Unique Gene-environment Interactions Research Articles

Genetic associations between serum low LDL-cholesterol levels and variants in LDLR, APOB, PCSK9 and LDLRAP1 in African populations

Non-communicable diseases, including cardiovascular diseases (CVDs), are increasing in African populations. High serum low density lipoprotein cholesterol (LDL-cholesterol) levels are a known risk factor for CVDs in European populations, but the link remains poorly understood among Africans. This study investigated the associations between serum LDL-cholesterol levels and selected variants in the low density lipoprotein receptor (LDLR), apolipoprotein B (APOB), proprotein convertase subtilisin/kexin type 9 (PCSK9) and low density lipoprotein receptor adaptor protein 1 (LDLRAP1) genes in some selected African populations. Nineteen SNPs were selected from publicly available African whole genome sequence data based on functional prediction and allele frequency. SNPs were genotyped in 1000 participants from the AWI-Gen, study selected from the extremes of LDL-cholesterol level distribution (500 with LDL-cholesterol>3.5 mmol/L and 500 with LDL-cholesterol<1.1 mmol/L). The minor alleles at five of the six associated SNPs were significantly associated (P<0.05) with lower LDL-cholesterol levels: LDLRAP1 rs12071264 (OR 0.56, 95% CI: 0.39–0.75, P = 2.73x10-4) and rs35910270 (OR 0.78, 95% CI: 0.64–0.94, P = 0.008); APOB rs6752026 (OR 0. 55, 95% CI: 0.41–0.72, P = 2.82x10-5); LDLR: rs72568855 (OR 0.47, 95% CI: 0.27–0.82, P = 0.008); and PCSK9 rs45613943 (OR = 0.72, 95% CI: 0.58–0.88, P = 0.001). The minor allele of the sixth variant was associated with higher LDL-cholesterol levels: APOB rs679899 (OR 1.41, 95% CI: 1.06–1.86, P = 0.016). A replication analysis in the Africa America Diabetes Mellitus (AADM) study found the PCSK9 variant to be significantly associated with low LDL-cholesterol levels (Beta = -0.10). Since Africans generally have lower LDL-cholesterol levels, these LDL-cholesterol associated variants may be involved in adaptation due to unique gene-environment interactions. In conclusion, using a limited number of potentially functional variants in four genes, we identified significant associations with lower LDL-cholesterol levels in sub-Saharan Africans.

Epigenetics and the exposomes: Obesity and beyond

ABSTRACT: The specific genetic alterations that result in diseases and complex syndromes have been and continue to be identified. Search for the origins of disease have led to investigations into the roles of dietary and environmental factors as potential triggers or modifiers of risk. Genome-wide association studies have identified concepts such as the rare variant-common disease hypothesis and the common variant-common disease hypothesis.1 Through association studies, unique gene-environment interactions, which may occur with or without specific periods of permissiveness or vulnerabilities, have also been identified. Major conditions where the role of exposomes and epigenetics are rapidly evolving are obesity, neurological disorders, immune disorders and cancers. These concepts are particularly intriguing in the context of obesity.

The Secrets to Better Athletic Performance

Genetic contributions to athletic performance are remarkably complex with unique gene-environment interactions specific to each athlete, including effects on physiological, motor and psychological characteristics...

Environmental influence on Pristionchus pacificus mouth form through different culture methods

Environmental cues can impact development to elicit distinct phenotypes in the adult. The consequences of phenotypic plasticity can have profound effects on morphology, life cycle, and behavior to increase the fitness of the organism. The molecular mechanisms governing these interactions are beginning to be elucidated in a few cases, such as social insects. Nevertheless, there is a paucity of systems that are amenable to rigorous experimentation, preventing both detailed mechanistic insight and the establishment of a generalizable conceptual framework. The mouth dimorphism of the model nematode Pristionchus pacificus offers the rare opportunity to examine the genetics, genomics, and epigenetics of environmental influence on developmental plasticity. Yet there are currently no easily tunable environmental factors that affect mouth-form ratios and are scalable to large cultures required for molecular biology. Here we present a suite of culture conditions to toggle the mouth-form phenotype of P. pacificus. The effects are reversible, do not require the costly or labor-intensive synthesis of chemicals, and proceed through the same pathways previously examined from forward genetic screens. Different species of Pristionchus exhibit different responses to culture conditions, demonstrating unique gene-environment interactions, and providing an opportunity to study environmental influence on a macroevolutionary scale.

Epigenetics and the exposomes: Obesity and beyond

ABSTRACTThe specific genetic alterations that result in diseases and complex syndromes have been and continue to be identified. Search for the origins of disease have led to investigations into the roles of dietary and environmental factors as potential triggers or modifiers of risk. Genome-wide association studies have identified concepts such as the rare variant-common disease hypothesis and the common variant-common disease hypothesis.1 Through association studies, unique gene-environment interactions, which may occur with or without specific periods of permissiveness or vulnerabilities, have also been identified. Major conditions where the role of exposomes and epigenetics are rapidly evolving are obesity, neurological disorders, immune disorders and cancers. These concepts are particularly intriguing in the context of obesity. BACKGROUND: Epigenetics can be defined as heritable traits resulting from changes in DNA or chromatin structure without alterations in the DNA sequence.2 Nutritional epigenetics is seen as a means for the prevention of developmental diseases and cancer, and to delay processes associated with aging.3,4 Diseases in which epigenetic factors are considered significant include type 2 diabetes mellitus, obesity, inflammation, cardiovascular diseases, neurocognitive disorders, and immune diseases, with neural function influenced by environmental factors including early experience.5 Studies with rodent models suggest that during both early development and in adult life, environmental signals can activate intracellular pathways that directly remodel the epigenome, leading to changes in gene expression and function. These studies define a biological basis for the interplay between environmental signals and the genome in the regulation of individual differences in behavior, cognition, and physiology.6 In reproduction, certain genes are turned on while others are turned off in the process of imprinting. In the case of imprinting, even though there are two copies of the gene, only one copy is expressed and there is no substitute functional allele. For this reason, imprinting makes the imprinted genes more vulnerable to the negative effects of mutations.7

Breast Cancer Risk After Use of Fertility Drugs: Stimulating New Controversy

Breast Cancer Risk After Use of Fertility Drugs: Stimulating New Controversy

Genetics of Pediatric Obesity

Onset of obesity has been anticipated at earlier ages, and prevalence has dramatically increased worldwide over the past decades. Epidemic obesity is mainly attributable to modern lifestyle, but family studies prove the significant role of genes in the individual's predisposition to obesity. Advances in genotyping technologies have raised great hope and expectations that genetic testing will pave the way to personalized medicine and that complex traits such as obesity will be prevented even before birth. In the presence of the pressing offer of direct-to-consumer genetic testing services from private companies to estimate the individual's risk for complex phenotypes including obesity, the present review offers pediatricians an update of the state of the art on genomics obesity in childhood. Discrepancies with respect to genomics of adult obesity are discussed. After an appraisal of findings from genome-wide association studies in pediatric populations, the rare variant-common disease hypothesis, the theoretical soil for next-generation sequencing techniques, is discussed as opposite to the common disease-common variant hypothesis. Next-generation sequencing techniques are expected to fill the gap of "missing heritability" of obesity, identifying rare variants associated with the trait and clarifying the role of epigenetics in its heritability. Pediatric obesity emerges as a complex phenotype, modulated by unique gene-environment interactions that occur in periods of life and are "permissive" for the programming of adult obesity. With the advent of next-generation sequencing techniques and advances in the field of exposomics, sensitive and specific tools to predict the obesity risk as early as possible are the challenge for the next decade.

Obesity and type 2 diabetes mellitus in a birth cohort of First Nation children born to mothers with pediatric-onset type 2 diabetes

Children who are born to mothers with pediatric-onset type 2 diabetes mellitus are exposed to a hyperglycemic intra-uterine environment throughout pregnancy. The growth patterns and risk of type 2 diabetes in these offspring may be influenced by unique gene-environment interactions during intra-uterine and postnatal life. We established a cohort of offspring of First Nation mothers with onset of type 2 diabetes before age 18 years in Manitoba, Canada. We measured height or length and weight at study entry and annually thereafter with fasting blood glucose in offspring aged ≥ 7 years. We collected birth and breastfeeding history and determined the population-specific hepatic nuclear factor-1α (HNF-1α) G319S genotype of offspring at age 7 years. From July 2003 to April 2008, we enrolled 76 offspring of 37 mothers. Sixty-four percent (23/36) of the offspring aged 2-19 years were obese at initial assessment. The rates of obesity remained constant throughout the 5 years. As of April 2008, 7/28 (25%) of the offspring aged 7-19 years have diabetes including 6/14 (43%) aged 10-19 years. Most offspring with diabetes (5/7, 71%) were obese at diagnosis. All of the 7 offspring with diabetes have 1 or 2 copies of the G319S polymorphism. The prevalence of type 2 diabetes in this cohort of offspring of First Nation women with pediatric-onset type 2 diabetes is the highest ever reported. Obesity is an important postnatal risk factor for type 2 diabetes in this population and may result from a unique gene-environment interaction.

Allergic rhinitis and genetic components: focus on Toll-like receptors (TLRs) gene polymorphism.

Allergic rhinitis represents a global health issue affecting 10% to 25% of the population worldwide. Over the years, studies have found that allergic diseases, including allergic rhinitis, are associated with immunological responses to antigens driven by a Th2-mediated immune response. Because Toll-like receptors (TLRs) are involved in both innate and adaptive immune responses to a broad variety of antigens, the association between polymorphisms of TLRs and allergic diseases has been the focus in many animal and human studies. Although the etiology of allergic rhinitis is still unknown, extensive research over the years has confirmed that the underlying causes of allergic diseases are due to many genetic and environmental factors, along with the interactions among them, which include gene–environment, gene–gene, and environment–environment interactions. Currently, there is great inconsistency among studies mainly due to differences in genetic background and unique gene–environment interactions. This paper reviews studies focusing on the association between TLR polymorphisms and allergic diseases, including allergic rhinitis, which would help researchers better understand the role of TLR polymorphisms in the development of allergic rhinitis, and ultimately lead to more efficient therapeutic interventions being developed.

TLR4 and LPS hyporesponsiveness in humans

AbstractAsthma is a complex genetic disorder that is caused by a number of unique gene-gene and gene-environment interactions. The search for asthma susceptibility genes has been complicated by the broad clinical phenotype of asthma, the polygenic inheritance pattern of this disease, and the substantial role of environmental exposures in the development and progression of asthma. Inhaled environmental agents induce several biologic responses in asthmatics; including the induction of acquired and innate immunity that leads to acute and chronic forms of airway inflammation and airway remodeling. Acquired immune responses to protein antigens, such as house dust mite allergen, often induce type 2 T lymphocyte-driven responses (Th2) which appear to be important in atopic asthma. Recent studies by our group and others demonstrate that innate immunity, initiated by inhalation of bacterial and viral pathogens, organic dusts, endotoxin or lipopolysaccharide (LPS), air pollution particulate matter, and ozone, can also cause acute and chronic forms of airflow obstruction, airway inflammation, and even airway remodeling. Emerging evidence indicates that both acquired and innate immune responses in the lung may be influenced by polymorphic genes. For instance, functional polymorphisms in the IL-4 receptor gene are thought to preferentially stimulate acquired Th2 immune responses to inhaled allergens, and we have recently shown that common co-segregating mutations in TLR4 (a transmembrane receptor for LPS) are associated with diminished airway responsiveness to inhaled LPS. These observations suggest that environmental challenges can be used to narrow the phenotype of asthma and allow scientists to investigate unique gene-environment interactions that are involved in the development of biologically specific forms of asthma.