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Perspective: Quality Versus Quantity; Is It Important to Assess the Role of Enhancers in Complex Disease from an In Vivo Perspective?

ABSTRACT: Sequencing of the human genome has permitted the development of genome-wide association studies (GWAS) to analyze the genetics of a number of complex disorders such as depression, anxiety and substance abuse. Thanks to their ability to analyze huge cohort sizes, these studies have successfully identified thousands of loci associated with a broad spectrum of complex diseases. Disconcertingly, the majority of these GWAS hits occur in non-coding regions of the genome, much of which controls the cell-type-specific expression of genes essential to health. In contrast to gene coding sequences, it is a challenge to understand the function of this non-coding regulatory genome using conventional biochemical techniques in cell lines. The current commentary scrutinizes the field of complex genetics from the standpoint of the large-scale whole-genome functional analysis of the promoters and cis-regulatory elements using chromatin markers. We contrast these large scale quantitative techniques against comparative genomics and in vivo analyses including CRISPR/CAS9 genome editing to determine the functional characteristics of these elements and to understand how polymorphic variation and epigenetic changes within these elements might contribute to complex disease and drug response. Most importantly, we suggest that, although the role of chromatin markers will continue to be important in identifying and characterizing enhancers, more emphasis must be placed on their analysis in relevant in-vivo models that take account of the appropriate cell-type-specific roles of these elements. It is hoped that offering these insights might refocus progress in analyzing the data tsunami of non-coding GWAS and whole-genome sequencing "hits" that threatens to overwhelm progress in the field.

SUBMITTER: McEwan AR

PROVIDER: S-EPMC7660172 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Perspective: Quality Versus Quantity; Is It Important to Assess the Role of Enhancers in Complex Disease from an In Vivo Perspective?

McEwan Andrew R AR MacKenzie Alasdair A

International journal of molecular sciences 20201023 21

Sequencing of the human genome has permitted the development of genome-wide association studies (GWAS) to analyze the genetics of a number of complex disorders such as depression, anxiety and substance abuse. Thanks to their ability to analyze huge cohort sizes, these studies have successfully identified thousands of loci associated with a broad spectrum of complex diseases. Disconcertingly, the majority of these GWAS hits occur in non-coding regions of the genome, much of which controls the cel ...[more]

PMID: 33113946

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Project description:BackgroundHigh glycemic index (GI) diets have been linked to elevated risk of cardiometabolic diseases. One possible underlying mechanism comes from high GI diet's potential to promote lipid peroxidation.ObjectivesWe aim to evaluate whether and to what extent dietary carbohydrate quality and quantity are associated with systemic levels of lipid peroxidation in females.MethodsIn this cross-sectional analysis of 2163 middle-aged women, a subset of the Shanghai Women's Health Study, we measured lipid peroxidation biomarkers F2-isoprostanes (F2-IsoPs) and its metabolite, 2,3-dinor-5,6-dihydro-15-F2t-IsoP (F2-IsoP-M), in urine. The quality of carbohydrate was defined by dietary GI, assessed using a validated FFQ via in-person interviews. A multivariable linear regression model with restricted cubic spline functions was used to evaluate the association of measured biomarkers with carbohydrate intake and dietary GI.ResultsAfter adjustment for potential confounding factors such as cigarette smoking, BMI, and comorbidities, among others, we found that F2-IsoP-M concentrations were positively associated with both carbohydrate intake and dietary GI. Carbohydrate intake and dietary GI were weakly correlated (r = 0.12). When further mutually adjusted for the 2 factors, the positive association with F2-IsoP-M remained statistically significant for GI (P = 0.004) but not for carbohydrate intake (P = 0.50). Compared with those in the 10th percentile of dietary GI, fold increases (95% CI) in F2-IsoP-M concentrations for those in the 30th, 50th, 70th, and 90th percentiles were 1.03 (1.00, 1.07), 1.06 (1.01, 1.10), 1.09 (1.03, 1.14), and 1.13 (1.05, 1.21), respectively. Moreover, there appeared a threshold regarding the association between dietary GI and F2-IsoP-M concentrations, with the dose-effect slope of GI being 2.3 times greater when GI was ≥75 relative to GI <75.ConclusionsThis study provides evidence that the quality of dietary carbohydrate may be more important than the quantity of the intake with regard to systemic lipid peroxidation.

Dataset Information

Perspective: Quality Versus Quantity; Is It Important to Assess the Role of Enhancers in Complex Disease from an In Vivo Perspective?

Publications

Perspective: Quality Versus Quantity; Is It Important to Assess the Role of Enhancers in Complex Disease from an In Vivo Perspective?

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