Genome-wide DNA methylation profiling in anorexia nervosa discordant identical twins

Up until now, no study has looked specifically at epigenomic landscapes throughout twin samples, discordant for Anorexia nervosa (AN). Our goal was to find evidence to confirm the hypothesis that epigenetic variations play a key role in the aetiology of AN. In this study, we quantified genome-wide patterns of DNA methylation using the Infinium Human DNA Methylation EPIC BeadChip array (“850 K”) in DNA samples isolated from whole blood collected from a group of 7 monozygotic twin pairs discordant for AN. Results were then validated performing a genome-wide DNA methylation profiling using DNA extracted from whole blood of a group of non-family-related AN patients and a group of healthy controls. Our first analysis using the twin sample revealed 9 CpGs associated to a gene. The validation analysis showed two statistically significant CpGs with the rank regression method related to two genes associated to metabolic traits, PPP2R2C and CHST1. When doing beta regression, 6 of them showed statistically significant differences, including 3 CpGs associated to genes JAM3, UBAP2L and SYNJ2. Finally, the overall pattern of results shows genetic links to phenotypes which the literature has constantly related to AN, including metabolic and psychological traits. The genes PPP2R2C and CHST1 have both been linked to the metabolic traits type 2 diabetes through GWAS studies. The genes UBAP2L and SYNJ2 have been related to other psychiatric comorbidity.

Genetic inactivation of zinc transporter SLC39A5 improves liver function and hyperglycemia in obesogenic settings

Background & Aims: Recent studies have revealed a role for zinc in insulin secretion and systemic glucose homeostasis. Randomized placebo-controlled zinc supplementation trials have demonstrated improved glycemic traits in patients with type II diabetes (T2D). Moreover, carriers of rare loss-of-function variants in the zinc efflux transporter SLC30A8 have been reported to reduce T2D risk. Despite this accumulated evidence, mechanistic understanding of how zinc influences systemic glucose homeostasis and consequently T2D risk remains unclear. Methods: To further explore the relationship between zinc and metabolic traits, we searched the exome database of the Regeneron Genetics Center-Geisinger Health System DiscovEHR cohort for genes that regulate zinc levels and associate with changes in metabolic traits. We then explored our main finding using in vitro and in vivo models. Results: We identified rare loss-of-function (LOF) variants (MAF<1%) in Solute Carrier Family 39, Member 5 (SLC39A5) associated with increased circulating zinc (p=4.9x10-4). Trans-ancestry meta-analysis across four studies exhibited nominal association of SLC39A5 LOF variants with decreased T2D risk (OR 0.82, 95%CI 0.68-0.99, p=3.7x10-2). To explore the mechanistic aspects of these associations, we generated mice lacking Slc39a5. Slc39a5-/- mice display improved liver function and reduced hyperglycemia when challenged with congenital or diet-induced obesity. These improvements result from elevated hepatic zinc levels and concomitant activation of hepatic AMPK and AKT signaling, in part due to zinc mediated inhibition of hepatic protein phosphatase activity. Furthermore, under conditions of diet-induced non-alcoholic steatohepatitis (NASH), Slc39a5-/- mice display significantly attenuated fibrosis and inflammation. Conclusions: Taken together, these results suggest SLC39A5 as a potential therapeutic target for non-alcoholic fatty liver disease (NAFLD) and consequent metabolic derangements including T2D.

Mitochondrial Genome Variation and Metabolic Traits in a Maori Community

<p>The mitochondrion is the energy producing factory of cells and it has long been thought that disruption to mitochondrial systems is linked to energy metabolism dysfunction. Sequence variants in the mitochondrial genome are plausible candidate risk factors for numerous human diseases, and research has identified specific mitochondrial DNA (mtDNA) variants associated with metabolic disorders such as obesity and type-2 diabetes. As part of the Rakaipaaka Health and Ancestry Study (RHAS) it has been observed that the Maori community of Nuhaka (Ngati Rakaipaaka) have a high incidence of certain metabolic diseases, namely obesity and diabetes. The reason for this is not well understood, but is likely to be a combination of both current lifestyle (e.g. dietary) and ancestral genetic factors. This study set out to sequence the entire mitochondrial genome in a sample of RHAS Maori participants. The aim was to discover genetic variation that might be specific to this Maori community and test whether such variants are associated with diabetes and other metabolic traits. This study used a novel RFLP assay to screen the mtDNA control region for Polynesian mtDNA ancestry. This established an initial group (n=30) with high levels of Maori mtDNA. Hypervariable (HVRI) sequencing was then used to generate a large dataset of sequences (n=94). This dataset was representative of individuals showing high Maori ancestry and aided the selection of 20 mtDNA's for Mitochip analysis. Combining the RHAS Maori HVRI sequences with those from previous studies indicated elevated variation in Maori mtDNA. Haplotype analysis identified 17 unique Maori haplotypes, 10 more than previously recorded. Mitochip resequencing has provided the first complete Maori mtDNA sequences to date. When compared to other mtDNA sequences it was identified that RHAS Maori share similar haplotype markers with Polynesians. Seven novel undocumented variants were found, as well as four variants that had previously been associated with various metabolic disorders. Mitochip analysis of mtDNA sequences revealed three variants which created a RHAS Maori specific signature; C1185T, G4769A, and T16126C. These variants also defined 3 unique mtDNA haplotypes within RHAS Maori, which are the first Maori specific haplotypes reported. Variant genotyping and correlation with metabolic traits identified significant associations within the wider RHAS Maori community. It was identified that RHAS Maori with T16189C showed elevation in both vitamin B12 levels and mean diastolic blood pressure. Individuals with the G4769A variant were shown to have significant increases in specific metabolic risk factors for cardiovascular disease. Conversely individuals with the more common A4769G variant were 2 times less likely to be diagnosed with diabetes. The findings from this study have identified a series of potential markers of metabolic disease within the RHAS Maori community. The goal now is to understand how these markers interact with environmental variables to increase the risk of metabolic syndrome. Such an outcome may open the way to designing personalised intervention strategies (e.g. dietary) to increase the health and well-being of at risk individuals.</p>

Mitochondrial Genome Variation and Metabolic Traits in a Maori Community

<p>The mitochondrion is the energy producing factory of cells and it has long been thought that disruption to mitochondrial systems is linked to energy metabolism dysfunction. Sequence variants in the mitochondrial genome are plausible candidate risk factors for numerous human diseases, and research has identified specific mitochondrial DNA (mtDNA) variants associated with metabolic disorders such as obesity and type-2 diabetes. As part of the Rakaipaaka Health and Ancestry Study (RHAS) it has been observed that the Maori community of Nuhaka (Ngati Rakaipaaka) have a high incidence of certain metabolic diseases, namely obesity and diabetes. The reason for this is not well understood, but is likely to be a combination of both current lifestyle (e.g. dietary) and ancestral genetic factors. This study set out to sequence the entire mitochondrial genome in a sample of RHAS Maori participants. The aim was to discover genetic variation that might be specific to this Maori community and test whether such variants are associated with diabetes and other metabolic traits. This study used a novel RFLP assay to screen the mtDNA control region for Polynesian mtDNA ancestry. This established an initial group (n=30) with high levels of Maori mtDNA. Hypervariable (HVRI) sequencing was then used to generate a large dataset of sequences (n=94). This dataset was representative of individuals showing high Maori ancestry and aided the selection of 20 mtDNA's for Mitochip analysis. Combining the RHAS Maori HVRI sequences with those from previous studies indicated elevated variation in Maori mtDNA. Haplotype analysis identified 17 unique Maori haplotypes, 10 more than previously recorded. Mitochip resequencing has provided the first complete Maori mtDNA sequences to date. When compared to other mtDNA sequences it was identified that RHAS Maori share similar haplotype markers with Polynesians. Seven novel undocumented variants were found, as well as four variants that had previously been associated with various metabolic disorders. Mitochip analysis of mtDNA sequences revealed three variants which created a RHAS Maori specific signature; C1185T, G4769A, and T16126C. These variants also defined 3 unique mtDNA haplotypes within RHAS Maori, which are the first Maori specific haplotypes reported. Variant genotyping and correlation with metabolic traits identified significant associations within the wider RHAS Maori community. It was identified that RHAS Maori with T16189C showed elevation in both vitamin B12 levels and mean diastolic blood pressure. Individuals with the G4769A variant were shown to have significant increases in specific metabolic risk factors for cardiovascular disease. Conversely individuals with the more common A4769G variant were 2 times less likely to be diagnosed with diabetes. The findings from this study have identified a series of potential markers of metabolic disease within the RHAS Maori community. The goal now is to understand how these markers interact with environmental variables to increase the risk of metabolic syndrome. Such an outcome may open the way to designing personalised intervention strategies (e.g. dietary) to increase the health and well-being of at risk individuals.</p>

Effect of Gut Microbial Enterotypes on the Association between Habitual Dietary Fiber Intake and Insulin Resistance Markers in Mexican Children and Adults

Dietary fiber (DF) is a major substrate for the gut microbiota that contributes to metabolic health. Recent studies have shown that diet–metabolic phenotype effect might be related to individual gut microbial profiles or enterotypes. Thus, the aim of this study was to examine whether microbial enterotypes modify the association between DF intake and metabolic traits. This cross-sectional study included 204 children (6–12 years old) and 75 adults (18–60 years old). Habitual DF intake was estimated with a Food Frequency Questionnaire and biochemical, clinical and anthropometric data were obtained. Gut microbiota was assessed through 16S sequencing and participants were stratified by enterotypes. Correlations adjusting for age and sex were performed to test the associations between dietary fiber components intake and metabolic traits. In children and adults from the Prevotella enterotype, a nominal negative correlation of hemicellulose intake with insulin and HOMA-IR levels was observed (p < 0.05), while in individuals of the other enterotypes, these associations were not observed. Interestingly, the latter effect was not related to the fecal short-chain-fatty acids profile. Our results contribute to understanding the enterotype influence on the diet–phenotype interaction, which ultimate could provide evidence for their use as potential biomarkers for future precision nutrition strategies.

Generalizability of GWA-Identified Genetic Risk Variants for Metabolic Traits to Populations from the Arabian Peninsula

The Arabian Peninsula, located at the nexus of Africa, Europe, and Asia, was implicated in early human migration. The Arab population is characterized by consanguinity and endogamy leading to inbreeding. Global genome-wide association (GWA) studies on metabolic traits under-represent the Arab population. Replicability of GWA-identified association signals in the Arab population has not been satisfactorily explored. It is important to assess how well GWA-identified findings generalize if their clinical interpretations are to benefit the target population. Our recent study from Kuwait, which performed genome-wide imputation and meta-analysis, observed 304 (from 151 genes) of the 4746 GWA-identified metabolic risk variants replicable in the Arab population. A recent large GWA study from Qatar found replication of 30 GWA-identified lipid risk variants. These complementing studies from the Peninsula increase the confidence in generalizing metabolic risk loci to the Arab population. However, both the studies reported a low extent of transferability. In this review, we examine the observed low transferability in the context of differences in environment, genetic correlations (allele frequencies, linkage disequilibrium, effect sizes, and heritability), and phenotype variance. We emphasize the need for large-scale GWA studies on deeply phenotyped cohorts of at least 20,000 Arab individuals. The review further presents GWA-identified metabolic risk variants generalizable to the Arab population.