects. We observed that 16, 1 and 5 transcripts were differentially expressed post- vs. pre-ingestion for VitD3, BPH or VitD3 + BPH treatments, respectively. VitD3-containing treatments affected the expression of the solute carrier family 25 member 20 (SLC25A20) gene involved in fatty acid oxidation, various transcription factors and genes related to glucose metabolism. These results suggest that VitD3 rapidly modulates genes related to CVD risk factors in blood while BPH seems to moderately modulate gene expression levels.

Familial resemblances in human whole blood transcriptome.

BACKGROUND: Considering the implication of gene expression in the susceptibility of chronic diseases and the familial clustering of chronic diseases, the study of familial resemblances in gene expression levels is then highly relevant. Few studies have considered the contribution of both genetic and common environmental effects to familial resemblances in whole blood gene expression levels. The objective is to quantify the contribution of genetic and common environmental effects in the familial resemblances of whole blood genome-wide gene expression levels. We also make comparisons with familial resemblances in blood leukocytes genome-wide DNA methylation levels in the same cohort in order to further investigate biological mechanisms. RESULTS: Maximal heritability, genetic heritability, and common environmental effect were computed for all probes (20.6%, 15.6%, and 5.0% respectively) and for probes showing a significant familial effect (78.1%, 60.1%, and 18.0% respectively). Pairwise phenotypic correlations between gene expression and DNA methylation levels adjusted for blood cell heterogeneity were computed for probes showing significant familial effect. A total of 78 probe pairs among the 7,618,401 possible pairs passed Bonferroni correction (corrected P-value = 6.56 × 10- 9). Significant genetic correlations between gene expression and DNA methylation levels were found for 25 probe pairs (absolute genetic correlation of 0.97). CONCLUSIONS: Familial resemblances in gene expression levels were mainly attributable to genetic factors, but common environmental effect also played a role especially in probes showing a significant familial effect. Probes and CpG sites with familial effect seem to be under a strong shared genetic control.

Plasma Triglyceride Levels May Be Modulated by Gene Expression of IQCJ, NXPH1, PHF17 and MYB in Humans.

A genome-wide association study (GWAS) by our group identified loci associated with the plasma triglyceride (TG) response to ω-3 fatty acid (FA) supplementation in IQCJ, NXPH1, PHF17 and MYB. Our aim is to investigate potential mechanisms underlying the associations between single nucleotide polymorphisms (SNPs) in the four genes and TG levels following ω-3 FA supplementation. 208 subjects received 3 g/day of ω-3 FA (1.9-2.2 g of EPA and 1.1 g of docosahexaenoic acid (DHA)) for six weeks. Plasma TG were measured before and after the intervention. 67 SNPs were selected to increase the density of markers near GWAS hits. Genome-wide expression and methylation analyses were conducted on respectively 30 and 35 participants' blood sample together with in silico analyses. Two SNPs of IQCJ showed different affinities to splice sites depending on alleles. Expression levels were influenced by genotype for one SNP in NXPH1 and one in MYB. Associations between 12 tagged SNPs of IQCJ, 26 of NXPH1, seven of PHF17 and four of MYB and gene-specific CpG site methylation levels were found. The response of plasma TG to ω-3 FA supplementation may be modulated by the effect of DNA methylation on expression levels of genes revealed by GWAS.

Effect of n-3 fatty acids on the expression of inflammatory genes in THP-1 macrophages.

BACKGROUND: Uncontrolled inflammation participates in the development of inflammatory diseases. Beneficial effects of polyunsaturated fatty acids belonging to the n-3 family such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on inflammation have been reported. The present study investigates the basal effects of EPA, DHA and a mixture EPA + DHA on the expression of 10 genes (AKT1, MAPK, NFKB, TNFA, IL1Β, MCP1, ALOX5, PTGS2, MGST1 and NOS2) related to inflammation in unstimulated cultured THP1 macrophages. Cells were incubated for 24 h with n-3 PUFAs (50 µM and 10 µM EPA, DHA, EPA + DHA). Expression levels of inflammatory genes were analyzed by real-time PCR. RESULTS: 50 µM, 10 µM EPA and 50 µM EPA + DHA decreased the expression of genes involved in the NF-κB pathway (MAPK, AKT1, and NFKB). Treatment with 50 µM, 10 µM EPA, 50 µM DHA and EPA + DHA decreased expression levels of cytokines genes IL1Β and MCP1. TNFA expression was decreased by 50 µM, 10 µM of EPA, DHA and with 50 µM EPA + DHA. Two genes involved in the fatty acid metabolism (PTGS2 and ALOX5) were also modulated by the n-3 FAs. 50 µM of DHA and EPA + DHA inhibited PTGS2 expression when the two concentrations of EPA, 50 µM DHA and EPA + DHA inhibited ALOX5 expression. Finally, the effects of n-3 FAs were studied among genes involved in the oxidative stress. 50 µM of each fatty acid increased MGST1 expression. Both concentration of EPA and 50 µM DHA decreased NOS2 expression. CONCLUSION: EPA seems to be more effective than DHA and EPA + DHA in modulating expression levels of selected inflammatory genes. The concentration of 50 µM was globally more effective than 10 µM.

A CpG-SNP Located within the ARPC3 Gene Promoter Is Associated with Hypertriglyceridemia in Severely Obese Patients.

AIMS: To test the potential association of cytosine-phosphate-guanine dinucleotides (CpG)-single-nucleotide polymorphisms (SNPs) located within actin-related protein 2/3 complex subunit 3 (ARPC3), a gene recently linked to adipogenesis and lipid accumulation, with metabolic syndrome (MetS) features in severely obese patients. METHODS: Prioritized SNPs within the ARPC3 locus were genotyped and tested for associations with MetS features in a cohort of 1,749 obese patients with and without MetS. Association testing with CpG methylation levels was performed in a methylation sub-cohort of 16 obese men. RESULTS: A significant association was found between the CpG-SNP rs3759384 (C>T) and plasma triglyceride (TG) levels (false discovery rate-corrected p = 3.5 × 10-2), with 0.6% of the phenotypic variance explained by the CpG-SNP, and with TT homozygotes showing the highest plasma TG levels (1.89 mmol/l). The carriers of the rs3759384 T allele also showed a significant decrease in methylation levels of the ARPC3 promoter-associated CpG site cg10738648 in both visceral adipose tissue and blood. ARPC3 expression levels showed a strong correlation with plasma TG levels (r = 0.70; p = 0.02). CONCLUSIONS: The increased plasma TG levels found in homozygous rs3759384 T allele carriers argue for a relevant role of this CpG-SNP in lipid management among obese individuals, which may be driven by an epigenetic-mediated mechanism.

Differential methylation in glucoregulatory genes of offspring born before vs. after maternal gastrointestinal bypass surgery.

Obesity and overnutrition during pregnancy affect fetal programming of adult disease. Children born after maternal bariatric gastrointestinal bypass surgery (AMS) are less obese and exhibit improved cardiometabolic risk profiles carried into adulthood compared with siblings born before maternal surgery (BMS). This study was designed to analyze the impact of maternal weight loss surgery on methylation levels of genes involved in cardiometabolic pathways in BMS and AMS offspring. Differential methylation analysis between a sibling cohort of 25 BMS and 25 AMS (2-25 y-old) offspring from 20 mothers was conducted to identify biological functions and pathways potentially involved in the improved cardiometabolic profile found in AMS compared with BMS offspring. Links between gene methylation and expression levels were assessed by correlating genomic findings with plasma markers of insulin resistance (fasting insulin and homeostatic model of insulin resistance). A total of 5,698 genes were differentially methylated between BMS and AMS siblings, exhibiting a preponderance of glucoregulatory, inflammatory, and vascular disease genes. Statistically significant correlations between gene methylation levels and gene expression and plasma markers of insulin resistance were consistent with metabolic improvements in AMS offspring, reflected in genes involved in diabetes-related cardiometabolic pathways. This unique clinical study demonstrates that effective treatment of a maternal phenotype is durably detectable in the methylome and transcriptome of subsequent offspring.

Genome-wide association study of the plasma triglyceride response to an n-3 polyunsaturated fatty acid supplementation.

Studies have shown a large interindividual variability in plasma TG response to long-chain n-3 PUFA supplementation, which may likely be attributable to genetic variability within the populations studied. The objective is to compare the frequency of SNPs in a genome-wide association study between responders (reduction in plasma TG levels ≥0.01 mM) and nonresponders (increase in plasma TG of ≥0 mM) to supplementation. Genomic DNA from 141 subjects who completed a 2-week run-in period followed by 6-week supplementation with 5 g of fish oil daily (1.9-2.2 g EPA and 1.1 g DHA daily) were genotyped on Illumina HumanOmni-5-QuadBeadChip. Thirteen loci had frequency differences between responders and nonresponders (P < 1 × 10(-5)), including SNPs in or near IQCJ-SCHIP1, MYB, NELL1, NXPH1, PHF17, and SLIT2 genes. A genetic risk score (GRS) was constructed by summing the number of risk alleles. This GRS explained 21.53% of the variation in TG response to n-3 PUFA supplementation when adjusted for age, sex, and BMI (P = 0.0002). Using Fish Oil Intervention and Genotype as a replication cohort, the GRS was able to explain 2% of variation in TG response when adjusted. In conclusion, subjects who decrease their plasma TG levels following n-3 PUFA supplementation may have a different genetic profile than individuals who do not respond.

Differential methylation in visceral adipose tissue of obese men discordant for metabolic disturbances.

Obesity is associated with an increased risk of Type 2 diabetes and cardiovascular diseases (CVD). The severely obese population is heterogeneous regarding CVD risk profile. Our objective was to identify metabolic pathways potentially associated with development of metabolic syndrome (MetS) through an analysis of overrepresented pathways from differentially methylated genes between severely obese men with (MetS+) and without (MetS-) the MetS. Genome-wide quantitative DNA methylation analysis in VAT of severely obese men was carried out using the Infinium HumanMethylation450 BeadChip. Differences in methylation levels between MetS+ (n = 7) and MetS- (n = 7) groups were tested. Overrepresented pathways from the list of differentially methylated genes were identified and visualized with the Ingenuity Pathway Analysis system. Differential methylation analysis between MetS+ and MetS- groups identified 8,578 methylation probes (3,258 annotated genes) with significant differences in methylation levels (false discovery rate-corrected DiffScore ≥ |13| ∼ P ≤ 0.05). Pathway analysis from differentially methylated genes identified 41 overrepresented (P ≤ 0.05) pathways. The most overrepresented pathways were related to structural components of the cell membrane, inflammation and immunity and cell cycle regulation. This study provides potential targets associated with adipose tissue dysfunction and development of the MetS.

Impact of maternal cardiometabolic status after bariatric surgery on the association between telomere length and adiposity in offspring.

The impact of bariatric surgery on metabolic and inflammatory status are reflected in the epigenetic profile and telomere length mediated by the changes in the metabolic status of the patients. This study compared the telomere length of children born before versus after maternal bariatric surgery as a surrogate to test the influence of the mother's metabolic status on children's telomere length. DNA methylation telomere length (DNAmTL) was estimated from Methylation-EPIC BeadChip array data from a total of 24 children born before and after maternal bariatric surgery in the greater Quebec City area. DNAmTL was inversely associated with chronological age in children (r = - 0.80, p < 0.001) and significant differences were observed on age-adjusted DNAmTL between children born before versus after the maternal bariatric surgery. The associations found between body mass index and body fat percentage with DNAmTL in children born after the surgery were influenced by maternal triglycerides, TG/HDL-C ratio and TyG index. This study reports the impact of maternal bariatric surgery on offspring telomere length. The influence of maternal metabolic status on the association between telomere length and markers of adiposity in children suggests a putative modulating effect of bariatric surgery on the cardiometabolic risk in offspring.

Genetic contribution to C-reactive protein levels in severe obesity.

Obese individuals are characterized by a chronic, low-grade inflammatory state. Increased levels of C-reactive protein (CRP), a marker of inflammation, have been observed in subjects with the metabolic syndrome. We have previously reported that genes encoding proteins involved in the anti-inflammatory and immune response are differentially expressed in visceral adipose tissue of obese men with or without the metabolic syndrome. Among these genes, the interferon-gamma-inducible protein 30 (IFI30), CD163 molecule (CD163), chemokine (C-X-C motif) ligand 9 (CXCL9) and thymic stromal lymphopoietin (TSLP), were selected for further genetic analyses. The aim of the study was to verify whether IFI30, CD163, CXCL9 and TSLP gene polymorphisms contribute to explain the inter-individual variability of the inflammatory profile of obesity assessed by plasma high-sensitivity CRP concentrations. A total of 1185 severely obese individuals were genotyped for single nucleotide polymorphisms (SNPs) covering most of the sequence-derived genetic variability at the IFI30, CD163, CXCL9 and TSLP gene loci (total of 27 SNPs). Following measurement of plasma CRP levels, subjects were divided into two groups, low vs. high using the median value of plasma CRP levels (8.31 mg/L) as a cutoff point. Genotype frequencies were compared between groups. Associations between genotypes and plasma CRP levels (continuous variable) were also tested after adjustments for age, sex, smoking and BMI. The rs11554159 and rs7125 IFI30 SNPs showed a significant difference in genotype frequencies (p<0.05) between subgroups of low vs. high plasma CRP levels (wild type homozygotes: rs11554159=47% vs. 55%, rs7125=31% vs. 24%, for low vs. high CRP groups, respectively). The association between rs11554159 and CRP levels as a continuous variable remained significant (p=0.004). Both carriers of the GA and AA genotypes demonstrated, on average, a 13% lower CRP levels in comparison with GG homozygotes. No association was observed between SNPs in the CD163, CXCL9 and TSLP genes and CRP levels. The IFI30 rs11554159 polymorphism could partially explain the inter-individual variability observed in the inflammatory profile associated with obesity.

Identification of Phenotypic Lipidomic Signatures in Response to Long Chain n-3 Polyunsaturated Fatty Acid Supplementation in Humans.

Background Supplementation with long chain n-3 polyunsaturated fatty acids is used to reduce total circulating triacylglycerol (TAG) concentrations. However, in about 30% of people, supplementation with long chain n-3 polyunsaturated fatty acids does not result in decreased plasma TAG. Lipidomic analysis may provide insight into this inter-individual variability. Methods Lipidomic analyses using targeted, mass spectrometry were performed on plasma samples obtained from a clinical study in which participants were supplemented with 3 g/day of long chain n-3 in the form of fish oil capsules over a 6-week period. TAG species and cholesteryl esters (CE) were quantified for 130 participants pre- and post-supplementation. Participants were segregated into 3 potential responder phenotypes: (1) positive responder (Rpos; TAG decrease), (2) non-responder (Rnon; lacking TAG change), and (3) negative responder (Rneg; TAG increase) representing 67%, 18%, and 15% of the study participants, respectively. Separation of the 3 phenotypes was attributed to differential responses in TAG with 50 to 54 carbons with 1 to 4 desaturations. Elevated TAG with higher carbon number and desaturation were common to all phenotypes following supplementation. Using the TAG responder phenotype for grouping, decreases in total CE and specific CE occurred in the Rpos phenotype versus the Rneg phenotype with intermediate responses in the Rnon phenotype. CE 20:5, containing eicosapentaenoic acid (20:5n-3), was elevated in all phenotypes. A classifier combining lipidomic and genomic features was built to discriminate triacylglycerol response phenotypes and reached a high predictive performance with a balanced accuracy of 75%. Conclusions These data identify lipidomic signatures, TAG and CE, associated with long chain n-3 response p henotypes and identify a novel phenotype based upon CE changes. Registration URL: https://www.ClinicalTrials.gov; Unique Identifier: NCT01343342.

An 8-week freeze-dried blueberry supplement impacts immune-related pathways: a randomized, double-blind placebo-controlled trial.

BACKGROUND: Blueberries contain high levels of polyphenolic compounds with high in vitro antioxidant capacities. Their consumption has been associated with improved vascular and metabolic health. PURPOSE: The objective was to examine the effects of blueberry supplement consumption on metabolic syndrome (MetS) parameters and potential underlying mechanisms of action. METHODS: A randomized double-blind placebo-controlled intervention trial was conducted in adults at risk of developing MetS. Participants consumed 50 g daily of either a freeze-dried highbush blueberry powder (BBP) or a placebo powder for 8 weeks (n = 49). MetS phenotypes were assessed at weeks 0, 4 and 8. Fasting blood gene expression profiles and plasma metabolomic profiles were examined at baseline and week 8 to assess metabolic changes occurring in response to the BBP. A per-protocol analysis was used. RESULTS: A significant treatment effect was observed for plasma triglyceride levels that was no longer significant after further adjustments for age, sex, BMI and baseline values. In addition, the treatment*time interactions were non-significant therefore suggesting that compared with the placebo, BBP had no statistically significant effect on body weight, blood pressure, fasting plasma lipid, insulin and glucose levels, insulin resistance (or sensitivity) or glycated hemoglobin concentrations. There were significant changes in the expression of 49 genes and in the abundance of 35 metabolites following BBP consumption. Differentially regulated genes were clustered in immune-related pathways. CONCLUSION: An 8-week BBP intervention did not significantly improve traditional markers of cardiometabolic health in adults at risk of developing MetS. However, changes in gene expression and metabolite abundance suggest that clinically significant cardiometabolic changes could take longer than 8 weeks to present and/or could result from whole blueberry consumption or a higher dosage. BBP may also have an effect on factors such as immunity even within a shorter 8-week timeframe. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov, NCT03266055 , 2017.

Integrative Network Analysis of Multi-Omics Data in the Link between Plasma Carotenoid Concentrations and Lipid Profile.

INTRODUCTION: Carotenoids, which are a reliable biomarker of fruit and vegetable consumption, are positively associated with the lipid profile. Circulating carotenoid concentrations may interact with several omics profiles including genome, transcriptome, and epigenome. Few studies have used multi-omics approaches, and they rarely include environmental factors, such as diet. OBJECTIVE: The objective of this observational study was to examine the potential role of multi-omics data in the interconnection between diet, represented by total carotenoids, and lipid profile using weighted gene correlation network analysis (WGCNA). METHODS: Blood leukocyte DNA methylation levels of 472,245 CpG sites and whole blood gene expression levels of 18,160 transcripts were tested for associations with total carotenoid concentrations using regressions in 48 healthy subjects. WGCNA was used to identify co-omics modules and hub genes related to the lipid profile. RESULTS: Among genes associated with total carotenoid concentrations, a total of 236 genes were identified at both DNA methylation and gene expression levels. Using WGCNA, six modules, consisting of groups of highly correlated genes represented by colors, were identified and linked to the lipid profile. Probes clustered in the turquoise and green modules correlated with plasma lipid concentrations. A total of 28 hub genes were identified. CONCLUSIONS: Genome-wide DNA methylation and gene expression levels were both associated with plasma total carotenoid concentrations. Several hub genes, mostly involved in lipid metabolism and inflammatory response with several genetic variants associated with plasma lipid concentrations, came out of the integrative analysis. This provides a comprehensive understanding of the interactive molecular system between carotenoids, omics, and plasma lipid profile.

Genetic risk prediction of the plasma triglyceride response to independent supplementations with eicosapentaenoic and docosahexaenoic acids: the ComparED Study.

BACKGROUND: We previously built a genetic risk score (GRS) highly predictive of the plasma triglyceride (TG) response to an omega-3 fatty acid (n-3 FA) supplementation from marine sources. The objective of the present study was to test the potential of this GRS to predict the plasma TG responsiveness to supplementation with either eicosapentaenoic (EPA) or docosahexaenoic (DHA) acids in the Comparing EPA to DHA (ComparED) Study. METHODS: The ComparED Study is a double-blind, controlled, crossover trial, with participants randomized to three supplemented phases of 10 weeks each: (1) 2.7 g/day of DHA, (2) 2.7 g/day of EPA, and (3) 3 g/day of corn oil (control), separated by 9-week washouts. The 31 SNPs used to build the previous GRS were genotyped in 122 participants of the ComparED Study using TaqMan technology. The GRS for each participant was computed by summing the number of rare alleles. Ordinal and binary logistic models, adjusted for age, sex, and body mass index, were used to calculate the ability of the GRS to predict TG responsiveness. RESULTS: The GRS predicted TG responsiveness to EPA supplementation (p = 0.006), and a trend was observed for DHA supplementation (p = 0.08). The exclusion of participants with neutral TG responsiveness clarified the association patterns and the predictive capability of the GRS (EPA, p = 0.0003, DHA p = 0.01). CONCLUSION: Results of the present study suggest that the constructed GRS is a good predictor of the plasma TG response to supplementation with either DHA or EPA. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01810003. The study protocol was registered on March 4, 2013.

Prevention of Potential Adverse Metabolic Effects of a Supplementation with Omega-3 Fatty Acids Using a Genetic Score Approach.

INTRODUCTION: The consumption of long-chain omega-3 polyunsaturated fatty acids (n-3 PUFA) has been reported to have beneficial health effects, notably, by reducing plasma triglyceride levels. Nonetheless, a concomitant decrease in insulin sensitivity has also been observed, but is highly variable among subjects. Herein, we aimed to determine the importance of the genetic background in the interindividual variability of the insulin sensitivity response following an n-3 PUFA supplementation. METHODS: A total of 210 participants completed a 6-week n-3 PUFA supplementation with 5 g/day of fish oil (providing 1.9-2.2 g of eicosapentaenoic acid + 1.1 g of docosahexaenoic acid). Insulin resistance was estimated by the homeostatic model assessment (HOMA-IR), and participants were further classified as high-risk or low-risk depending on their HOMA-IR change following the n-3 PUFA supplementation, as compared to pre-supplementation values. Genome-wide genotyping data were obtained for 138 participants using HumanOmni-5-Quad BeadChips containing 4,301,331 single nucleotide polymorphisms. A genome-wide association analysis (GWAS) was carried out between high-risk and low-risk participants. The population study was split into training (60%) and testing (40%) datasets to assess the predictive accuracy of a genetic risk score (GRS) constructed by summing the number of risk alleles. RESULTS: Following the n-3 PUFA supplementation, 32 participants had increased HOMA-IR as compared to initial values and were classified as high risk (23.2%), whereas remaining subjects were classified as low risk (n = 106, 76.8%). A total of 8 loci had frequency differences between high-risk and low-risk participants at a suggestive GWAS association threshold (p value <1 × 10-5). After applying 10-fold cross validation, the GRS showed a significant association with the risk of increased HOMA-IR in the testing dataset (OR = 3.16 [95% CI, 1.85-7.14]), with a predictive accuracy of 0.85, and explained 40% of variation in HOMA-IR change. CONCLUSIONS: These results suggest that the genetic background has a relevant role in the interindividual variability observed in the insulin sensitivity response following an n-3 PUFA supplementation. Subjects being at risk of insulin sensitivity lowering following an n-3 PUFA supplementation may be identified using genetic-based precision nutrition approaches.

Animal and Cellular Studies Demonstrate Some of the Beneficial Impacts of Herring Milt Hydrolysates on Obesity-Induced Glucose Intolerance and Inflammation.

The search for bioactive compounds from enzymatic hydrolysates has increased in the last few decades. Fish by-products have been shown to be rich in these valuable molecules; for instance, herring milt is a complex matrix composed of lipids, nucleotides, minerals, and proteins. However, limited information is available on the potential health benefits of this by-product. In this context, three industrial products containing herring milt hydrolysate (HMH) were tested in both animal and cellular models to measure their effects on obesity-related metabolic disorders. Male C57Bl/6J mice were fed either a control chow diet or a high-fat high-sucrose (HFHS) diet for 8 weeks and received either the vehicle (water) or one of the three HMH products (HMH1, HMH2, and HMH3) at a dose of 208.8 mg/kg (representing 1 g/day for a human) by daily oral gavage. The impact of HMH treatments on insulin and glucose tolerance, lipid homeostasis, liver gene expression, and the gut microbiota profile was studied. In parallel, the effects of HMH on glucose uptake and inflammation were studied in L6 myocytes and J774 macrophages, respectively. In vivo, daily treatment with HMH2 and HMH3 improved early time point glycemia during the oral glucose tolerance test (OGTT) induced by the HFHS diet, without changes in weight gain and insulin secretion. Interestingly, we also observed that HMH2 consumption partially prevented a lower abundance of Lactobacillus species in the gut microbiota of HFHS diet-fed animals. In addition to this, modulations of gene expression in the liver, such as the upregulation of sucrose nonfermenting AMPK-related kinase (SNARK), were reported for the first time in mice treated with HMH products. While HMH2 and HMH3 inhibited inducible nitric oxide synthase (iNOS) induction in J774 macrophages, glucose uptake was not modified in L6 muscle cells. These results indicate that milt herring hydrolysates reduce some metabolic and inflammatory alterations in cellular and animal models, suggesting a possible novel marine ingredient to help fight against obesity-related immunometabolic disorders.

Genetic sequence variations of BRCA1-interacting genes AURKA, BAP1, BARD1 and DHX9 in French Canadian families with high risk of breast cancer.

Breast cancer is a heterogeneous disease displaying some degree of familial clustering. Highly penetrant breast cancer susceptibility genes represent approximately 20-25% of the familial aggregation of breast cancer. A significant proportion of this familial aggregation of breast cancer is thus yet to be explained by other breast cancer susceptibility genes. Given the high susceptibility conferred by the two major breast cancer predisposition genes, BRCA1 and BRCA2 and the implication of these genes in many key cellular processes, assessment of genes encoding BRCA1-interacting proteins as plausible breast cancer candidate genes is thus attractive. In this study, four genes encoding BRCA1-interacting proteins were analyzed in a cohort of 96 breast cancer individuals from high-risk non-BRCA1/BRCA2 French Canadian families. Although no deleterious truncating germline mutations or aberrant spliced mRNA species were identified, a total of 10, 4, 11 and 6 variants were found in the AURKA, BAP1, BARD1 and DHX9 genes, respectively. The allele frequency of each variant was further ascertained in a cohort of 98 healthy French Canadian unrelated women and a difference in allele frequency was observed for one BARD1 variant based on single-marker analysis. Haplotype estimation, haplotype blocks and tagging SNPs identification were then performed for each gene, providing a valuable tool for further searches of common disease-associated variants in these genes and therefore further analyses on these genes in larger cohorts is warranted in the search of low-to-moderate penetrance breast cancer susceptibility alleles.

Weighted gene co-expression network analysis to explain the relationship between plasma total carotenoids and lipid profile.

BACKGROUND: Variability in circulating carotenoids may be attributable to several factors including, among others, genetic variants and lipid profile. However, relatively few studies have considered the impact of gene expression in the inter-individual variability in circulating carotenoids. Most studies considered expression of genes individually and ignored their high degree of interconnection. Weighted gene co-expression network analysis (WGCNA) is a systems biology method used for finding gene clusters with highly correlated expression levels and for relating them to phenotypic traits. The objective of the present observational study is to examine the relationship between plasma total carotenoid concentrations and lipid profile using WGCNA. RESULTS: Whole blood expression levels of 533 probes were associated with plasma total carotenoids. Among the four WGCNA distinct modules identified, turquoise, blue, and brown modules correlated with plasma high-density lipoprotein cholesterol (HDL-C) and total cholesterol. Probes showing a strong association with HDL-C and total cholesterol were also the most important elements of the brown and blue modules. A total of four and 29 hub genes associated with total carotenoids were potentially related to HDL-C and total cholesterol, respectively. CONCLUSIONS: Expression levels of 533 probes were associated with plasma total carotenoid concentrations. Using WGCNA, four modules and several hub genes related to lipid and carotenoid metabolism were identified. This integrative analysis provides evidence for the potential role of gene co-expression in the relationship between carotenoids and lipid concentrations. Further studies and validation of the hub genes are needed.

Familial resemblances in human plasma metabolites are attributable to both genetic and common environmental effects.

Metabolites are of great importance for understanding the pathogenesis of several diseases. Understanding the genetic contribution to metabolite concentrations may provide insights into mechanisms of complex diseases. Several studies have investigated heritability of metabolites but none investigated potential influences of genetic and environmental factors on the relationship between metabolites and cardiometabolic (CM) risk factors. Thus, we tested the hypothesis that both genetic and common environmental effects contribute to the variance of plasma metabolite concentrations and that shared genetic and environmental effects explain their phenotypic correlations with CM risk factors. To test this hypothesis, variance component method and bivariate genetic analysis were performed in a family-based sample of 48 French Canadians from 16 families. Familial resemblances were computed for all 147 detected metabolites and 9 (acetylornithine, acylcarnitine C9, arginine, phosphatidylcholine acyl-alkyl C36:4, serotonin, lysophosphatidylcholine acyl C20:4, citrulline, asymmetric dimethylarginine, phosphatidylcholine acyl-alkyl C36:5) showed a significant familial effect (55.7%, 18.7%, and 37.0% for maximal heritability, genetic heritability, and common environmental effect, respectively). Citrulline, phosphatidylcholine acyl-alkyl C36:4, phosphatidylcholine acyl-alkyl C36:5, and serotonin had significant phenotypic correlations with CM risk factors. Citrulline had a positive genetic correlation with apolipoprotein B100, while phosphatidylcholine acyl-alkyl C36:5 had a positive environmental correlation with total cholesterol. In conclusion, familial resemblances in metabolite concentrations were mainly attributable to common environmental effect when considering metabolites with a significant familial effect. Common genetic and environmental factors may also influence the relationship between metabolites and CM risk factors.

Network Analysis of the Potential Role of DNA Methylation in the Relationship between Plasma Carotenoids and Lipid Profile.

Variability in plasma carotenoids may be attributable to several factors including genetic variants and lipid profile. Until now, the impact of DNA methylation on this variability has not been widely studied. Weighted gene correlation network analysis (WGCNA) is a systems biology method used for finding gene clusters (modules) with highly correlated methylation levels and for relating them to phenotypic traits. The objective of the present study was to examine the role of DNA methylation in the relationship between plasma total carotenoid concentrations and lipid profile using WGCNA in 48 healthy subjects. Genome-wide DNA methylation levels of 20,687 out of 472,245 CpG sites in blood leukocytes were associated with total carotenoid concentrations. Using WGCNA, nine co-methylation modules were identified. A total of 2734 hub genes (17 unique top hub genes) were potentially related to lipid profile. This study provides evidence for the potential implications of gene co-methylation in the relationship between plasma carotenoids and lipid profile. Further studies and validation of the hub genes are needed.