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{
"created_at": "2024-04-18T18:30:30.982190Z",
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"answer": "Gene-environment interactions influence diabetes risk and progression by the interplay of genetic predisposition and environmental factors such as diet, physical activity, and lifestyle. Certain genetic variants may increase the risk of type 2 diabetes (T2D), but this risk can be modified by environmental factors. For instance, the adverse effect of some T2D-associated genetic variants may be attenuated by higher physical activity levels or a healthy lifestyle. Conversely, low physical activity and dietary factors characterizing a Western dietary pattern may augment the risk. Understanding these interactions can help in the development of personalized prevention strategies and treatments for T2D.",
"context": {
"1e3a2816-2a1f-41c3-88d6-03330f04652b": [
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"document_id": "1e3a2816-2a1f-41c3-88d6-03330f04652b",
"text": "\n\nAdditional evidence supporting a potentially important role for environmental modulation of genetic risk was found in previous population studies.For example, although some of the GWASidentified T2D loci could be replicated successfully in various populations (e.g., CDKAL1, HHEX, IGF2BP2, TCF7L2 and SLC30A8), more genetic variants have been identified only in some specific populations [26].T2D risk alleles showed extreme directional differentiation between different populations compared with other common diseases [29].Different T2D loci and loci frequencies across different populations may reflect the adaptation to the local environments and diets along with human migration [30].Therefore, the interplay between gene and environment leads to a more complex pathogenesis of T2D and related traits.These hypotheses are strongly supported by a number of recent GxE studies [7,11,31,32].For example, Qi et al. [31] generated a genetic risk score (GRS) using ten GWAS-identified SNPs and observed a significant interaction between the Western dietary pattern and GRS in the Health Professionals Follow-Up Study.The Western dietary pattern was only positively associated with risk of T2D among men with a high GRS, but not with low GRS subjects.Another large meta-analysis of 14 cohort studies [32] revealed that dietary whole-grain intake potentially interacted with one GCKR variant (rs780094) for fasting insulin in individuals of European descent.Greater whole-grain intake was associated with a smaller reduction of fasting insulin in individuals with the insulin-raising allele of rs780094, compared to the non-risk allele."
}
],
"2a7da18e-3756-45c5-b18c-a2231685fefd": [
{
"document_id": "2a7da18e-3756-45c5-b18c-a2231685fefd",
"text": "Gene–exercise interaction in type 2 diabetes\nWhen studying gene–environment interaction on the quantitative traits that\nunderlie diabetes, the power to detect interaction is highly dependent on the precision with which non-genetic exposures are measured (Wareham et al 2002). Achievement of optimal glycaemic control is the focus of traditional treatment\nparadigms. Regular exercise, both aerobic (walking, jogging, or cycling) and resistance (weightlifting) training results in increased glucose uptake and insulin sensitivity and is a primary modality used in the treatment of type 2 diabetes patients\n(Sigal et al 2007)."
}
],
"559a3a15-da15-4132-a8b5-5401bfe770ef": [
{
"document_id": "559a3a15-da15-4132-a8b5-5401bfe770ef",
"text": "Gene-Environment Interaction\n\nEvidence from the epidemiology of T2D overwhelmingly supports a strong environmental influence interacting with genetic predisposition in a synergistic fashion as has been recently reviewed [123], however current state-of-the-art methods for measuring environmental effects lack precision and can result in changes in statistical power to detect interaction [123,124].Since lifestyle factors are important in preventing diabetes [125,126], interaction of gene variants with measures of dietary intake and exercise have been selected for studies on gene-environment interaction.For example, HNF1B (rs 4430796) was shown to interact with exercise; low levels of activity enhanced the risk of T2D in association with absence of the risk allele, but there was no protective effect of exercise when the allele was present.It follows that subgrouping by genotype may serve to enhance risk prediction while considering gene-environment interaction as has been done for exercise [127].Also lifestyle including exercise modified the effect of a CDKN2A/B variant on 2-hour glucose levels in the Diabetes Prevention Program [128] but was not confirmed in the HERITAGE study using different measurements and phenotypes involving insulin sensitivity and β-cell function [129].The pro12ala PPARG variant also interacts with physical activity for effect on 2-hour glucose levels [130], which was confirmed in the smaller HERITAGE study [129].In addition, a relationship of dietary fat intake with plasma insulin and BMI differs by the pro12ala PPARG genotype [131]."
}
],
"5d1d5baa-75f4-42d5-8e4c-fb038a71bbec": [
{
"document_id": "5d1d5baa-75f4-42d5-8e4c-fb038a71bbec",
"text": "\n\nA person's risk of type 2 diabetes or obesity reflects the joint effects of genetic predisposition and relevant environmental exposures.Efforts to determine whether these genetic and environmental components of risk interact (in the statistical sense that joint effects cannot be predicted from main effects alone) 70 face challenges associated with measuring relevant exposures (diet and physical activity being notoriously difficult to estimate) and the effect of imprecision on statistical power. 71Although claims that statistical interactions reflect shared mechanisms (i.e., that the interacting factors act through the same pathways) are probably overstated, understanding the relative contributions of genetic and environmental components to risk is important.After all, environmental factors can be modified more readily than genetic factors.Genetic discoveries have provided a molecular basis for the clinically useful classification of monogenic forms of diabetes and obesity. 3,4Will the same be true for the common forms of these conditions?Probably not: as far as the common variants are concerned, each patient with diabetes or obesity has an individual \"barcode\" of susceptibility alleles and protective alleles across many loci.It is possible to show that the genetic profiles of lean subjects with type 2 diabetes and obese subjects with type 2 diabetes are not identical, but these differences appear to be inadequate for clinically useful subclassification. 22,72f efforts to uncover less prevalent, higher-penetrance alleles are successful, more precise classification of disease subtypes may become possible, particularly if genetic data can be integrated with clinical and biochemical information.For example, in persons presenting with diabetes in early adulthood, there are several possible diagnoses: various subtypes of maturity-onset diabetes of the young or mitochondrial diabetes, for example, as well as type 1 or type 2 diabetes.Assigning the correct diagnosis has both prognostic and therapeutic benefits for the patient (Table 3)."
}
],
"646689fd-501b-4b27-b8fa-dc098f613044": [
{
"document_id": "646689fd-501b-4b27-b8fa-dc098f613044",
"text": "Genes, environment, and development of type 2 diabetes\n\nGenes and the environment together are important determinants of insulin resistance and β-cell dysfunction (fi gure 2).Because changes in the gene pool cannot account for the rapid increase in prevalence of type 2 diabetes in recent decades, environmental changes are essential to understanding of the epidemic."
}
],
"8ab10856-5df7-4f76-897a-84e6f25cd3f5": [
{
"document_id": "8ab10856-5df7-4f76-897a-84e6f25cd3f5",
"text": "\nType 2 diabetes (T2D) is thought to arise from the complex interplay of both genetic and environmental factors.Since the advent of genomewide association studies (GWAS), we have seen considerable progress in our understanding of the role that genetics and gene-environment interactions play in the development of T2D.Recent work suggests that the adverse effect of several T2D loci may be abolished or at least attenuated by higher physical activity levels or healthy lifestyle, whereas low physical activity and dietary factors characterizing a Western dietary pattern may augment it.However, there still remain inconsistencies warranting further investigation.Lack of statistical power and measurement errors for the environmental factors continue to challenge our efforts for characterizing interactions.Although our recent focus on established T2D loci is reasonable, we may be overlooking many other potential loci not captured by recent T2D GWAS.Agnostic approaches to the discovery of gene and environment interactions may address this possibility, but their application to the field is currently limited and still faces conceptual challenges.Nonetheless, continued investment in gene-environment interaction studies through large collaborative efforts holds promise in furthering our understanding of the interplay between genetic and environmental factors."
},
{
"document_id": "8ab10856-5df7-4f76-897a-84e6f25cd3f5",
"text": "\n\nType 2 diabetes (T2D) is thought to arise from the complex interplay of both genetic and environmental factors.Since the advent of genomewide association studies (GWAS), we have seen considerable progress in our understanding of the role that genetics and gene-environment interactions play in the development of T2D.Recent work suggests that the adverse effect of several T2D loci may be abolished or at least attenuated by higher physical activity levels or healthy lifestyle, whereas low physical activity and dietary factors characterizing a Western dietary pattern may augment it.However, there still remain inconsistencies warranting further investigation.Lack of statistical power and measurement errors for the environmental factors continue to challenge our efforts for characterizing interactions.Although our recent focus on established T2D loci is reasonable, we may be overlooking many other potential loci not captured by recent T2D GWAS.Agnostic approaches to the discovery of gene and environment interactions may address this possibility, but their application to the field is currently limited and still faces conceptual challenges.Nonetheless, continued investment in gene-environment interaction studies through large collaborative efforts holds promise in furthering our understanding of the interplay between genetic and environmental factors."
},
{
"document_id": "8ab10856-5df7-4f76-897a-84e6f25cd3f5",
"text": "Gene and Environment Selection\n\nEnvironmental factors selected for recent G × E interactions studies continue to be the established modifiable risk factors for T2D such as obesity, physical activity, dietary fat, and carbohydrate quality as well as measures of pre-and post-uterine environment.The genetic factors selected, however, have shifted from biological candidates based on functional evidence to genome-wide established loci for T2D or related traits (Table 1).This approach may improve power to detect and strengthen causal inference for an interaction (49).Focusing on established T2D loci may also further our understanding of their functional role in disease development in addition to their public health relevance in the context of genetic risk modification (13)."
},
{
"document_id": "8ab10856-5df7-4f76-897a-84e6f25cd3f5",
"text": "\n\nWe have seen considerable progress in our understanding of the role that both environment and genetics play in the development of T2D.Recent work suggests that the adverse effect of some established T2D-associated loci may be greatly attenuated by appropriate changes in certain lifestyle factors.Our recent approach to studies of G × E interactions in T2D has gained considerable advantage over previous approaches, but it is clearly not optimal.Lack of statistical power and measurement error for environmental factors will continue to challenge our efforts to characterize G × E interactions.Although our recent focus on established T2D loci is reasonable, we may be overlooking many other potential loci not captured by recent T2D GWAS.Agnostic approaches to the discovery of G × E interactions may address this possibility, but their application to the field is currently limited and still faces conceptual challenges.Nevertheless, large collaborative efforts have the potential to uncover true G × E interactions, which will enhance our understanding of the interplays between genes and environment in the etiology of T2D."
},
{
"document_id": "8ab10856-5df7-4f76-897a-84e6f25cd3f5",
"text": "\n\nThe purpose of the present review is to summarize recent epidemiological approaches and progress pertaining to gene-environment (G × E) interactions potentially implicated in the pathogenesis of T2D and its related traits.We also discuss continuing challenges, evolving approaches, and recommendations for future efforts in this field."
},
{
"document_id": "8ab10856-5df7-4f76-897a-84e6f25cd3f5",
"text": "FUTURE PERSPECTIVES\n\nContinued investment in studies of G × E interactions for T2D holds promise on several grounds.First, such studies may provide insight into the function of novel T2D loci and pathways by which environmental exposures act and, therefore, yield a better understanding of T2D etiology (66).They could also channel experimental studies in a productive direction.Second, knowledge of G × E interactions may help identify high-risk individuals for diet and lifestyle interventions.This may also apply to pharmacological interventions if individuals carrying certain genotypes are more or less responsive to specific medications.The finding that patients with rare forms of neonatal diabetes resulting from KCNJ11 mutations respond better to sulfonylurea than to insulin therapy is just one example demonstrating the potential for this application of G × E interaction research (69).Third, we are fast approaching an era when individuals can feasibly obtain their complete genetic profile and thus a snapshot of their genetic predisposition to disease.It will therefore be the responsibility of health professionals to ensure that their patients have an accurate interpretation of this information and a means to curb their genetic risk.A long-held goal of genetic research has been to tailor diet and lifestyle advice to an individual's genetic profile, which will, in turn, motivate him or her to adopt and maintain a protective lifestyle.There is currently no evidence that this occurs.Findings to date, however, indicate that behavioral changes can substantially mitigate diabetogenic and obesogenic effects of individual or multiple risk alleles, which has much broader clinical and public health implications."
}
],
"8cd81e24-a326-4443-bc37-0e6e421e70b2": [
{
"document_id": "8cd81e24-a326-4443-bc37-0e6e421e70b2",
"text": "Gene-Nutrient or Dietary Pattern Interactions in The Development of T2DM\n\nRecently, several studies have demonstrated the significant effects of genotype by environment interactions on T2DM [48,49].However, further clarification of the role of these interactions at the genome-wide level could help predict disease risk more accurately and facilitate the development of dietary recommendations to improve prevention and treatment.Moreover, it would be very interesting to identify the specific dietary factors that are the most influential in the variation of a given T2DM-related phenotype and to what extent these dietary factors contribute to the phenotypic variation (Table 2).In particular, the dietary factors considered are macro-and micronutrients, foods and type of diets.A recent review present evidence on the dietary environment and genetics as risk factors for T2DM [50]. * Adiponectin (ADIPOQ)."
}
],
"90015638-c92d-4506-95b5-b789f08d613a": [
{
"document_id": "90015638-c92d-4506-95b5-b789f08d613a",
"text": "Introduction\n\nGenome wide association studies (GWAS) of type 2 diabetes mellitus and relevant endophenotypes have shed new light on the complex etiology of the disease and underscored the multiple molecular mechanisms involved in the pathogenic processes leading to hyperglycemia [1].Even though these studies have successfully mapped many diabetes risk genetic loci that could not be detected by linkage analysis, the risk single nucleotide polymorphisms (SNP) have small effect sizes and generally explain little of disease heritability estimates [2].The poor contribution of risk loci to diabetes inheritance suggests a prominent role of environmental factors (eg.diet, physical activity, lifestyle), gene  environment interactions and epigenetic mechanisms in the pathological processes leading to the deterioration of glycemic control [3,4]."
}
],
"940283a4-b7e7-4bbe-ba34-c80c4717c15a": [
{
"document_id": "940283a4-b7e7-4bbe-ba34-c80c4717c15a",
"text": "\n\nThe literature on gene-environment interactions in diabetes-related traits is extensive, but few studies are accompanied by adequate replication data or compelling mechanistic explanations.Moreover, most studies are cross-sectional, from which temporal patterns and causal effects cannot be confidently ascertained.This has undermined confidence in many published reports of gene-environment interactions across many diseases; although interaction studies in psychiatry have been especially heavily criticized [3], many of the points made in that area relate to other diseases, not least to T2D, where the diagnostic phenotype (elevated blood glucose or HbA1c) is a consequence of underlying and usually unmeasured physiological defects (e.g., at the level of the pancreatic beta-cell, peripheral tissue, liver, and gut), and the major environmental risk factors are difficult to measure well.Nevertheless, several promising examples of geneenvironment interactions relating to cardiometabolic disease exist, as discussed below and described in Table 1, and interaction studies with deep genomic coverage in large cohorts are now conceivable; the hope is that these studies will highlight novel disease mechanisms and biological pathways that will fuel subsequent functional and clinical translation studies.This is important, because diabetes medicine may rely increasingly on genomic stratification of patient populations and disease phenotype, for which gene-environment interaction studies might prove highly informative."
},
{
"document_id": "940283a4-b7e7-4bbe-ba34-c80c4717c15a",
"text": "\nThe genome is often the conduit through which environmental exposures convey their effects on health and disease.Whilst not all diseases act by directly perturbing the genome, the phenotypic responses are often genetically determined.Hence, whilst diseases are often defined has having differing degrees of genetic determination, genetic and environmental factors are, with few exceptions, inseparable features of most diseases, not least type 2 diabetes.It follows that to optimize diabetes, prevention and treatment will require that the etiological roles of genetic and environmental risk factors be jointly considered.As we discuss here, studies focused on quantifying gene-environment and gene-treatment interactions are gathering momentum and may eventually yield data that helps guide health-related choices and medical interventions for type 2 diabetes and other complex diseases."
},
{
"document_id": "940283a4-b7e7-4bbe-ba34-c80c4717c15a",
"text": "\n\nThe genome is often the conduit through which environmental exposures convey their effects on health and disease.Whilst not all diseases act by directly perturbing the genome, the phenotypic responses are often genetically determined.Hence, whilst diseases are often defined has having differing degrees of genetic determination, genetic and environmental factors are, with few exceptions, inseparable features of most diseases, not least type 2 diabetes.It follows that to optimize diabetes, prevention and treatment will require that the etiological roles of genetic and environmental risk factors be jointly considered.As we discuss here, studies focused on quantifying gene-environment and gene-treatment interactions are gathering momentum and may eventually yield data that helps guide health-related choices and medical interventions for type 2 diabetes and other complex diseases."
}
],
"95a5a00b-9cf4-4988-bc6c-9df0e8e1b155": [
{
"document_id": "95a5a00b-9cf4-4988-bc6c-9df0e8e1b155",
"text": "\n\nPredisposition is influenced by the level of certain environmental exposures, personal factors, access to good-quality primary care, and by genotype.Interactions between genetic and nongenetic risk factors are hypothesized to raise diabetes risk in a synergistic manner; reciprocally, health-enhancing changes in behavior, body composition, or medication may reduce the risk of disease conveyed by genetic factors.Defining the nature of these interactions and identifying ways through which reliable observations of gene-environment interactions (GEIs) can be translated into the public health setting might help 1) optimize targeting of health interventions to persons most likely to respond well to them, 2) improve cost-and health-effectiveness of existing preventive and treatment paradigms; 3) reduce unnecessary adverse consequences of interventions; 4) increase patient adherence to health practitioners' recommendations; and 5) identify novel interventions that are beneficial only in a defined genetic subgroup of the population.In this Perspective, we describe the rationale and evidence relating to the existence of gene-environment and genetreatment interactions in type 2 diabetes.We discuss the tried, tested, and oftenfailed approaches to investigating genelifestyle interactions in type 2 diabetes; we discuss some recent developments in gene-treatment interactions (pharmacogenetics); and we look forward to the strategies that are likely to dominate these fields of research in the future.We conclude with a discussion of the requirements for translating findings from these future studies into a form where they can be used to help predict, prevent, or treat diabetes.Here we describe the rationale and evidence concerning GEIs and gene-treatment interactions in type 2 diabetes, provide an interpretation of current findings and strategies, and offer a view for their future translation."
}
],
"b07d827c-136a-4938-b3f5-b1cde90a2332": [
{
"document_id": "b07d827c-136a-4938-b3f5-b1cde90a2332",
"text": "\n\nT2DM results from the contribution of many genes [10] , many environmental factors [11] , and the interactions among those genetic and environmental factors.Physical activity and dietary fat have been reported to be important modifiers of the associations between glucose homeostasis and well-known candidate genes for T2DM [12] and there is reason to believe that a significant proportion of the susceptibility genes identified by GWASs will interact with these environmental factors to influence the disease risk.Florez et al. [13] reported that response to the Diabetes Prevention Program lifestyle intervention did not differ by genotype groups at TCF7L2 rs7903146 [13] .A more recent report from the Diabetes Prevention Program [14] showed that among 10 of the recently identified diabetes susceptibility polymorphisms (single nucleotide polymorphisms, SNPs), only CDKN2A/B rs10811661 was shown to marginally modify the effect of the lifestyle intervention on diabetes risk reduction.Similarly, the study of Brito et al. [15] reported that among 17 of the diabetes SNPs, only HNF1B rs4430796 significantly interacted with physical activity to influence impaired glucose tolerance risk and incident diabetes."
}
],
"df542302-18b9-43c2-a421-cba1dba0b3be": [
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"document_id": "df542302-18b9-43c2-a421-cba1dba0b3be",
"text": "Gene-Environment\n\nInteractions.An risk of developing T2D is the product of interaction between the individual's genetic constitution and the environment inhabited by the individual.Whilst the contribution of genetic factors to disease risk is relatively easy to quantify, the impact of environmental exposure is less easily measured in a clinical setting.Nevertheless, efforts have been made to study the interactions between some of the known susceptibility loci for T2D and the environment, and these findings may be useful for the development of prediction models and tailoring clinical treatment for T2D [122,123].For example, for carriers of the risk allele for TCF7L2, diets of low glycaemic load [124,125] and a more intensive lifestyle modification regime (versus that recommended for nonrisk carriers) [61,62,126,127] have been shown to reduce the risk of T2D.Meaningful studies for gene-environment interactions will require samples of sufficient size to increase statistical power [128] and accurate methods for measuring environmental exposure, for example, the use of metabolomics to identify and assess metabolic characteristics, changes, and phenotypes in response to the environment, diet, lifestyle, and pathophysiological states.This information will allow the generation of better risk prediction models and personalisation/stratification of treatment, the holy grail of GWAS."
}
],
"fcf8fb37-20cf-491c-96f8-04a5621812a2": [
{
"document_id": "fcf8fb37-20cf-491c-96f8-04a5621812a2",
"text": "\n\nOther aspects that have been overlooked in large GWAS on T2DM relate to environmental effects such as diet, physical activity, and stresses, which may affect gene expression.For example, fish oil may stimulate PPARG in much the same fashion as the thiazolidinedione class of drugs; however, studies on the interaction of the PPARG variant with dietary components have not been performed.The spectacular rise in the incidence of diabetes among Pima Indians and other populations as they adopt Western diets and lifestyles dramatically demonstrates the key role of the environment [12].Consequently, it could be expected that the effect of a common gene variant among populations that have very different diets and exercise habits might be totally different, thus explaining some instances of lack of replication. [4].Another variable that influences the statistical and real association of an SNP with a disease or response to a diet is epigenetic interaction.Epigenesis is the study of heritable changes in gene function that occur without a change in the DNA sequence, such as DNA methylation and chromatin remodeling.Both mechanisms can affect gene expression by altering the accessibility of DNA to regulatory proteins or complexes such as transcription factors, and they can be influenced by certain nutrients and by overall caloric intake.Thus, it can be expected that long-term exposure to certain diets could produce permanent epigenetic changes in the genome [7]."
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