Search Results (18)

Insulin resistance (IR) is a key mechanism underlying type 2 diabetes mellitus and is closely associated with obesity. Although numerous genome-wide association studies (GWASs) have identified variants that influence IR-related traits, it remains unclear whether the genetic architecture of IR differs according to obesity status. We conducted a stratified GWAS of the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) in 8906 Korean individuals from the Korean Genome and Epidemiology Study. Participants were categorized into a normal-weight group (Body Mass Index (BMI) ≤ 23 kg/m²) and an overweight or obese group (BMI > 23 kg/m²), and the GWAS was performed separately within each group. No significant genome-wide variants were identified in the normal-weight group; however, seven loci showed suggestive associations. In contrast, in the overweight and obese group, two loci, rs662799 in Apolipoprotein A5 (APOA5) and rs671 in Aldehyde Dehydrogenase 2 (ALDH2), showed genome-wide significance, with seven loci showing suggestive associations. The risk allele of rs662799 was associated with increased HOMA-IR values, with a stronger effect observed in the overweight and obese group. This finding aligns with the known role of APOA5 in triglyceride metabolism, suggesting that a higher BMI may exacerbate its effect on IR. These results highlight obesity-specific genetic susceptibility to IR and the need to consider obesity status in genetic studies of metabolic traits. Full article

Obesity is a global health challenge characterized by significant heterogeneity in causes and treatment responses, complicating sustainable management. This narrative review explores the genomic architecture of obesity and its implications for personalized interventions, focusing on how genetic variations influence key biological pathways and treatment outcomes. A comprehensive literature search, guided by the authors’ expertise, was conducted to identify key publications on the genomics of obesity and personalized approaches. The selection of articles prioritized those that provided direct insights into the genomic basis of obesity and its potential for informing tailored strategies. Genomic studies reveal both monogenic and polygenic influences on obesity, identifying numerous susceptibility loci. Genome-wide association studies (GWASs) have linked common variants in genes like FTO and MC4R to increased BMI and appetite dysregulation, respectively. Epigenetic research highlights the role of DNA methylation and other modifications in gene–environment interactions. Genetic and polygenic risk scores (GRSs and PRSs) show potential for refining risk stratification and predicting treatment response. The gut microbiome and metabolome also contribute to obesity pathogenesis, offering novel targets for intervention. Personalized medicine offers significant potential for improving obesity management through tailored interventions based on an individual’s genetic and ‘omics’ profile. Future research should focus on elucidating the functional consequences of identified variants, exploring gene–environment interactions, and developing strategies to overcome current limitations in clinical translation. With continued advancements, precision medicine can enhance treatment efficacy, increase sustainability, and help reduce the global burden of obesity-related diseases. Full article

Background/Objectives: Turner syndrome (TS) is a genetic chromosomal disorder including various manifestations depending on the karyotype; endocrine, gastrointestinal, respiratory, neurological, urogenital, musculoskeletal, and cardiovascular disorders contribute to increased morbidity and mortality. Liver function abnormalities are less well studied and mostly associated with insulin resistance, obesity, diabetes, hypogonadism, hypothyroidism, and autoimmune conditions. The association of liver pathology with architectural changes in various etiologies and the metabolic dysfunction-associated liver disease is of particular interest. Methods: Herein, we present three cases of adult women with TS and the persistent elevation of liver enzymes due to porto-sinusoidal vascular disorder (PSVD). Results: In one case, the diagnosis of TS followed the liver biopsy results. The absence of cardiometabolic risk factors, low liver stiffness and cardiovascular malformations may predict this histological diagnosis. Conclusions: Liver function impairment in TS may derive from a broad spectrum of liver pathology, including PSVD, and requires careful evaluation to decrease the risk of complications. Full article

The pathogenesis of obesity is complex and incompletely understood, with an underlying interplay between our genetic architecture and obesogenic environment. The public understanding of the development of obesity is shrouded in myths with widespread societal misconceptions. Body Mass Index (BMI) is a highly heritable trait. However, despite reports from recent genome-wide association studies, only a small proportion of the overall heritability of BMI is known to be lurking within the human genome. Other non-genetic heritable traits may contribute to BMI. The gut microbiome is an excellent candidate, implicating complex interlinks with hypothalamic control of appetite and metabolism via entero-endocrine, autonomic, and neuro-humeral pathways. The neonatal gut microbiome derived from the mother via transgenerational transmission (vaginal delivery and breastfeeding) tends to have a permanence within the gut. Conversely, non-maternally derived gut microbiota manifest mutability that responds to changes in lifestyle and diet. We should all strive to optimize our lifestyles and ensure a diet that is replete with varied and unprocessed plant-based foods to establish and nurture a healthy gut microbiome. Women of reproductive age should optimize their gut microbiome, particularly pre-conception, ante- and postnatally to enable the establishment of a healthy neonatal gut microbiome in their offspring. Finally, we should redouble our efforts to educate the populace on the pathogenesis of obesity, and the role of heritable (but modifiable) factors such as the gut microbiome. Such renewed understanding and insights would help to promote the widespread adoption of healthy lifestyles and diets, and facilitate a transition from our current dispassionate and stigmatized societal approach towards people living with obesity towards one that is epitomized by understanding, support, and compassion. Full article

In the domain of swine production, body weight (BW) and average daily gain (ADG) are recognized as the primary performance indicators. Nevertheless, the genetic architecture of ADG and BW in Dongliao black (DLB) pigs remains to be fully elucidated. In this study, we performed a genome-wide association analysis of BW, ADG, and body mass index (BMI) in 358 DLB pigs of different days of age. The genome-wide association study (GWAS) showed the following: (1) The most significant single nucleotide polymorphism (SNP) detected for BW was on Sus scrofa chromosome (SSC) 11:100,808 (p-value = 1.16 × 10⁻⁶) that was also the most significant SNP for ADG. (2) The most significant SNP associated with BMI was SSC17:51,463,521 (p-value = 5.16 × 10⁻⁸). (3) SNPs SSC10:6,523,844 and SSC17:23,852,682 were identified in both BW and ADG. A meta-analysis was conducted on BW at different days and demonstrated SSC5:39,028,335 (p-value = 8.37 × 10⁻⁶) which was not identified in the results of each single trait. The regions of two SNPs (SSC11:100,808, SSC4:10,703,277) exhibited considerable influence on both BW and ADG and the related regions were selected for linkage disequilibrium (LD) analyses that exhibited a notable linkage. In addition, several genes were identified that are associated with obesity and play roles in lipid metabolism, including MACROD2, PHLPP2, CYP2E1, and STT3B. Full article

Background: Over the past few decades, the prevalence of obesity has significantly increased worldwide, particularly among children. This trend represents a global health challenge. Considering the pivotal role of obesity in the development of metabolic disorders, the identification and characterization of pathogenic gene variants in children with severe forms of obesity are key priorities in fundamental endocrinology. Methods: We performed whole-exome sequencing (WES) in 163 Russian children with morbid obesity and identified 96 pathogenic or likely pathogenic variants in 61 genes. These variants were clinically significant in 64 children (38.79% of the cohort). Results: Notably, 42 of the identified variants have not been previously described in the literature or reported in existing databases. Conclusions: The findings of this study will enable a more personalized approach to the diagnosis and treatment of patients with syndromic and polygenic forms of obesity. Moreover, these results advance our understanding of the genetic architecture of obesity in the Russian population. Full article

Acute kidney injury (AKI) is one of the main conditions responsible for chronic kidney disease (CKD), including end-stage renal disease (ESRD) as a long-term complication. Besides short-term complications, such as electrolyte and acid-base disorders, fluid overload, bleeding complications or immune dysfunctions, AKI can develop chronic injuries and subsequent CKD through renal fibrosis pathways. Kidney fibrosis is a pathological process defined by excessive extracellular matrix (ECM) deposition, evidenced in chronic kidney injuries with maladaptive architecture restoration. So far, cited maladaptive kidney processes responsible for AKI to CKD transition were epithelial, endothelial, pericyte, macrophage and fibroblast transition to myofibroblasts. These are responsible for smooth muscle actin (SMA) synthesis and abnormal renal architecture. Recently, AKI progress to CKD or ESRD gained a lot of interest, with impressive progression in discovering the mechanisms involved in renal fibrosis, including cellular and molecular pathways. Risk factors mentioned in AKI progression to CKD are frequency and severity of kidney injury, chronic diseases such as uncontrolled hypertension, diabetes mellitus, obesity and unmodifiable risk factors (i.e., genetics, older age or gender). To provide a better understanding of AKI transition to CKD, we have selected relevant and updated information regarding the risk factors responsible for AKIs unfavorable long-term evolution and mechanisms incriminated in the progression to a chronic state, along with possible therapeutic approaches in preventing or delaying CKD from AKI. Full article

Despite enormous global efforts within clinical research and medical practice to reduce cardiovascular disease(s) (CVD), it still remains the leading cause of death worldwide. While genetic factors clearly contribute to CVD etiology, the preponderance of epidemiological data indicate that a major common denominator among diverse ethnic populations from around the world contributing to CVD is the composite of Western lifestyle cofactors, particularly Western diets (high saturated fat/simple sugar [particularly high fructose and sucrose and to a lesser extent glucose] diets), psychosocial stress, depression, and altered sleep/wake architecture. Such Western lifestyle cofactors are potent drivers for the increased risk of metabolic syndrome and its attendant downstream CVD. The central nervous system (CNS) evolved to respond to and anticipate changes in the external (and internal) environment to adapt survival mechanisms to perceived stresses (challenges to normal biological function), including the aforementioned Western lifestyle cofactors. Within the CNS of vertebrates in the wild, the biological clock circuitry surveils the environment and has evolved mechanisms for the induction of the obese, insulin-resistant state as a survival mechanism against an anticipated ensuing season of low/no food availability. The peripheral tissues utilize fat as an energy source under muscle insulin resistance, while increased hepatic insulin resistance more readily supplies glucose to the brain. This neural clock function also orchestrates the reversal of the obese, insulin-resistant condition when the low food availability season ends. The circadian neural network that produces these seasonal shifts in metabolism is also responsive to Western lifestyle stressors that drive the CNS clock into survival mode. A major component of this natural or Western lifestyle stressor-induced CNS clock neurophysiological shift potentiating the obese, insulin-resistant state is a diminution of the circadian peak of dopaminergic input activity to the pacemaker clock center, suprachiasmatic nucleus. Pharmacologically preventing this loss of circadian peak dopaminergic activity both prevents and reverses existing metabolic syndrome in a wide variety of animal models of the disorder, including high fat-fed animals. Clinically, across a variety of different study designs, circadian-timed bromocriptine-QR (quick release) (a unique formulation of micronized bromocriptine—a dopamine D2 receptor agonist) therapy of type 2 diabetes subjects improved hyperglycemia, hyperlipidemia, hypertension, immune sterile inflammation, and/or adverse cardiovascular event rate. The present review details the seminal circadian science investigations delineating important roles for CNS circadian peak dopaminergic activity in the regulation of peripheral fuel metabolism and cardiovascular biology and also summarizes the clinical study findings of bromocriptine-QR therapy on cardiometabolic outcomes in type 2 diabetes subjects. Full article

Bilirubin is the end product of heme catabolism, mainly produced by the breakdown of mature red blood cells. Due to its anti-inflammatory, antioxidant, antidiabetic, and antilipemic properties, circulating bilirubin concentrations are inversely associated with the risk of cardiovascular disease, type 2 diabetes, and all-cause mortality in adults. Some genetic loci associated with circulating bilirubin concentrations have been identified by genome-wide association studies in adults. We aimed to examine the relationship between circulating bilirubin, cardiometabolic risk factors, and inflammation in children and adolescents and the genetic architecture of plasma bilirubin concentrations. We measured fasting plasma bilirubin, cardiometabolic risk factors, and inflammatory markers in a sample of Danish children and adolescents with overweight or obesity (n = 1530) and in a population-based sample (n = 1820) of Danish children and adolescents. Linear and logistic regression analyses were performed to analyze the associations between bilirubin, cardiometabolic risk factors, and inflammatory markers. A genome-wide association study (GWAS) of fasting plasma concentrations of bilirubin was performed in children and adolescents with overweight or obesity and in a population-based sample. Bilirubin is associated inversely and significantly with a number of cardiometabolic risk factors, including body mass index (BMI) standard deviation scores (SDS), waist circumference, high-sensitivity C-reactive protein (hs-CRP), homeostatic model assessment for insulin resistance (HOMA-IR), hemoglobin A1c (HbA1c), low-density lipoprotein cholesterol (LDL-C), triglycerides, and the majority of measured inflammatory markers. In contrast, bilirubin was positively associated with fasting plasma concentrations of alanine transaminase (ALT), high-density lipoprotein cholesterol (HDL-C), systolic blood pressure (SDS), and the inflammatory markers GH, PTX3, THBS2, TNFRSF9, PGF, PAPPA, GT, CCL23, CX3CL1, SCF, and TRANCE. The GWAS showed that two loci were positively associated with plasma bilirubin concentrations at a p-value threshold of <5 × 10⁻⁸ (rs76999922: β = −0.65 SD; p = 4.3 × 10⁻⁸, and rs887829: β = 0.78 SD; p = 2.9 × 10⁻²⁴⁷). Approximately 25% of the variance in plasma bilirubin concentration was explained by rs887829. The rs887829 was not significantly associated with any of the mentioned cardiometabolic risk factors except for hs-CRP. Our findings suggest that plasma concentrations of bilirubin non-causally associates with cardiometabolic risk factors in children and adolescents. Full article

Depression and obesity are highly comorbid with one another, with evidence of bidirectional causal links between each disorder and a shared biological basis. Genetic factors play a major role in influencing both the occurrence of comorbid depression and obesity, their courses, and their response to existing treatments. The current paper is a scoping review of studies that have evaluated the contribution of specific genetic variants to the comorbidity between obesity and depression. Based on a search of the PubMed and EMBASE databases, 28 studies were included in this review, covering 54 candidate genes. Positive associations were identified for 14 genetic loci (AKR1C2, APOA5, COMT, DAT1, FTO, KCNE1, MAOA, MC4R, MCHR2, NPY2R, NR3C1, Ob, PCSK9, and TAL1). Replicated findings across two or more independent samples were observed for the FTO and MC4R genes. Many of these gene products represent novel molecular targets for the pharmacological management of obesity that interact with each other and are not pharmacologically influenced by existing anti-obesity or antidepressant medications. The implications of these associations for future drug development are discussed, with an emphasis on recent evidence on the polygenic architecture of comorbid depression and obesity and on a precision-medicine approach to these conditions. Full article

Throughout the animal kingdom, our two chemical senses, olfaction and gustation, are defined by two primary factors: genomic architecture of the organisms and their living environment. During the past three years of the global COVID-19 pandemic, these two sensory modalities have drawn much attention at the basic science and clinical levels because of the strong association of olfactory and gustatory dysfunction with viral infection. Loss of our sense of smell alone, or together with a loss of taste, has emerged as a reliable indicator of COVID-19 infection. Previously, similar dysfunctions have been detected in a large cohort of patients with chronic conditions. The research focus remains on understanding the persistence of olfactory and gustatory disturbances in the post-infection phase, especially in cases with long-term effect of infection (long COVID). Also, both sensory modalities show consistent age-related decline in studies aimed to understand the pathology of neurodegenerative conditions. Some studies using classical model organisms show an impact on neural structure and behavior in offspring as an outcome of parental olfactory experience. The methylation status of specific odorant receptors, activated in parents, is passed on to the offspring. Furthermore, experimental evidence indicates an inverse correlation of gustatory and olfactory abilities with obesity. Such diverse lines of evidence emerging from basic and clinical research studies indicate a complex interplay of genetic factors, evolutionary forces, and epigenetic alterations. Environmental factors that regulate gustation and olfaction could induce epigenetic modulation. However, in turn, such modulation leads to variable effects depending on genetic makeup and physiological status. Therefore, a layered regulatory hierarchy remains active and is passed on to multiple generations. In the present review, we attempt to understand the experimental evidence that indicates variable regulatory mechanisms through multilayered and cross-reacting pathways. Our analytical approach will add to enhancement of prevailing therapeutic interventions and bring to the forefront the significance of chemosensory modalities for the evaluation and maintenance of long-term health. Full article

With the increasing popularity of genomic sequencing, breeders pay more attention to identifying the crucial molecular markers and quantitative trait loci for improving the body size and reproduction traits that could affect the production efficiency of pig-breeding enterprises. Nevertheless, for the Shaziling pig, a well-known indigenous breed in China, the relationship between phenotypes and their corresponding genetic architecture remains largely unknown. Herein, in the Shaziling population, a total of 190 samples were genotyped using the Geneseek Porcine 50K SNP Chip, obtaining 41857 SNPs for further analysis. For phenotypes, two body measurement traits and four reproduction traits in the first parity from the 190 Shaziling sows were measured and recorded, respectively. Subsequently, a genome-wide association study (GWAS) between the SNPs and the six phenotypes was performed. The correlation between body size and reproduction phenotypes was not statistically significant. A total of 31 SNPs were found to be associated with body length (BL), chest circumference (CC), number of healthy births (NHB), and number of stillborns (NSB). Gene annotation for those candidate SNPs identified 18 functional genes, such as GLP1R, NFYA, NANOG, COX7A2, BMPR1B, FOXP1, SLC29A1, CNTNAP4, and KIT, which exert important roles in skeletal morphogenesis, chondrogenesis, obesity, and embryonic and fetal development. These findings are helpful to better understand the genetic mechanism for body size and reproduction phenotypes, while the phenotype-associated SNPs could be used as the molecular markers for the pig breeding programs. Full article

Paralleling the increasing trends of maternal obesity, gestational diabetes (GDM) has become a global health challenge with significant public health repercussions. In addition to short-term adverse outcomes, such as hypertensive pregnancy disorders and fetal macrosomia, in the long term, GDM results in excess cardiometabolic morbidity in both the mother and child. Recent data suggest that women with GDM are characterized by notable phenotypic and genotypic heterogeneity and that frequencies of adverse obstetric and perinatal outcomes are different between physiologic GDM subtypes. However, as of yet, GDM treatment protocols do not differentiate between these subtypes. Mapping the genetic architecture of GDM, as well as accurate phenotypic and genotypic definitions of GDM, could potentially help in the individualization of GDM treatment and assessment of long-term prognoses. In this narrative review, we outline recent studies exploring genetic risk factors of GDM and later type 2 diabetes (T2D) in women with prior GDM. Further, we discuss the current evidence on gene–lifestyle interactions in the development of these diseases. In addition, we point out specific research gaps that still need to be addressed to better understand the complex genetic and metabolic crosstalk within the mother–placenta–fetus triad that contributes to hyperglycemia in pregnancy. Full article

Numerous epidemiological studies place patients with T2D at a higher risk for cancer. Many risk factors, such as obesity, ageing, poor diet and low physical activity, are shared between T2D and cancer; however, the biological mechanisms linking the two diseases remain largely unknown. The advent of genome wide association studies (GWAS) revealed large numbers of genetic variants associated with both T2D and cancer. Most significant disease-associated variants reside in non-coding regions of the genome. Several studies show that single nucleotide polymorphisms (SNPs) at or near long non-coding RNA (lncRNA) genes may impact the susceptibility to T2D and cancer. Therefore, the identification of genetic variants predisposing individuals to both T2D and cancer may help explain the increased risk of cancer in T2D patients. We aim to investigate whether lncRNA genetic variants with significant diabetes and cancer associations overlap in the UAE population. We first performed an annotation-based analysis of UAE T2D GWAS, confirming the high prevalence of variants at or near non-coding RNA genes. We then explored whether these T2D SNPs in lncRNAs were relevant to cancer. We highlighted six non-coding genetic variants, jointly reaching statistical significance in T2D and cancer, implicating a shared genetic architecture between the two diseases in the UAE population. Full article

The coronavirus disease (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is characterized by a wide spectrum of clinical phenotypes ranging from asymptomatic to symptomatic with mild or moderate presentation and severe disease. COVID-19 susceptibility, severity and recovery have demonstrated high variability worldwide. Variances in the host genetic architecture may underlie the inter-individual and population-scale differences in COVID-19 presentation. We performed a genome-wide association analysis employing the genotyping data from AncestryDNA for COVID-19 patients of European descent and used asymptomatic subjects as the control group. We identified 621 genetic variants that were significantly distinct between asymptomatic and acutely symptomatic COVID-19 patients (multiple-testing corrected p-value < 0.001). These variants were found to be associated with pathways governing host immunity, such as interferon, interleukin and cytokine signalling, and known COVID-19 comorbidities, such as obesity and cholesterol metabolism. Further, our ancestry analysis revealed that the asymptomatic COVID-19 patients possess discernibly higher proportions of the Ancestral North Eurasian (ANE) and Eastern Hunter-Gatherer (EHG) ancestry, which was introduced to Europe through Bell Beaker culture (Yamnaya related) and lower fractions of Western Hunter-Gatherer (WHG) ancestry, while severely symptomatic patients have higher fractions of WHG and lower ANE/EHG ancestral components, thereby delineating the likely ancestral differences between the two groups. Full article