Search Results (58)

Obesity is a multifaceted disorder influenced by various factors, with heredity being a significant contributor. Bariatric surgery is the most effective long-term intervention for morbid obesity and associated comorbidities, while outcomes vary significantly across individuals. Recent studies indicate that genetic and molecular determinants, particularly alterations in the leptin–melanocortin signalling pathway involving the fat mass and obesity-associated gene (FTO), pro-opiomelanocortin (POMC), melanocortin 4 receptor (MC4R), leptin (LEP), and leptin receptor (LEPR), influence the efficacy of weight loss and metabolic adaptations post-surgery. This narrative review consolidates evidence from peer-reviewed papers available in PubMed and Scopus until July 2025. The emphasis was on novel research and systematic reviews examining genetic polymorphisms, gene–environment interactions, and outcomes following bariatric procedures such as Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG). Recent research emphasised the integration of genetic screening and precision medicine models into clinical bariatric workflows. Variants in FTO (e.g., rs9939609), MC4R (e.g., rs17782313), LEPR, and POMC are associated with diminished weight loss post-surgery, an increased likelihood of weight regain, and reduced metabolic enhancement. Patients with bi-allelic mutations in MC4R, POMC, or LEPR exhibited poor long-term outcomes despite receiving effective physical interventions. Furthermore, genes regulating mitochondrial metabolism (such as PGC1A), adipokine signalling (such as ADIPOQ), and glucose regulation (such as GLP1R) have been demonstrated to influence the body’s response to sugar and the extent of weight gain or loss. Two recent systematic reviews elucidate that candidate gene investigations are beneficial; however, larger genome-wide association studies (GWAS) and machine learning techniques are necessary to enhance predictive accuracy. Integrating genetic and molecular screening with bariatric surgery planning possesses significant therapeutic potential. Genotyping can assist in patient selection, procedural decisions, and medication additions, particularly for those with variants that influence appetite regulation or metabolic flexibility. Advancements in precision medicine, including the integration of polygenic risk scores, omics-based profiling, and artificial intelligence, will enhance the customisation of surgical interventions and extend the lifespan of individuals with severe obesity. The epigenetic regulators of energy balance DNA methylation, histone changes, and microRNAs that may affect individual differences in weight-loss patterns after bariatric surgery are also briefly contextualised. We discuss the concept that epigenetic modulation of gene expression, mediated by microRNAs in response to food and exercise, may account for variations in metabolic outcomes post-surgery. Full article

Obesity is a highly complex, multifactorial disease influenced by dynamic interactions among genetic, epigenetic, environmental, and behavioral determinants that explicitly position genetics as the core. While advances in multi-omic integration have revolutionized our understanding of adiposity pathways, translation into personalized clinical nutrition remains a critical challenge. This review systematically consolidates emerging insights into the molecular and nutrigenomic architecture of obesity by integrating data from large-scale GWAS, functional epigenomics, nutrigenetic interactions, and microbiome-mediated metabolic programming. The primary aim is to systematically organize and synthesize recent genetic and genomic findings in obesity, while also highlighting how these discoveries can be contextualized within precision nutrition frameworks. A comprehensive literature search was conducted across PubMed, Scopus, and Web of Science up to July 2024 using MeSH terms, nutrigenomic-specific queries, and multi-omics filters. Eligible studies were classified into five domains: monogenic obesity, polygenic GWAS findings, epigenomic regulation, nutrigenomic signatures, and gut microbiome contributions. Over 127 candidate genes and 253 QTLs have been implicated in obesity susceptibility. Monogenic variants (e.g., LEP, LEPR, MC4R, POMC, PCSK1) explain rare, early-onset phenotypes, while FTO (polygenic) and MC4R (monogenic mutations as well as common polygenic variants) represent major loci across populations. Epigenetic mechanisms, dietary composition, physical activity, and microbial diversity significantly recalibrate obesity trajectories. Integration of genomics, functional epigenomics, precision nutrigenomics, and microbiome science presents transformative opportunities for personalized obesity interventions. However, translation into evidence-based clinical nutrition remains limited, emphasizing the need for functional validation, cross-ancestry mapping, and AI-driven precision frameworks. Specifically, this review systematically identifies and integrates evidence from genomics, epigenomics, nutrigenomics, and microbiome studies published between 2000 and 2024, applying structured inclusion/exclusion criteria and narrative synthesis to highlight translational pathways for precision nutrition. Full article

Melanocortin receptors (MCRs) are responsible for various functions ranging from skin pigmentation, regulation of appetite, stress response and cognition, steroid synthesis, and energy balance to cellular regeneration and immunomodulation. The genetic polymorphism with tissue distribution ranging from the brain, limbic system, and adrenal cortex to neutrophils, monocytes, and macrophages is evident in MCRs. The mutations in MC1R, MC2R, MC3R, and MC4R genes are associated with risk of melanoma, familial glucocorticoid deficiency, obesity, and type 2 diabetes mellitus, respectively. Meanwhile, MC1R, MC2R, and MC5R genes are involved in the risk of major depressive disorder. Melanocortin receptors are involved in different inflammatory disorders, i.e., atopic dermatitis, autoimmune uveitis, sarcoidosis, respiratory diseases, multiple sclerosis, scleroderma, inflammatory bowel disease, amyotrophic lateral sclerosis, Alzheimer’s disease, arthritis, and reperfusion injury. Several newer therapeutic agents related to MCRs have numerous advantages over the current anti-inflammatory drugs, demonstrating therapeutic relevance. Among them, α-MSH analogs play a role in atopic dermatitis and scleroderma, and MC1R agonist Dersimelagon has shown effectiveness in systemic sclerosis. The FDA has recently approved the repository corticotropin injection (RCI) to treat sarcoidosis. The FDA has also approved various melanocortin agonists, i.e., Bremelanotide, Afamelanotide, and Setmelanotide, for the treatment of hypoactive sexual desire disorder, Erythropoietic protoporphyria, and obesity, due to pro-opiomelanocortin and leptin receptor deficiency, respectively. Therefore, this review aims to summarize the function and genetic polymorphism of melanocortin receptors, regulatory pathways involving MCRs, and the existing evidence of the prime effect of MCRs on inflammatory responses via different mechanisms and their potential therapeutic use in inflammatory diseases. Full article

Background: Patients diagnosed with melanoma are at increased risk of developing multiple primary melanomas (MPMs). Identifying clinical and genetic factors associated with MPM is critical for implementing personalized surveillance strategies. This study aims to describe the clinical, histopathological, and genetic characteristics of patients with MPM managed in a tertiary hospital and to contextualize findings within the current literature. Methods: We conducted a retrospective review of patients diagnosed with two or more primary melanomas between 2010 and 2023 at a tertiary dermatology unit. Demographic data, personal and family cancer history, phototype, melanoma characteristics, genetic testing, staging, treatments, and outcomes were collected. These data were compared with findings from the recent literature. Results: Thirteen patients (ten males, three females; median age: 59 years) were found to have a total of 33 melanomas. Most patients had Fitzpatrick phototype II and no immunosuppression. The number of melanomas per patient ranged from two to five. Synchronous lesions were observed in two patients. Common locations included the trunk and extremities. Histologically, 57% were in situ melanomas, and subsequent melanomas were generally thinner than the index lesion. Two patients showed progression to advanced disease. One patient was positive for MC1R mutation; the rest were negative or inconclusive. Additional phenotypic and environmental risk factors were extracted from patient records and are summarized as follows: Ten patients (76.9%) had Fitzpatrick skin phototype II, and three (23.1%) had phototype III. Chronic occupational sun exposure was reported in four patients (30.8%), while five (38.5%) recalled having suffered multiple sunburns during childhood or adolescence. Eight patients (61.5%) presented with a total nevus count exceeding 50, and five (38.5%) exhibited clinically atypical nevi. None of the patients reported use of tanning beds. Conclusions: Our findings are consistent with the existing literature indicating that patients with MPM often present with thinner subsequent melanomas and require long-term dermatologic follow-up. The inclusion of genetic testing and phenotypic risk factors enables stratified surveillance and supports the application of personalized medicine in melanoma management. Full article

Background/Objectives: The resistance mutations EGFR^{L858R/T790M/C797S} in epidermal growth factor receptor (EGFR) are key factors in the reduced efficacy of Osimertinib. Predicting the inhibitory effects of Osimertinib derivatives against these mutations is crucial for the development of more effective inhibitors. This study aims to predict the inhibitory effects of Osimertinib derivatives against EGFR^{L858R/T790M/C797S} mutations. Methods: Six models were established using heuristic method (HM), random forest (RF), gene expression programming (GEP), gradient boosting decision tree (GBDT), polynomial kernel function support vector machine (SVM), and mixed kernel function SVM (MIX-SVM). The descriptors for these models were selected by the heuristic method or XGBoost. Comprehensive learning particle swarm optimizer was adopted to optimize hyperparameters. Additionally, the internal and external validation were performed by leave-one-out cross-validation ($Q_{LOO}^2$), 5-fold cross validation ($Q_{5-fold}^2$) and concordance correlation coefficient (CCC), $Q_{F1}^2$, and $Q_{F2}^2$. The properties of novel EGFR inhibitors were explored through molecular docking analysis. Results: The model established by MIX-SVM whose kernel function is a convex combination of three regular kernel functions is best: $R^2$ and RMSE for training set and test set are 0.9445, 0.1659 and 0.9490, 0.1814, respectively; $Q_{LOO}^2$, $Q_{5-fold}^2$, CCC, $Q_{F1}^2$, and $Q_{F2}^2$ are 0.9107, 0.8621, 0.9835, 0.9689, and 0.9680. Based on these results, the IC₅₀ values of 162 newly designed compounds were predicted using the HM model, and the top four candidates with the most favorable physicochemical properties were subsequently validated through PEA. Conclusions: The MIX-SVM method will provide useful guidance for the design and screening of novel EGFR^{L858R/T790M/C797S} inhibitors. Full article

Mammals display a wide range of coat colors, with the melanocortin 1 receptor gene (MC1R) playing a pivotal role in the genetic regulation of pigmentation. In this study, we investigated MC1R genetic variants in goat populations from four Asian countries to identify genetic factors associated with coat color variation. The complete coding sequence of MC1R was analyzed to detect variants and determine genotypes in goats from Nepal (n = 122), the Philippines (n = 110), Cambodia (n = 30), and Kazakhstan (n = 30). Seven variants were identified, three of which were novel, while four had been previously reported in other goat populations. Among the novel variants, a frameshift mutation (c.147delG) unique to Nepalese goats was predicted to cause substantial disruption of the MC1R protein structure, suggesting its potential role in coat color determination. Additionally, two known missense variants (c.676A > G and c.801C > G) were inferred to affect MC1R function and may contribute to pigmentation variation. Further investigations with larger sample sizes are warranted to clarify the phenotypic effects of these genotypic variants and to better understand the genetic basis of coat color in goats. Full article

Abnormal expressions and genetic mutations of EGFR are broadly involved in the progression of many human solid tumors, which has led to the development of small molecule inhibitors (TKIs). However, patients’ tumors usually develop resistance to targeted therapeutic TKIs after a period of treatment, mostly due to secondary mutations in EGFR. To date, three major and prevalent point mutations in EGFR, including L858R, T790M, and C797S, impact the use of TKIs in non-small cell lung cancer patients. Although at least four generations of TKIs have been designed and developed by targeting these mutations, how each mono, dual, or triple variant responds to clinical TKIs remains largely undeciphered. To fill this gap, we constructed a series of EGFR mutants and assessed their responses to clinical TKIs in vitro. The first-generation TKI, erlotinib, completely blocked the autophosphorylation of WT, L858R, C797S, and C797S/L858R, but only partially, if at all, in EGFR containing the T790M mutation alone or in combination. The third generation, osimertinib, completely abolished the autophosphorylation of WT, T790M, L858R, and T790M/L858R. It also significantly inhibited C797S and C790S/L858R, but had no effect on T790M/C797S or T790M/C797S/L858R. EAI045, as the fourth-generation TKI, almost completely inhibited WT and all mutants in complete growth media, but EGF-mediated phosphorylation of WT, C797S, and C797S/L858R were only partially inhibited in quiescence media, while the other mutants were fully inhibited. Furthermore, the abolishment of the enhanced tolerance to Dox in cells transiently expressing T790M/L858R and T790M/C797S/L858R by EAI045 suggests that their enhanced autophosphorylation is involved in their resistant ability. These findings provide some insights into how patients carrying typical mutations should be correctly and efficiently treated and why patients present side effects (because of non-specific inhibitory effects on cells without EGFR mutations). Full article

Background/Objectives: Severe early-onset obesity is a complex condition shaped by genetic and metabolic influences. The melanocortin 4 receptor (MC4R) gene plays a crucial role in energy balance, and pathogenic variants are associated with monogenic forms of obesity. This study aims to examine the clinical, metabolic, and genetic characteristics of a patient with severe early-onset obesity and his family, to assess the contribution of an MC4R variant to the observed phenotype. Methods: A 22-year-old male with severe obesity, first recognized at age 3, underwent detailed clinical, metabolic, and genetic evaluations. Laboratory assessments included insulin, lipid profile, uric acid, and IGF-1 levels. Whole-exome sequencing (WES) was performed on the patient and selected family members to identify potential pathogenic variants associated with obesity. Results: Clinical assessment revealed a body mass index (BMI) of 44.68 kg/m², hyperinsulinemia (98.2 µIU/mL), prediabetes (HbA1c: 5.85%), dyslipidemia, hyperuricemia (421.0 µmol/L), and elevated IGF-1 levels (646.7 ng/mL). WES identified a heterozygous MC4R:c.216C>G (p.Asn72Lys) variant present in the patient, his mother, and maternal relatives. This variant, with a population frequency of 0.0004%, is predicted as likely pathogenic by SIFT, MutationTaster, and PrimateAI. However, its segregation pattern suggests a complex inheritance mechanism rather than classical autosomal dominant or recessive inheritance. Conclusions: Early genetic testing in individuals with severe obesity is essential for guiding personalized treatment strategies. Although the MC4R:c.216C>G variant may contribute to the patient’s metabolic profile, further functional studies are required to confirm its pathogenicity and elucidate its role in obesity pathogenesis. Full article

Genetic obesity results from loss-of-function mutations, including those affecting the leptin–melanocortin system, which regulates body weight. Pro-opiomelanocortin (POMC)-derived neurohormones act as ligands for melanocortin receptors (MCRs), regulating the leptin–melanocortin pathway through protein–protein interactions. Loss-of-function mutations in the genes encoding POMC, MC3R, and MC4R can lead to the dysregulation of energy expenditure and feeding balance, early-onset obesity, and developmental dysregulation. Recent studies have identified new genetic regulatory mechanisms and potential biomarker regions for the POMC gene and MC4R secondary messenger pathway associated with obesity. Recent advances in crystal structure studies have enhanced our understanding of the protein interactions in this pathway. This narrative review focuses on recent developments in two key areas related to POMC regulation and the leptin–melanocortin pathway: (1) genetic variations in and functions of POMC, and (2) MC3R and MC4R variants that lead to genetic obesity in humans. Understanding these novel mutations in POMC and MC4R/MC3R, as well as their structural and intracellular mechanisms, may help identify strategies for the treatment and diagnosis of obesity, particularly childhood obesity. Full article

Onychostoma macrolepis is not only a protected Cyprinid species in the wild but also an emerging commercial aquaculture fish in China. The objective of this research was to genetically modify the genes associated with commercial traits by CRISPR/Cas9 for the protection and utilization of the germplasm resources of O. macrolepis. To that end, one-cell stage embryos were obtained via hormone-induced ovulation and artificial insemination in O. macrolepis. Eight genes related to body color, growth, intermuscular bone, and sex differentiation were mutated in O. macrolepis using the CRISPR/Cas9 system by microinjection of gRNA/Cas9 mRNA. The optimal dose of gRNA/Cas9 mRNA was determined by injection of different concentrations of tyr (tyrosinase)-gRNA/Cas9 and examination of the mutation rate and hatching rate of embryos. Indels were detected by T7 endonuclease I digestion and Sanger sequencing. F0 mutants with high mutation rates were selected for phenotype analyses. Disruption of body color gene tyr, mpv17 (mitochondrial inner membrane protein MPV17), and csf1ra (colony-stimulating factor 1 receptor, a) resulted in obvious phenotype with decreased or even absence of melanophores, iridophores, and xanthophores, respectively. Mutation of mstnb (myostatin b) led to improved growth performance. Mutation of mc4r (melanocortin 4 receptor) led to no obvious phenotype. Mutation of runx2b (RUNX family transcription factor 2b) and bmp6 (bone morphogenetic protein 6) resulted in decreased or absence of intermuscular bones, as revealed by alizarin red S staining. Mutation of cyp19a1a (cytochrome P450, family 19, subfamily A, polypeptide 1a) resulted in ovarian degeneration as revealed by gonadal histological examination. Therefore, this study successfully obtained mutants with obvious phenotypes of genes associated with body color, growth, intermuscular bone, and sex differentiation by CRISPR/Cas9 in O. macrolepis. Full article

The Chinese Tan sheep is a unique breed of sheep that is typical throughout China, mainly used for fur and meat production. They are widely distributed in northwestern China and are famous for their lambskin and shiny white curly wool. In this study, the phenotypic traits of wool length, birth weight, and head coat color were evaluated in 256 Chinese Tan sheep breeds. Whole genome sequencing generated 23.67 million high-quality SNPs for genome-wide association studies (GWAS). We identified 208 significant SNPs associated with birth wool length, implicating RAD50, MACROD2, SAMD5, SASH1, and SPTLC3 as potential candidate genes for this trait. For birth weight, 1056 significant SNPs, with 76.89% of them located on chromosome 2, were identified by GWAS, and XPA, INVS, LOC121818504, GABBR2, LOC101114941, and LOC106990096 were identified as potential candidate genes for birth weight. The GWAS for head coat color identified 1424 significant SNPs across three chromosomes, with 99.65% on chromosome 14, and SPIRE2, TCF25, and MC1R as candidate genes were found to be possibly involved in the development of the black-headed coat color in sheep. Furthermore, we selected head coat color as a representative trait and performed an independent test of our GWAS findings through multiplex PCR SNP genotyping. The findings validated five mutation sites in chromosome 14 (14,251,947 T>A, 14,252,090 G>A, 14,252,158 C>T, 14,252,329 T>G, and 14,252,464 C>T) within the exon1 of the MC1R gene (517 bp), as identified by GWAS in an additional 102 Tan sheep individuals, and revealed that black-headed sheep predominantly exhibited heterozygous genotypes, possibly contributing to their color change. Our results provide a valuable foundation for further study of these three economically important traits, and enhance our understanding of genetic structure and variation in Chinese Tan sheep. Full article

Plumage color is one of the most important traits characterizing chicken breeds. Black-boned chickens constitute a specific group of breeds with a unique phenotype. One of the representatives is the Indonesian Ayam Cemani. The extraordinary black phenotype results from a specific chromosomal rearrangement. We used complete CDS of crucial color-related gene MC1R, which plays a key role in melanin distribution but has not been previously studied in Ayam Cemani. It turned out that Ayam Cemani individuals possess a newly found non-synonymous mutation G355A resulting in amino acid substitution D119N. Together with the presence of G274A (E92K), the new missense variant enabled us to distinguish a new extended black allele at the E locus. All of the investigated birds were heterozygous in terms of the new mutation. Previous studies and our own results indicate a high level of genetic variation within the MC1R gene within and between chicken breeds. Besides the key mutations that make it possible to distinguish particular major alleles, there are also numerous substitutions that give haplotypes more characteristics for individual breeds. Full article

Four dominant coat color phenotypes are found in fallow deer (Dama dama). Brown is the most common. Black, menil, and white occur with varying frequencies. In order to gain insights into the molecular genetic background of these phenotypes, 998 fallow animals (772 brown, 62 black, 126 menil, and 38 white) were examined for mutations in the ASIP, MC1R, TYR, and SLC45A2 genes. In ASIP, two mutations (ASIP-M-E2, located at the boundary from exon 2 to intron 2; and ASIP-M-E3, an InDel of five nucleotides) were found, leading to black fallow deer being either homozygous or heterozygous in combination. There were also two mutations found in MC1R. Whereby the mutation MC1R-M1 (leucine to proline, L48P) homozygous leads to a white coat, while the mutation MC1R-M2 (glycine to aspartic acid, G236D) homozygous is associated with the menil phenotype. When both mutations occur together in a heterozygous character state, it results in a menil coat. Since the mutations in the two genes are only present alternatively, 36 genotypes can be identified that form color clusters to which all animals can be assigned. No mutations were found in the TYR and SLC45A2 genes. Our investigations demonstrate that the four dominant coat colors in fallow deer can be explained by ASIP and MC1R mutations only. Full article

The melanocortin 4 receptor (MC4R) gene plays a central role in regulating energy homeostasis and food intake in livestock, thereby affecting their economic worth and growth. In a previous study, the p.T117M mutation in the sheep MC4R gene, which leads to the transition of threonine to methionine, was found to affect the body weight at six months and the average daily gain in Hu sheep. However, there are still limited studies on the frequency of the sheep p.T117M missense mutation globally, and the underlying cellular mechanism remains elusive. Therefore, this study first used WGS to investigate the distribution of the MC4R gene p.T117M mutation in 652 individuals across 22 breeds worldwide. The results showed that the mutation frequency was higher in European breeds compared with Chinese sheep breeds, particularly in Poll Dorset sheep (mutation frequency > 0.5). The p.T117M mutation occurs in the first extracellular loop of MC4R. Mechanistically, the basal activity of the mutated receptor is significantly increased. Specifically, upon treatment with α-MSH and ACTH ligands, the cAMP and MAPK/ERK signaling activation of M117 MC4R is enhanced. These results indicate that the T117M mutation may change the function of the gene by increasing the constitutive activity and signaling activation of cAMP and MAPK/ERK, and, thus, may regulate the growth traits of sheep. In conclusion, this study delved into the global distribution and underlying cellular mechanisms of the T117M mutation of the MC4R gene, establishing a scientific foundation for breeding sheep with superior growth, thereby contributing to the advancement of the sheep industry. Full article

Ultraviolet (UV) radiation plays a crucial role in the development of melanoma and non-melanoma skin cancers. The types of UV radiation are differentiated by wavelength: UVA (315 to 400 nm), UVB (280 to 320 nm), and UVC (100 to 280 nm). UV radiation can cause direct DNA damage in the forms of cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts (6-4PPs). In addition, UV radiation can also cause DNA damage indirectly through photosensitization reactions caused by reactive oxygen species (ROS), which manifest as 8-hydroxy-2′-deoxyguanine (8-OHdG). Both direct and indirect DNA damage can lead to mutations in genes that promote the development of skin cancers. The development of melanoma is largely influenced by the signaling of the melanocortin one receptor (MC1R), which plays an essential role in the synthesis of melanin in the skin. UV-induced mutations in the BRAF and NRAS genes are also significant risk factors in melanoma development. UV radiation plays a significant role in basal cell carcinoma (BCC) development by causing mutations in the Hedgehog (Hh) pathway, which dysregulates cell proliferation and survival. UV radiation can also induce the development of squamous cell carcinoma via mutations in the TP53 gene and upregulation of MMPs in the stroma layer of the skin. Full article