Current insights into the genetics of food allergy Kanchan, Kanika; Clay, Selene; Irizar, Haritz ...
Journal of allergy and clinical immunology,
January 2021, 2021-01-00, 20210101, Letnik:
147, Številka:
1
Journal Article
Recenzirano
Food allergy (FA), a growing public health burden in the United States, and familial aggregation studies support strong roles for both genes and environment in FA risk. Deepening our understanding of ...the molecular and cellular mechanisms driving FAs is paramount to improving its prevention, diagnosis, and clinical management. In this review, we document lessons learned from the genetics of FA that have aided our understanding of these mechanisms. Although current genetic association studies suffer from low power, heterogeneity in definition of FA, and difficulty in our ability to truly disentangle FA from food sensitization (FS) and general atopy genetics, they reveal a set of genetic loci, genes, and variants that continue to implicate the importance of barrier and immune function genes across the atopic march, and FA in particular. The largest reported effects on FA are from MALT1 (odds ratio, 10.99), FLG (average odds ratio, ∼2.9), and HLA (average odds ratio, ∼2.03). The biggest challenge in the field of FA genetics is to elucidate the specific mechanism of action on FA risk and pathogenesis for these loci, and integrative approaches including genetics/genomics with transcriptomics, proteomics, and metabolomics will be critical next steps to translating these genetic insights into practice.
Dietary essential omega-6 (
-6) and omega-3 (
-3) 18 carbon (18C-) polyunsaturated fatty acids (PUFA), linoleic acid (LA) and α-linolenic acid (ALA), can be converted (utilizing desaturase and ...elongase enzymes encoded by
and
genes) to biologically-active long chain (LC; >20)-PUFAs by numerous cells and tissues. These
-6 and
-3 LC-PUFAs and their metabolites (ex, eicosanoids and endocannabinoids) play critical signaling and structural roles in almost all physiologic and pathophysiologic processes.
This review summarizes: (1) the biosynthesis, metabolism and roles of LC-PUFAs; (2) the potential impact of rapidly altering the intake of dietary LA and ALA; (3) the genetics and evolution of LC-PUFA biosynthesis; (4) Gene-diet interactions that may lead to excess levels of
-6 LC-PUFAs and deficiencies of
-3 LC-PUFAs; and (5) opportunities for precision nutrition approaches to personalize
-3 LC-PUFA supplementation for individuals and populations.
The rapid nature of transitions in 18C-PUFA exposure together with the genetic variation in the LC-PUFA biosynthetic pathway found in different populations make mal-adaptations a likely outcome of our current nutritional environment. Understanding this genetic variation in the context of 18C-PUFA dietary exposure should enable the development of individualized
-3 LC-PUFA supplementation regimens to prevent and manage human disease.
In the past 2 years, there continue to be advances in our understanding of the genetic and epigenetic underpinnings of atopy pertaining to disease risk and disease severity. The joint role of ...genetics and the environment has been emphasized in multiple studies. Combining genetics with family history, biomarkers, and comorbidities is further refining our ability to predict the development of individual atopic diseases as well as the advancement of the atopic march. Polygenic risk scores will be an important next step for the field moving toward clinical translation of the genetic findings thus far. A systems biology approach, as illustrated by studies of the microbiome and epigenome, will be necessary to fully understand disease development and to develop increasingly targeted therapeutics.
We estimate and partition genetic variation for height, body mass index (BMI), von Willebrand factor and QT interval (QTi) using 586,898 SNPs genotyped on 11,586 unrelated individuals. We estimate ...that ∼45%, ∼17%, ∼25% and ∼21% of the variance in height, BMI, von Willebrand factor and QTi, respectively, can be explained by all autosomal SNPs and a further ∼0.5-1% can be explained by X chromosome SNPs. We show that the variance explained by each chromosome is proportional to its length, and that SNPs in or near genes explain more variation than SNPs between genes. We propose a new approach to estimate variation due to cryptic relatedness and population stratification. Our results provide further evidence that a substantial proportion of heritability is captured by common SNPs, that height, BMI and QTi are highly polygenic traits, and that the additive variation explained by a part of the genome is approximately proportional to the total length of DNA contained within genes therein.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Long chain polyunsaturated fatty acids (LC-PUFAs) are essential for brain structure, development, and function, and adequate dietary quantities of LC-PUFAs are thought to have been necessary for both ...brain expansion and the increase in brain complexity observed during modern human evolution. Previous studies conducted in largely European populations suggest that humans have limited capacity to synthesize brain LC-PUFAs such as docosahexaenoic acid (DHA) from plant-based medium chain (MC) PUFAs due to limited desaturase activity. Population-based differences in LC-PUFA levels and their product-to-substrate ratios can, in part, be explained by polymorphisms in the fatty acid desaturase (FADS) gene cluster, which have been associated with increased conversion of MC-PUFAs to LC-PUFAs. Here, we show evidence that these high efficiency converter alleles in the FADS gene cluster were likely driven to near fixation in African populations by positive selection ∼85 kya. We hypothesize that selection at FADS variants, which increase LC-PUFA synthesis from plant-based MC-PUFAs, played an important role in allowing African populations obligatorily tethered to marine sources for LC-PUFAs in isolated geographic regions, to rapidly expand throughout the African continent 60-80 kya.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The "modern western" diet (MWD) has increased the onset and progression of chronic human diseases as qualitatively and quantitatively maladaptive dietary components give rise to obesity and ...destructive gene-diet interactions. There has been a three-fold increase in dietary levels of the omega-6 (n-6) 18 carbon (C18), polyunsaturated fatty acid (PUFA) linoleic acid (LA; 18:2n-6), with the addition of cooking oils and processed foods to the MWD. Intense debate has emerged regarding the impact of this increase on human health. Recent studies have uncovered population-related genetic variation in the LCPUFA biosynthetic pathway (especially within the fatty acid desaturase gene (FADS) cluster) that is associated with levels of circulating and tissue PUFAs and several biomarkers and clinical endpoints of cardiovascular disease (CVD). Importantly, populations of African descent have higher frequencies of variants associated with elevated levels of arachidonic acid (ARA), CVD biomarkers and disease endpoints. Additionally, nutrigenomic interactions between dietary n-6 PUFAs and variants in genes that encode for enzymes that mobilize and metabolize ARA to eicosanoids have been identified. These observations raise important questions of whether gene-PUFA interactions are differentially driving the risk of cardiovascular and other diseases in diverse populations, and contributing to health disparities, especially in African American populations.
We used a deeply sequenced dataset of 910 individuals, all of African descent, to construct a set of DNA sequences that is present in these individuals but missing from the reference human genome. We ...aligned 1.19 trillion reads from the 910 individuals to the reference genome (GRCh38), collected all reads that failed to align, and assembled these reads into contiguous sequences (contigs). We then compared all contigs to one another to identify a set of unique sequences representing regions of the African pan-genome missing from the reference genome. Our analysis revealed 296,485,284 bp in 125,715 distinct contigs present in the populations of African descent, demonstrating that the African pan-genome contains ~10% more DNA than the current human reference genome. Although the functional significance of nearly all of this sequence is unknown, 387 of the novel contigs fall within 315 distinct protein-coding genes, and the rest appear to be intergenic.
Telomere length (TL) is widely studied as a possible biomarker for stress-related cellular aging and decreased longevity. There have been conflicting findings about the relationship between family ...caregiving stress and TL. Several initial cross-sectional studies have found associations between longer duration of caregiving or perceived stressfulness of caregiving and shortened TL, suggesting that caregiving poses grave risks to health. Previous reviews have suggested the need for longitudinal methods to investigate this topic. This study examined the association between the transition to family caregiving and change in TL across ~9 years. Data was utilized from the Caregiving Transitions Study, an ancillary study to the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study. TL was assayed using qPCR and analyzed as the telomere-to-single copy gene ratio for each participant at baseline and follow-up. General linear models examined the association between caregiving status and the change in TL for 208 incident caregivers and 205 controls, as well as associations between perceived stress and TL among caregivers. No association was found between TL change and caregiving (p = 0.494), and fully adjusted models controlling for health and socioeconomic factors did not change the null relationship (p = 0.305). Among caregivers, no association was found between perceived caregiving stress and change in TL (p = 0.336). In contrast to earlier cross-sectional studies, this longitudinal, population-based study did not detect a significant relationship between the transition into a family caregiving role and changes in TL over time. Given the widespread citation of previous findings suggesting that caregiving shortens telomeres and places caregivers at risk of early mortality, these results demonstrate the potential need of a more balanced narrative about caregiving.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We investigated the interplay between genetics and oral peanut protein exposure in the determination of the immunological response to peanut using the targeted intervention in the LEAP clinical ...trial. We identified an association between peanut-specific IgG4 and HLA-DQA1*01:02 that was only observed in the presence of sustained oral peanut protein exposure. The association between IgG4 and HLA-DQA1*01:02 was driven by IgG4 specific for the Ara h 2 component. Once peanut consumption ceased, the association between IgG4-specific Ara h 2 and HLA-DQA1*01:02 was attenuated. The association was validated by observing expanded IgG4-specific epitopes in people who carried HLA-DQA1*01:02. Notably, we confirmed the previously reported associations with HLA-DQA1*01:02 and peanut allergy risk in the absence of oral peanut protein exposure. Interaction between HLA and presence or absence of exposure to peanut in an allergen- and epitope-specific manner implicates a mechanism of antigen recognition that is fundamental to driving immune responses related to allergy risk or protection.
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