Identification and validation of novel breed-specific biomarker for the purpose of village chicken authentication using genomics approaches.

Local village chicken, or "Ayam kampung" as it's known in Malaysia, is considered a premium chicken breed with a higher price than other chicken breeds. As a result of their comparable appearances and sizes, colored broiler chickens are often sold as village chickens, which is a form of food fraud that can result in a 3- to 4-fold rise in profit. Therefore, developing a breed-specific authentication method is crucial for preventing food fraud in the poultry industry. This study aims to investigate the genetic diversity of village chickens from other commercial chicken breed populations available in the market (broiler [Cobb], colored broiler [Hubbard], and layer [DeKalb]) to identify breed-specific DNA fragments as biomarkers for village chicken authentication. The Whole-genome sequencing and mutation calling of 12 chickens (3 chickens/breed) led to the identification of a total of 73,454,654 single nucleotide polymorphisms (SNP) and 8,762,338 insertion and deletions (InDel) variants, with more variants detected in the village chicken population (6,346,704 SNPs; 752,408 InDels) compared to commercial breeds. Therefore, this study revealed that village chickens were more genetically variable compared to other breeds in Malaysia. Furthermore, the breed-specific genomic region located on chromosome 1 (1:84,405,652) harboring SNP (C-T) with high discrimination power was discovered and validated which can be considered as a novel breed-specific biomarker to develop a method for accurate authentication of village chickens in Malaysia. This authentication method offers potentialw applications in the chicken industry and food safety.

KCNG4 Genetic Variant Linked to Migraine Prevents Expression of KCNB1.

Migraines are a common type of headache affecting around 15% of the population. The signalling pathways leading to migraines have not been fully understood, but neuronal voltage-gated ion channels, such as KCNG4, have been linked to this pathology. KCNG4 (Kv6.4) is a silent member of the superfamily of voltage-gated potassium (Kv) channels, which expresses in heterotetramers with members of the KCNB (Kv2) family. The genetic variant Kv6.4-L360P has previously been linked to migraines, but their mode of action remains unknown. Here, we characterized the molecular characteristics of Kv6.4-L360P when co-expressed with Kv2.1. We found that Kv6.4-L360P almost completely abolishes Kv2 currents, and we propose that this mechanism in the trigeminal system, linked to the initiation of migraine, leads to the pathology.

Genetic Variations and Nonalcoholic Fatty Liver Disease: Field Synopsis, Systematic Meta-Analysis, and Epidemiological Evidence.

Objective: To systematically summarize the published literature on the genetic variants associated with nonalcoholic fatty liver disease (NAFLD). Methods: Literature from Web of Science, PubMed, and Embase between January 1980 and September 2022 was systematically searched. Meta-analyses of the genetic variants were conducted using at least five data sources. The epidemiologic credibility of the significant associations was graded using the Venice criteria. Results: Based on literature screening, 399 eligible studies were included, comprising 381 candidate gene association, 16 genome-wide association, and 2 whole-exome sequencing studies. We identified 465 genetic variants in 173 genes in candidate gene association studies, and 25 genetic variants in 17 genes were included in the meta-analysis. The meta-analysis identified 11 variants in 10 genes that were significantly associated with NAFLD, with cumulative epidemiological evidence of an association graded as strong for two variants in two genes ( HFE, TNF), moderate for four variants in three genes ( TM6SF2, GCKR, and ADIPOQ), and weak for five variants in five genes ( MBOAT7, PEMT, PNPLA3, LEPR, and MTHFR). Conclusion: This study identified six variants in five genes that had moderate to strong evidence of an association with NAFLD, which may help understand the genetic architecture of NAFLD risk.

The Outcome of Metabolic and Bariatric Surgery in Morbidly Obese Patients with Different Genetic Variants Associated with Obesity: A Systematic Review.

Metabolic and bariatric surgery (MBS) effectively treats obesity and related comorbidities, though individual responses vary. This systematic review examines how genetic variants influence MBS outcomes in morbidly obese patients. A comprehensive search in PubMed, Embase, Medline, and the Cochrane Library identified 1572 studies, with 52 meeting the inclusion criteria. Two reviewers independently filtered and selected studies, including relevant cross-references. Research focused on polymorphisms in genes such as UCP2, UCP3, 5-HT2C, MC4R, FKBP5, FTO, CAT haplotypes, LYPAL-1, PTEN, FABP-2, CNR1, LEP656, LEP223, GLP-1R, APOA-1, APOE, ADIPOQ, IL-6, PGC1a, TM6SF2, MBOAT7, PNPLA3, TCF7L2, ESR1, GHSR, GHRL, CD40L, DIO2, ACSL5, CG, TAS2R38, CD36, OBPIIa, NPY, BDNF, CLOCK, and CAMKK2. Most studies explored associations with post-surgery weight loss, while some examined metabolic, cardiovascular, taste, and eating behavior effects as well. Understanding the role of genetic factors in weight loss and metabolic outcomes post-MBS can help tailor personalized treatment plans for improved efficacy and long-term success. Further research with larger sample sizes and extended follow-up is needed to clarify the effects of many genetic variants on MBS outcomes in morbidly obese patients.

Leveraging human-mouse studies to advance the genetics of hearing impairment in Africa.

Mouse models are used extensively to understand human pathobiology and mechanistic functions of disease-associated loci. However, in this review, we investigate the potential of using genetic mouse models to identify genetic markers that can disrupt hearing thresholds in mice and then target the hearing-enriched orthologues and loci in humans. Currently, little is known about the real prevalence of genes that cause hearing impairment (HI) in Africa. Pre-screening mouse cell lines to identify orthologues of interest has the potential to improve the genetic diagnosis for HI in Africa to a significant percentage, for example, 10-20%. Furthermore, the functionality of a candidate gene derived from mouse screening with heterogeneous genetic backgrounds and multi-omic approaches can shed light on the molecular, genetic heterogeneity and plausible mode of inheritance of a gene in hearing-impaired individuals especially in the absence of large families to investigate.

MFRP variations cause nanophthalmos in five Chinese families with distinct phenotypic diversity.

Purpose: Nanophthalmos is a congenital ocular structural anomaly that can cause significant visual loss in children. The early diagnosis and then taking appropriate clinical and surgical treatment remains a challenge for many ophthalmologists because of genetic and phenotypic heterogeneity. The objective of this study is to identify the genetic cause of nanophthalmos in the affected families and analyze the clinical phenotype of nanophthalmos with MFRP gene variation (Microphthalmia, isolated; OMIM#611040 and Nanophthalmos 2; OMIM#609549, respectively). Methods: Comprehensive ophthalmic examinations were performed on participants to confirm the phenotype. The genotype was identified using whole exome sequencing, and further verified the results among other family members by Sanger sequencing. The normal protein structure was constructed using Alphafold. Mutant proteins were visualized using pymol software. Pathogenicity of identified variant was determined by in silico analysis and the guidelines of American College of Medical Genetics and Genomics (ACMG). The relationship between genetic variants and clinical features was analyzed. Results: Five nanophthalmos families were autosomal recessive, of which four families carried homozygous variants and one family had compound heterozygous variants in the MFRP gene. Both family one and family three carried the homozygous missense variant c.1486G>A (p.Glu496Lys) in the MFRP gene (Clinvar:SCV005060845), which is a novel variant and evaluated as likely pathogenic according to the ACMG guidelines and in silico analysis. The proband of family one presented papilloedema in both eyes, irregular borders, thickened retinas at the posterior pole, tortuous and dilated retinal vessels, and indistinguishable arteries and veins, while the proband of family three presented uveal effusion syndrome-like changes in the right eye. In families one and 3, despite carrying the same gene variant, the probands had completely different clinical phenotypes. The homozygous nonsense variant c.271C>T (p.Gln91Ter) (Clinvar:SCV005060846) of the MFRP gene was detected in family 2, presenting shallow anterior chamber in both eyes, pigmentation of peripheral retina 360° from the equator to the serrated rim showing a clear demarcation from the normal retina in the form of strips. Family four proband carried the homozygous missense variant c.1411G>A (p.Val471Met) in the MFRP gene (Clinvar:SCV005060847), family five proband carried compound heterozygous missense variants c.1486G>A (p.Glu496Lys) and c.602G>T (p.Arg201Leu) in the MFRP gene (Clinvar:SCV005060848), which is a novel variant and evaluated as likely pathogenic according to the ACMG guidelines and in silico analysis, and they all presented clinically with binocular angle-closure glaucoma, family four also had retinal vein occlusion in the right eye during the follow-up. Conclusion: In this study, pathogenic variants of the MFRP gene were detected in five nanophthalmos families, including two novel variants. It also revealed a distinct phenotypic diversity among five probands harboring variants in the MFRP gene. Our findings extend the phenotype associated with MFRP variants and is helpful for ophthalmologists in early diagnosis and making effective treatment and rehabilitation strategies.

Association between gut microbiota and hepatocellular carcinoma and biliary tract cancer: A mendelian randomization study.

BACKGROUND: An increasing number of studies have begun to discuss the relationship between gut microbiota and diseases, yet there is currently a lack of corresponding articles describing the association between gut microbiota and hepatocellular carcinoma (HCC) and biliary tract cancer (BTC). This study aims to explore the relationship between them using Mendelian randomization (MR) analysis method. AIM: To assess the relationship between gut microbiota and HCC and BTC. METHODS: We obtained Genome-wide association study (GWAS) data for the gut microbiome from the intestinal microbiota genomic library (MiBioGen, https://mibiogen.gcc.rug.nl/). Additionally, we accessed data pertaining to HCC and BTC from the IEU open GWAS platform (https://gwas.mrcieu.ac.uk/). Our analysis employed fundamental instrumental variable analysis methods, including inverse-variance weighted, MR and Egger. To ensure the dependability of the results, we subjected the results to tests for multiple biases and heterogeneity. RESULTS: During our investigation, we discovered 11 gut microbiota linked to an increased risk to BTC and HCC. The former included the genus Eubacterium hallii group (P = 0.017), Candidatus Soleaferrea (P = 0.034), Flavonifractor (P = 0.021), Lachnospiraceae FCS020 (P = 0.034), the order Victivallales (P = 0.018), and the class Lentisphaeria (P = 0.0.18). The latter included the genus Desulfovibrio (P = 0.042), Oscillibacter (P = 0.023), the family Coriobacteriaceae (P = 0.048), the order Coriobacteriales (P = 0.048), and the class Coriobacteriia (P = 0.048). Furthermore, in BTC, we observed 2 protective gut microbiota namely the genus Dorea (P = 0.041) and Lachnospiraceae ND3007 group (P = 0.045). All results showed no evidence of multiplicity or heterogeneity. CONCLUSION: This study explores a causal link between gut microbiota and HCC and BTC. These insights may enhance the mechanistic knowledge of microbiota-related HCC and BTC pathways, potentially informing therapeutic strategies.

Genetic and Epigenetic Association of FOXP3 with Papillary Thyroid Cancer Predisposition.

Papillary thyroid cancer (PTC) is the most common type of thyroid malignancy with an increased female incidence ratio. The specific traits of X chromosome inheritance may be implicated in gender differences of PTC predisposition. The aim of this study was to investigate the association of two X-linked genes, Forkhead Box P3 (FOXP3) and Protein Phosphatase 1 Regulatory Subunit 3F (PPP1R3F), with PTC predisposition and gender disparity. One hundred thirty-six patients with PTC and an equal number of matched healthy volunteers were enrolled in the study. Genotyping for rs3761548 (FOXP3) and rs5953283 (PPP1R3F) was performed using polymerase chain reaction-restriction fragment length polymorphism assay (PCR-RFLP). The methylation status of FOXP3 was assessed using the combined bisulfite restriction analysis (COBRA) method. The SPSS software was used for statistical analyses. Gender stratification analysis revealed that the CA and AA genotypes and the A allele of FOXP3 rs3761548 variant are associated with PTC predisposition only in females. Moreover, different methylation status was observed up to the promoter locus of FOXP3 between PTC female patients, carrying the CA and CC genotype, and controls. Both revealed associations may explain the higher PTC incidence in females through reducing FOXP3 expression as reported in immune related blood cells.

Hereditary Gastrointestinal Tumor Syndromes: When Risk Comes with Your Genes.

Despite recent campaigns for screening and the latest advances in cancer therapy and molecular biology, gastrointestinal (GI) neoplasms remain among the most frequent and lethal human tumors. Most GI neoplasms are sporadic, but there are some well-known familial syndromes associated with a significant risk of developing both benign and malignant GI tumors. Although some of these entities were described more than a century ago based on clinical grounds, the increasing molecular information obtained with high-throughput techniques has shed light on the pathogenesis of several of them. The vast amount of information gained from next-generation sequencing has led to the identification of some high-risk genetic variants, although others remain to be discovered. The opportunity for genetic assessment and counseling in these families has dramatically changed the management of these syndromes, though it has also resulted in significant psychological distress for the affected patients, especially those with indeterminate variants. Herein, we aim to summarize the most relevant hereditary cancer syndromes involving the stomach and colon, with an emphasis on new molecular findings, novel entities, and recent changes in the management of these patients.

Genetic Variants of the Receptor Activator Nuclear of κB Ligand Gene Increase the Risk of Rheumatoid Arthritis in a Mexican Mestizo Population: A Case-Control Study.

The Receptor Activator Nuclear of κB Ligand (RANKL) plays an important function in immune responses, activating osteoclast cells and unchanged bone resorption, which in turn leads to bone erosion and inflammation. Genetic variants in the promoter region of the RANKL gene could lead to a higher risk of rheumatoid arthritis (RA). OBJECTIVE: To assess the association of rs9533155 (-693C>G) and rs9533156 (-643T>C) genetic variants with RA risk. METHODS: A case-control study was carried out. A total of 94 patients with RA (RA group) and 134 subjects without any rheumatologic disease (control group) were included. Genetic DNA was extracted from peripheral white blood cells (leukocytes). Genetic variant rs9533155 (-693C>G) was screened by an approach based on Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP), while rs9533156 (-643T>C) was screened using quantitative polymerase chain reaction (qPCR) with TaqMan probes. RANKL serum levels were measured by ELISA. RESULTS: For rs9533155 (-693C>G), the polymorphic homozygous genotype frequencies (CC) were higher in the RA group (p = 0.006). Individuals carrying the risk genotype presented higher levels of serum RANKL. Carriers of the polymorphic homozygous genotype in the dominant model (CC vs. CG + GG) had an increased risk of developing RA (OR: 1.8, 95% CI 1.04 to 3.1). No association between rs9533156 (-643T>C) and the haplotypes with RA risk was observed. CONCLUSION: The rs9533155 (-693C>G) genetic variant exhibits a potential role in RA risk. The studied population had no association with the rs9533156 (-643T>C) genetic variant.

Uncovering newly identified aldehyde dehydrogenase 2 genetic variants that lead to acetaldehyde accumulation after an alcohol challenge.

BACKGROUND: Aldehyde dehydrogenase 2 (ALDH2) is critical for alcohol metabolism by converting acetaldehyde to acetic acid. In East Asian descendants, an inactive genetic variant in ALDH2, rs671, triggers an alcohol flushing response due to acetaldehyde accumulation. As alcohol flushing is not exclusive to those of East Asian descent, we questioned whether additional ALDH2 genetic variants can drive facial flushing and inefficient acetaldehyde metabolism using human testing and biochemical assays. METHODS: After IRB approval, human subjects were given an alcohol challenge (0.25 g/kg) while quantifying acetaldehyde levels and the physiological response (heart rate and skin temperature) to alcohol. Further, by employing biochemical techniques including human purified ALDH2 proteins and transiently transfected NIH 3T3 cells, we characterized two newly identified ALDH2 variants for ALDH2 enzymatic activity, ALDH2 dimer/tetramer formation, and reactive oxygen species production after alcohol treatment. RESULTS: Humans heterozygous for rs747096195 (R101G) or rs190764869 (R114W) had facial flushing and a 2-fold increase in acetaldehyde levels, while rs671 (E504K) had facial flushing and a 6-fold increase in acetaldehyde levels relative to wild type ALDH2 carriers. In vitro studies with recombinant R101G and R114W ALDH2 enzyme showed a reduced efficiency in acetaldehyde metabolism that is unique when compared to E504K or wild-type ALDH2. The effect is caused by a lack of functional dimer/tetramer formation for R101G and decreased Vmax for both R101G and R114W. Transiently transfected NIH-3T3 cells with R101G and R114W also had a reduced enzymatic activity by ~ 50% relative to transfected wild-type ALDH2 and when subjected to alcohol, the R101G and R114W variants had a 2-3-fold increase in reactive oxygen species formation with respect to wild type ALDH2. CONCLUSIONS: We identified two additional ALDH2 variants in humans causing facial flushing and acetaldehyde accumulation after alcohol consumption. As alcohol use is associated with a several-fold higher risk for esophageal cancer for the E504K variant, the methodology developed here to characterize ALDH2 genetic variant response to alcohol can lead the way precision medicine strategies to further understand the interplay of alcohol consumption, ALDH2 genetics, and cancer.

Bi-directional two-sample Mendelian randomization identifies causal association of depression with temporomandibular disorders.

BACKGROUND: Depression and anxiety have been suggested to be associated with temporomandibular disorders (TMD) in observational studies. However, the causal association and the direction in the relationship between depression/anxiety and TMD remain unknown. OBJECTIVES: This study investigated the potential causal relationship between depression/anxiety and TMD with two-sample bi-directional Mendelian randomization (MR). METHODS: Summary statistics of depression (N = 500 199), anxiety disorder (N = 17 310) and TMD (N = 195 930) were sourced from large-scale genome-wide association studies (GWAS). The primary Mendelian randomization (MR) estimation employed the inverse-variance weighted meta-analysis (IVW). Additional MR sensitivity methods and multivariate MR (MVMR) were applied to address pleiotropy. RESULTS: IVW results indicated a causal effect of genetically predicted depression on TMD (OR = 1.887, 95% CI = 1.504-2.367, p < .001), which was supported by other sensitivity MR approaches. MVMR results suggested that the negative effect of depression on TMD persisted after conditioning on other potential confounders. The association of anxiety disorder with TMD was not supported by our findings. In the reverse direction, we did not find compelling evidence suggesting the causal effect of TMD on depression and anxiety disorder. CONCLUSIONS: The present study suggests a potential causal association between genetic liability for depression and the risk of TMD. Our MR findings align with prior epidemiological research, underscoring the significance of early detection and prevention of depression in the treatment of TMD.

Allelic frequency of pathogenic α1-antitrypsin variants in the Japanese population: Results from a survey of open Japanese genetic variation databases.

α1-antitrypsin deficiency (AATD) is a hereditary disorder with a global prevalence that differs across regions. AATD is highly prevalent in Europe and North America but rarely found in Asian countries, including Japan, possibly because of the founder effect of the pathogenic SERPINA1 variants PI*Z and PI*S. However, AATD remains underdiagnosed even in high-prevalence and low-prevalence regions, possibly because of lack of awareness. In this study, we surveyed open Japanese genetic variation databases to estimate AATD prevalence in Japan. We identified allelic frequencies (AFs) of 5 among the 14 major pathogenic SERPINA1 variants from three datasets, collectively derived from 63,119 Japanese participants. The mean AF was determined to be 8.56 × 10-4 (95% confidence interval [CI]: 6.43 × 10-4 to 1.12 × 10-3). Given that this represents the entire Japanese population, one AATD patient was speculated to be born per 1.37 × 106 births (95% CI: 7.97 × 105 to 2.42 × 106) in Japan. Our results support the prevailing notion that AATD is extremely rare in Japan.

Genetic variants of dectin-1 and their antifungal immunity impact in hematologic malignancies: A comprehensive systematic review.

BACKGROUND: Fungal infections pose a significant threat to individuals with hematologic malignancies due to compromised immune systems. Dectin-1, a pivotal pattern recognition receptor, plays a central role in antifungal immune responses. Understanding its genetic variants' impact is crucial for advancing personalized therapeutic approaches. METHODS: Employing systematic review methods, studies were meticulously selected and assessed for relevance. Data extraction encompassed Dectin-1 genetic variants, antifungal immune responses, and disease outcomes. RESULTS: Findings unveiled a complex relationship between Dectin-1 genetic variants and antifungal immunity in hematologic malignancies. Variable associations emerged, influencing susceptibility to fungal infections and disease prognosis. Moreover, implications for treatment outcomes were explored, suggesting potential avenues for tailored interventions. CONCLUSIONS: This systematic review underscores the need for further investigation into the precise influence of Dectin-1 genetic variants on antifungal immunity and disease progression in hematologic malignancies. Insights gained could pave the way for personalized therapeutic strategies, optimizing infection prevention and malignancy management. By delving into the intricate connections between genetic nuances, immune responses, and clinical trajectories, this review contributes to the ongoing discourse surrounding hematologic malignancies, fungal infections, and their multifaceted interplay.

Whole genome resequencing reveals the adaptability of native chickens to drought, tropical and frigid environments in Xinjiang.

Chickens exhibit extensive genetic diversity and are distributed worldwide. Different chicken breeds have evolved to thrive in diverse environmental conditions. However, research on the genetic mechanisms underlying chicken adaptation to extreme environments, such as tropical, frigid and drought-prone regions, remains limited. In this study, we conducted whole-genome sequencing of 240 individuals from six native chicken breeds in Xinjiang, China, as well as 4 publicly available chicken breeds inhabiting regions with varying annual precipitations, temperatures, and altitudes. Our analysis revealed several genetic variants among the examined breeds. Furthermore, we investigated the genetic diversity and population structure of breeds residing in extreme drought and temperature environments by comparing them. Notably, native chicken breeds exhibited different genetic diversity and population structures. Moreover, we identified candidate genes associated with chicken adaptability to the environment, such as CORO2A, CTNNA3, AGMO, GRID2, BBOX1, COL3A1, INSR, SOX5, MAP2 and PLPPR1. Additionally, pathways such as lysosome, cysteine and methionine metabolism, glycosaminoglycan degradation, and Wnt signaling may be play crucial roles in regulating chicken adaptation to drought environments. Overall, these findings contribute to our understanding of the genetic mechanisms governing chicken adaptation to extreme environments, and also offer insights for enhancing the resilience of chicken breeds to different climatic conditions.

Serum 25-hydroxyvitamin D level and erectile dysfunction: a causal relationship? Findings from a two-sample Mendelian randomization study.

Background: Serum 25-hydroxyvitamin D level is associated with erectile dysfunction (ED) in observational studies. However, whether there is a causal association between them remains uncertain. Objective: Conduct a two-sample Mendelian randomization (MR) analysis to investigate the causal effect between serum 25-hydroxyvitamin D level and ED risk. Method: Genome-wide association study (GWAS) data of serum 25-hydroxyvitamin D levels comprising 6,896,093 single nucleotide polymorphisms (SNP) from 496,949 people of European ancestry were regarded as exposure for the MR analysis. Additional GWAS data involving 9,310,196 SNPs of 6,175 European ED cases and 217,630 controls were used as outcome data. The MR-Egger, inverse variance weighted (IVW) method, weighted median, simple mode, and weighted mode were employed to evaluate causal effects, among which IVW was the primary MR analysis method. The stability of the MR analysis results was confirmed by a heterogeneity test, a horizontal pleiotropy test, and the leave-one-out method. Result: There were 103 SNPs utilized as instrumental variables (p < 5 × 10-8). The results of MR analysis showed no causal effects of serum 25(OH) D concentration on ED risks (IVW; OR = 0.9516, 95% CI = 0.7994 to 1.1328, p = 0.5772). There was no heterogeneity and pleiotropy in the statistical models. Conclusion: The present MR study did not support a causal association for genetically predicted serum 25-hydroxyvitamin D concentration in the risk of ED in individuals of European descent.

The Importance of Molecular Genetic Testing for Precision Diagnostics, Management, and Genetic Counseling in MODY Patients.

Maturity-onset diabetes of the young (MODY) is part of the heterogeneous group of monogenic diabetes (MD) characterized by the non-immune dysfunction of pancreatic ß-cells. The diagnosis of MODY still remains a challenge for clinicians, with many cases being misdiagnosed as type 1 or type 2 diabetes mellitus (T1DM/T2DM), and over 80% of cases remaining undiagnosed. With the introduction of modern technologies, important progress has been made in deciphering the molecular mechanisms and heterogeneous etiology of MD, including MODY. The aim of our study was to identify genetic variants associated with MODY in a group of patients with early-onset diabetes/prediabetes in whom a form of MD was clinically suspected. Genetic testing, based on next-generation sequencing (NGS) technology, was carried out either in a targeted manner, using gene panels for monogenic diabetes, or by analyzing the entire exome (whole-exome sequencing). GKC-MODY 2 was the most frequently detected variant, but rare forms of KCNJ11-MODY 13, specifically, HNF4A-MODY 1, were also identified. We have emphasized the importance of genetic testing for early diagnosis, MODY subtype differentiation, and genetic counseling. We presented the genotype-phenotype correlations, especially related to the clinical evolution and personalized therapy, also emphasizing the particularities of each patient in the family context.

Farnesyl Diphosphate Synthase Gene Associated with Loss of Bone Mass Density and Alendronate Treatment Failure in Patients with Primary Osteoporosis.

Aminobisphosphonates (NBPs) are the first-choice medication for osteoporosis (OP); NBP treatment aims at increasing bone mineral density (BMD) by inhibiting the activity of farnesyl diphosphate synthase (FDPS) enzyme in osteoclasts. Despite its efficacy, inadequate response to the drug and side effects have been reported. The A allele of the rs2297480 (A > C) SNP, found in the regulatory region of the FDPS gene, is associated with reduced gene transcription. This study evaluates the FDPS variant rs2297480 (A > C) association with OP patients' response to alendronate sodium treatment. A total of 304 OP patients and 112 controls were enrolled; patients treated with alendronate sodium for two years were classified, according to BMD variations at specific regions (lumbar spine (L1-L4), femoral neck (FN) and total hip (TH), as responders (OP-R) (n = 20) and non-responders (OP-NR) (n = 40). We observed an association of CC genotype with treatment failure (p = 0.045), followed by a BMD decrease in the regions L1-L4 (CC = -2.21% ± 2.56; p = 0.026) and TH (CC = -2.06% ± 1.84; p = 0.015) after two years of alendronate sodium treatment. Relative expression of the FDPS gene was also evaluated in OP-R and OP-NR patients. Higher expression of the FDPS gene was also observed in OP-NR group (FC = 1.84 ± 0.77; p = 0.006) when compared to OP-R. In conclusion, the influence observed of FDPS expression and the rs2897480 variant on alendronate treatment highlights the importance of a genetic approach to improve the efficacy of treatment for primary osteoporosis.

Association of Glycoprotein IIIa PlA1/A2 Polymorphism with Risk of Stroke: Updated Meta-Analysis.

Cardiovascular diseases are the main cause of death in the world, with ischemic heart disease (i.e., myocardial infarction) and cerebrovascular disease (i.e., stroke) taking the highest toll. Advances in diagnosis and treatment have led to a significant alleviation of ischemic complications, specifically in the realm of pharmacotherapy and interventional devices, while pharmacogenomics has yet to be fully leveraged to improve the burden of disease. Atherothrombotic events might occur earlier or respond worse to treatment in patients with genetic variants of GP IIb/IIIa. Therefore, we aimed to quantitate the involvement of the PlA2 variant in the risk of cerebral stroke events. A systematic search and meta-analysis were performed by pooling the risks of individual studies. A total of 31 studies comprising 5985 stroke patients and 7886 controls were analyzed. A meta-analysis of four studies on hemorrhagic stroke patients showed no association with the PIA2 rs5918(C) polymorphism in both fixed-effect (OR = 0.90 95%CI [0.71; 1.14]; p = 0.398) and random-effect models (OR = 0.86 95%CI [0.62; 1.20]; p-value = 0.386). The power of this analysis was below <30%, indicating a limited ability to detect a true effect. An analysis of the 28 studies on ischemic stroke revealed a significant association with the PIA2 rs5918(C) allele in both fixed-effect (OR = 1.16 95%CI [1.06; 1.27]; p = 0.001) and random-effect models (OR = 1.20 95%CI [1.04; 1.38]; p-value = 0.012), with a power of >80%. The PIA2 allele was associated with an increased risk of ischemic stroke. No association was found with hemorrhagic stroke, most likely due to the small number of available studies, which resulted in a lack of power.

Association of genetic variants in soy isoflavones metabolism-related genes with decreased lung cancer risk.

BACKGROUND: Soy isoflavones have been reported to exhibit anti-tumor effects. We hypothesize that genetic variants in soy isoflavone metabolism-related genes are associated with the risk of lung cancer. METHODS: A two-stage case-control study design was conducted in this study. The discovery stage included 300 lung cancer cases and 600 healthy controls to evaluate the association of candidate genetic variants with lung cancer risk. The validation stage involved 1200 cases and 1200 controls to validate the associations found. Furthermore, qPCR was performed to assess the mRNA expression levels of different genotypes of the SNP. ELISA was used to explore the association between genotype and soy isoflavone levels, as well as the association between soy isoflavone levels and lung cancer risk. RESULTS: A nonlinear association was observed between plasma soy isoflavone levels and lung cancer risk, with higher soy isoflavone levels associated with lower lung cancer risk (P < 0.001). The two-stage case-control study identified that UGT1A1 rs3755319 A > C was associated with decreased lung cancer risk (Recessive model: adjusted OR = 0.69, 95 %CI = 0.57-0.84, P < 0.001). Moreover, eQTL analysis showed that the expression level of UGT1A1 in the rs3755319 CC genotype was lower than in the AA + AC genotype (P < 0.05). The plasma concentration of soy isoflavones in the rs3755319 CC genotype was higher than in the AA + AC genotype (P = 0.008). CONCLUSIONS: We identified a potentially functional SNP, UGT1A1 rs3755319 A > C, as being associated with decreased lung cancer risk. Further experiments will be needed to explore the mechanisms underlying the observed associations.