Search Results (283)

Background/Objectives: The transcription factor 7-like 2 (TCF7L2) rs7903146 polymorphism has been strongly associated with type 2 diabetes mellitus (T2DM) in various populations; however, its impact on different ethnic groups is not fully understood. Given the distinct minor allele frequency in Chinese populations, this study aimed to analyze the association of rs7903146 with the risk of T2DM in a Han Chinese cohort and its relationship with relevant clinical parameters. Methods: We conducted a case–control study including 600 patients with type 2 diabetes mellitus (T2DM) and 511 sex-matched non-diabetic controls of Han Chinese descent. The TCF7L2 rs7903146 (C/T) polymorphism was genotyped using a TaqMan™ SNP assay. Clinical parameters, including body mass index (BMI), fasting plasma glucose, hemoglobin A1c, lipid profile, and high-sensitivity C-reactive protein (hs-CRP), were compared between genotypes. Logistic regression analyses were performed under a dominant genetic model (CT/TT vs. CC), adjusting for age, sex, systolic and diastolic blood pressure, BMI, and smoking status. Subgroup analyses were conducted by sex, BMI category, age at diagnosis, and family history of T2DM. Given the exploratory nature of this study and the low frequency of the TT genotype, no formal correction for multiple testing was applied. Results: Frequencies of the CT and TT genotypes were higher in the diabetic group (p = 0.045) and were significantly associated with an increased risk of T2DM under a dominant genetic model (adjusted OR = 2.24, p = 0.025). Individuals with CT/TT genotypes had elevated fasting glucose and hs-CRP levels; these genotypes were also linked to higher BMI in the female T2DM patients. The T allele frequency varied across ethnic groups, being lowest in East Asians and highest in Latin (Brazilian/mixed ancestry) populations. Mechanistically, the T allele may contribute to T2DM via altered TCF7L2 expression, impaired insulin secretion, inflammation, and metabolic dysregulation. Conclusions: The TCF7L2 rs7903146 T allele was associated with an increased risk of T2DM and higher fasting glucose and hs-CRP levels in this Han Chinese cohort. The CT/TT genotypes were also associated with higher BMI in the female T2DM patients. While the findings are consistent with the known effects of this variant in other populations, mechanistic hypotheses such as the involvement of inflammatory or metabolic pathways remain hypothetical and warrant further functional validation. Full article

Enhancing protein–protein interactions is a key therapeutic strategy to ensure effective protein function in terms of pharmacokinetics and pharmacodynamics and can be accomplished with methods like directed evolution or rationale design. Previously, two papers suggested the possible enhancement of protein–protein binding affinity via destabilizing mutations. This paper reviews the results of the previous literature and adds new data to show the generality of the strategy that destabilizing the unbound protein without significantly changing the free energy of the complex can enhance protein–protein interactions for therapeutic benefit. The first example presented is that of a variant of human growth hormone (hGHv) containing 15 mutations that improve the binding to the hGH binding protein (hGHbp) by 400-fold while retaining full biological activity. The second example is that of the YTE mutations (M252Y/S354T/T256E) in the Fc region of a monoclonal antibody (mAb). The YTE mutations improve the binding of the mAb to FcRn at pH 6.0 10-fold, resulting in elongated serum half-life of the mAb. In both cases, (i) chemical titration or differential scanning calorimetry (DSC) showed the mutations destabilize the unbound mutant proteins, (ii) isothermal titration calorimetry (ITC) showed extremely favorable enthalpy (ΔH) and unfavorable entropy (ΔS) upon binding to their respective target molecule compared with the wildtype, and (iii) hydrogen/deuterium exchange–mass spectrometry (HDX-MS) revealed that these mutations increase the free energy of unbound mutant protein without significantly affecting the free energy of the bound state, resulting in an enhancement to the binding affinities. The third example presented is that of the JAWA mutations (T437R/K248E) also located in the Fc region of a mAb. The JAWA mutations facilitate antibody multimerization upon binding to cell surface antigens, allowing for enhanced agonism and effector functions. Both DSC and HDX-MS showed that the JAWA mutations destabilize the unbound Fc, although the complex was not characterized due to weak binding. Enhancement of protein–protein interactions through incorporation of mutations that increase the free energy of a protein’s unbound state represents an alternative route to decreasing the protein–protein complex free energy through optimization of the binding interface. Full article

Congenital hypothyroidism (CH) is a heterogeneous condition present at birth, resulting in severe-to-mild thyroid hormone deficiency. This condition is difficult to recognize shortly after birth. Therefore, many countries worldwide have implemented newborn screening (NBS) programs for CH since the 1970s. The most recent European guidelines strongly recommend screening for primary CH, as well as for central CH when financial resources are available. However, no consensus has been reached yet to screen more rare forms of CH, such as Allan–Herndon–Dudley syndrome (AHDS), an X-linked condition linked to mutations in the gene encoding a transmembrane monocarboxylate transporter (MCT8), resistance to thyroid hormone beta (RTHβ), and resistance to thyroid hormone alfa (RTHα). The combined measurement of thyroid-stimulating hormone (TSH) and total thyroxine (TT4) on DBS currently allows the recognition of central CH (TSH low/normal and low TT4 without defects in transport proteins). With the introduction of liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) for measurement of free triiodothyronine (FT3) and free thyroxine (FT4), it would be possible to screen for RTHβ (TSH normal/high and high FT4). More complicated would be the method to screen RTHα. It would require the combined measurement of FT4 and FT3 and the determination of FT3/FT4 ratio, while the combined measurement of FT3 and reverse T3 (rT3) to calculate FT3/rT3 ratio would be useful to screen AHDS. In this article, we provide some reflections on expanding NBS for primary CH also to other rare forms of CH. Full article

Type 2 diabetes mellitus (T2DM) affects 90% of diabetes cases and worsens cardiovascular health by causing oxidative stress, which leads to oxidized LDL (oxLDL) and foam cell formation, contributing to atherosclerosis. This study examined the relationship between CD36 gene variants, soluble CD36 (sCD36), oxLDL, and MDA-LDL in T2DM and ST-segment elevation myocardial infarction (STE-T2DM) patients in western Mexico. The analysis included 400 T2DM patients, 400 STE-T2DM patients, and 400 healthy controls. Results showed that STE-T2DM patients were older, mainly male, and had higher rates of smoking, sedentarism, and hypertension. Both diabetic groups exhibited elevated triacylglycerols and low HDL, with significantly higher C-reactive protein in STE-T2DM (p < 0.0001). No significant differences in CD36 gene variant frequencies were found, but sCD36 levels were elevated in STE-T2DM, with associations to specific genotypes. oxLDL was higher in STE-T2DM compared to controls (p = 0.0268). Binary logistic regression analysis identified male sex, younger age, sedentarism, and rs3173798 T/T genotype as independent risk factors for myocardial infarction (AUC: 0.9267, p < 0.0001). Elevated sCD36 levels may reflect atherosclerosis progression in diabetes, indicating the need for further studies to clarify CD36’s role in cardiometabolic dysfunction. These findings highlight CD36’s involvement in oxidative stress responses through its interaction with oxLDL and MDA-LDL, suggesting its potential role as a molecular target in antioxidant defense mechanisms. Full article

Background/Objectives: Chronic low-grade inflammation drives cardiometabolic risk; functional SNPs may influence individual cytokine and hematologic phenotypes. We investigated genotype-specific relationships between circulating immuno-inflammatory biomarkers and routine blood indices in apparently healthy adults. Methods: In this cross-sectional study, 155 fasting volunteers (26–72 years) were genotyped for IL1RN rs1149222 and TNF-proximal rs2071645. Serum IL-1β, TNF-α, oxidized LDL (oxLDL) and C-reactive protein (CRP) were quantified by ELISA, and complete blood counts were recorded simultaneously. Genotype effects were tested with ANOVA/Kruskal–Wallis; Spearman correlations and age-, sex-, BMI-adjusted linear models explored genotype-stratified associations. Results: Among 155 adults, IL1RN rs1149222 significantly affected IL-1β (TT > TG ≈ GG; ANOVA p = 0.042) and oxLDL (overall p = 0.036), with the clearest difference between heterozygotes and major-allele homozygotes. The same variant produced a modest fall in erythrocyte count and hemoglobin restricted to heterozygotes (RBC p = 0.036; Hb p = 0.041). TNF-proximal rs2071645 strongly raised TNF-α (GG > GA > AA; p < 0.0001) and led to a moderate oxLDL increase, driven by GA versus AA carriers (pairwise p = 0.013), while leaving red-cell indices and CRP unchanged. Baseline leukocyte counts, differentials and derived ratios showed no genotype dependence, and multivariable models revealed no epistatic interaction between the two loci. Conclusions: IL1RN rs1149222 and TNF-related rs2071645 generate two independent inflammatory signatures—an IL-1β-oxidative axis linked to mild erythropoietic suppression and a TNF-lipid axis without hematologic shift. Integrating targeted genotyping with inexpensive hematologic ratios may refine early risk stratification and guide tailored preventive strategies in ostensibly healthy populations. Full article

The blood orange arose from the insertion of a retrotransposon adjacent to the Ruby gene, an MYB-type transcriptional activator of anthocyanin production, as reported previously. However, the intricate process of anthocyanin regulation among different varieties of blood orange remains incompletely understood. In this study, mRNA levels of the transcription factors Ruby and TT8 were found to be upregulated in the juice vesicle tissues of a variety with higher concentrations of anthocyanins in the pulp compared with another variety with a lower anthocyanin content. In contrast, comparative analysis of the two varieties using two-dimensional electrophoresis and mass spectrometry did not identify differentially expressed proteins related to anthocyanin biosynthesis in the juice vesicle tissues. Furthermore, higher anthocyanin contents were observed in various tissues of transgenic Arabidopsis thaliana overexpressing the Ruby gene from blood orange compared with the wildtype plant. Moreover, the long terminal repeat (LTR) region of a retrotransposon inserted upstream of the Ruby locus exhibited the ability to drive reporter expression through histochemical assay in a transgenic seedling. Thus, a PCR-based molecular marker was developed, targeting the upstream sequence of the Ruby locus to identify Citrus hybrids with the unique trait of red-fleshed fruit. Intriguingly, bisulfite sequencing revealed differentially methylated regions within a Gag-Pol polyprotein-encoding sequence of a retrotransposon adjacent to Ruby locus when comparing two varieties with different anthocyanin contents. A higher average level of methylation status was observed in the fruit with a lower anthocyanin content. In conclusion, methylation modifications at specific upstream positions on the Ruby locus may influence anthocyanin production in blood oranges. Full article

Background/Objectives: Low folate intake before and during pregnancy increases the risk of neural tube defects and other adverse outcomes. Gene variants such as MTHFR 677C>T (rs1801133) may increase risks associated with suboptimal folate intake. Our objective was to use BALB/cJ Mthfr^677C>T mice to evaluate the effects of the TT genotype and low folate diets on embryonic development and MTHFR protein expression in pregnant mice. Methods: Female 677CC (mCC) and 677TT (mTT) mice were fed control (2 mg folic acid/kg (2D)), 1 mg folic acid/kg (1D) and 0.3 mg folic acid/kg (0.3D) diets before and during pregnancy. Embryos and maternal tissues were collected at embryonic day 10.5. Embryos were examined for developmental delays and defects. Methyltetrahydrofolate (methylTHF) and total homocysteine (tHcy) were measured in maternal plasma, and MTHFR protein expression was evaluated in maternal liver. Results: MethylTHF decreased due to the experimental diets and mTT genotype. tHcy increased due to 0.3D and mTT genotype; mTT 0.3D mice had significantly higher tHcy than the other groups. MTHFR expression was lower in mTT liver than mCC. MTHFR protein expression increased due to low folate diets in mCC mice, whereas in mTT mice, MTHFR expression increased only due to 1D. Developmental delays were increased in the litters of mTT mice fed 1D and 0.3D. Conclusions: The Mthfr^677C>T mouse models the effects of the MTHFR 677TT genotype in humans and provides a folate-responsive model for examination of the effects of folate intake and the MTHFR 677C>T variant during gestation. Full article

Background/Objectives: Androgen deprivation therapy (ADT) is widely used to manage prostate cancer (PC), but the emergence of treatment resistance remains a major clinical challenge. Although the GST family has been implicated in drug resistance, the specific role of GSTM5 remains poorly understood. This study investigates whether GSTM5, alone or in combination with clinical variables, can improve patient stratification based on the risk of early treatment resistance. Methods: In silico analyses were performed to examine GSTM5’s role in protein interactions, molecular pathways, and gene expression. The rs3768490 polymorphism was genotyped in 354 patients with PC, classified by ADT response. Descriptive analysis and logistic regression models were applied to evaluate associations between genotype, clinical variables, and ADT response. GSTM5 expression related to the rs3768490 genotype and ADT response was also analyzed in 129 prostate tissue samples. Results: The T/T genotype of rs3768490 was significantly associated with a lower likelihood of early ADT resistance in both individual (p = 0.0359, Odd Ratios (OR) = 0.18) and recessive models (p = 0.0491, OR = 0.21). High-risk classification according to D’Amico was strongly associated with early progression (p < 0.0004; OR > 5.4). Combining genotype and clinical risk improved predictive performance, highlighting their complementary value in stratifying patients by treatment response. Additionally, GSTM5 expression was slightly higher in T/T carriers, suggesting a potential protective role against ADT resistance. Conclusions: The T/T genotype of rs3768490 may protect against ADT resistance by modulating GSTM5 expression in PC. These preliminary findings highlight the potential of integrating genetic biomarkers into clinical models for personalized treatment strategies, although further studies are needed to validate these observations. Full article

Protein–polyelectrolyte nanostructures assembled via electrostatic interactions offer versatile applications in biomedicine, tissue engineering, and food science. However, several open questions remain regarding their intermolecular interactions and the influence of external conditions—such as temperature and pH—on their assembly, stability, and responsiveness. This study explores the formation and stability of networks between poly(acrylic acid) (PAA) and lysozyme (LYZ) at the nanoscale upon thermal treatment, using a combination of experimental and simulation measures. Experimental techniques of static and dynamic light scattering (SLS and DLS), Fourier transform infrared spectroscopy (FTIR), and circular dichroism (CD) are combined with all-atom molecular dynamics simulations. Model systems consisting of multiple PAA and LYZ molecules explore collective assembly and complexation in aqueous solution. Experimental results indicate that electrostatic complexation occurs between PAA and LYZ at pH values below LYZ’s isoelectric point. This leads to the formation of nanoparticles (NPs) with radii ranging from 100 to 200 nm, most pronounced at a PAA/LYZ mass ratio of 0.1. These complexes disassemble at pH 12, where both LYZ and PAA are negatively charged. However, when complexes are thermally treated (TT), they remain stable, which is consistent with earlier findings. Atomistic simulations demonstrate that thermal treatment induces partially reversible structural changes, revealing key microscopic features involved in the stabilization of the formed network. Although electrostatic interactions dominate under all pH and temperature conditions, thermally induced conformational changes reorganize the binding pattern, resulting in an increased number of contacts between LYZ and PAA upon thermal treatment. The altered hydration associated with conformational rearrangements emerges as a key contributor to the stability of the thermally treated complexes, particularly under conditions of strong electrostatic repulsion at pH 12. Moreover, enhanced polymer chain associations within the network are observed, which play a crucial role in complex stabilization. These insights contribute to the rational design of protein–polyelectrolyte materials, revealing the origins of association under thermally induced structural rearrangements. Full article

Background: Polycystic Ovary Syndrome (PCOS) is a prevalent endocrine disorder characterized by excess body weight, hyperandrogenism, hyperglycemia, and insulin resistance often resulting in hirsutism and infertility. Dietary strategies have been shown to ameliorate metabolic disturbances, hormonal imbalances, and inflammation associated with PCOS. Recent evidence indicates that intermittent fasting (IF) could effectively enhance health outcomes and regulate circadian rhythm; however, its impact on PCOS remain unclear. Objective: Therefore, this systematic review and meta-analysis aims to examine the effect of IF on women diagnosed with PCOS. Methods: Comprehensive research was conducted across three major databases including PubMed, Scopus, and Web of Science without date restrictions. Meta-analysis was performed using Cochrane Review Manager Version 5.4 software. Results: Five studies fulfilled the inclusion criteria. IF significantly reduced body weight (MD = −4.25 kg, 95% CI: −7.71, −0.79; p = 0.02), BMI (MD = −2.05 kg/m², 95% CI: −3.26, −0.85; p = 0.0008), fasting blood glucose (FBG; MD = −2.86 mg/dL, 95% CI: −4.83, −0.89; p = 0.004), fasting blood insulin (FBI; MD = −3.17 μU/mL, 95% CI: −5.18, −1.16; p = 0.002), insulin resistance (HOMA-IR; MD = −0.94, 95% CI: −1.39, −0.50; p < 0.0001), triglycerides (TG; MD = −40.71 mg/dL, 95% CI: −61.53, −19.90; p = 0.0001), dehydroepiandrosterone sulfate (DHEA-S; MD = −33.21 μg/dL, 95% CI: −57.29, −9.13; p = 0.007), free androgen index (FAI; MD = −1.61%, 95% CI: −2.76, −0.45; p = 0.006), and C-reactive protein (CRP; MD = −2.00 mg/L, 95% CI: −3.15, −0.85; p = 0.006), while increasing sex hormone-binding globulin (SHBG; SMD = 0.50, 95% CI: 0.22, 0.77; p = 0.004). No significant changes were observed in waist-to-hip ratio (WHR), total cholesterol (TC), LDL, HDL, total testosterone (TT), or anti-Mullerian hormone (AMH). Conclusions: IF represents a promising strategy for improving weight and metabolic, hormonal, and inflammatory profiles in women with PCOS. However, the existing evidence remains preliminary, necessitating further robust studies to substantiate these findings. Full article

Background: SET domain-containing 5 (SETD5) is a member of the protein lysine-methyltransferase family. SETD5 gene mutations cause disorders of the epigenetic machinery which determinate phenotypic overlap characterized by several abnormalities. SEDT5 gene variants have been described in patients with KBG and Cornelia de Lange (CdL) syndromes. Case description: A female patient with severe short stature and intellectual disability had been followed since she was 9 years old. Several causes of short stature were ruled out. At the age of 12 years, her height was 114 cm (−5.22 SDS), weight 19 kg (−5.88 SDS), BMI 14.6 kg/m² (−2.26 SDS), and was Tanner stage 1. The target height for the proband was 151.65 cm (−1.80 SDS). The bone age (BA) was delayed by 3 years compared to chronological age. The growth rate was persistently deficient (<<2 SDS). Physical examination revealed dysmorphic features. Genetic analysis documented a de novo SETD5 gene mutation (c.890_891delTT), responsible for phenotypes in the context of an overlap syndrome between the phenotype of MDR23, CdL and KBG syndromes. Recombinant growth hormone therapy (rhGH) was started at the age of 12 years. After both one year (+3.16 SDS) and two years (+2.9 SDS), the growth rate significantly increased compared with the pre-therapy period. Conclusion: This is the first case of a patient with overlap syndrome due to SETD5 mutation treated with rhGH. The review of the scientific literature highlighted the clinical and molecular features of SETD5 gene mutation and the use of rhGH therapy in patients suffering from CdL and KBG syndromes. Full article

The RasGAP SH3 domain binding protein (G3BP) is a highly conserved family of proteins in eukaryotic organisms that coordinates signal transduction and post-transcriptional gene regulation and functions in the formation of stress granules. G3BPs have important roles in abiotic/biotic stresses in mammals, and recent research suggests that they have similar functions in higher plants. Brassica contains many important oilseeds, vegetables, and ornamental plants, but there are no reports on the G3BP family in Brassica species. In this study, we identified G3BP family genes from six species of the U’s triangle (B. rapa, B. oleracea, B. nigra, B. napus, B. juncea, and B. carinata) at the genome-wide level. We then analyzed their gene structure, protein motifs, gene duplication type, phylogeny, subcellular localization, SSR loci, and upstream miRNAs. Based on transcriptome data, we analyzed the expression patterns of B. napus G3BP (BnaG3BP) genes in various tissues/organs in response to Sclerotinia disease, blackleg disease, powdery mildew, dehydration, drought, heat, cold, and ABA treatments, and its involvement in seed traits including germination, α-linolenic acid content, oil content, and yellow seed. Several BnaG3BP DEGs might be regulated by BnaTT1. The qRT-PCR assay validated the inducibility of two cold-responsive BnaG3BP DEGs. This study will enrich the systematic understanding of Brassica G3BP family genes and lay a molecular basis for the application of BnaG3BP genes in stress tolerance, disease resistance, and quality improvement in rapeseed. Full article

Wilson’s disease (WD) is an autosomal recessive disorder of copper metabolism caused by mutations in the ATP7B gene. While hepatic manifestations are frequent, psychiatric symptoms occur in up to 30% of patients and may precede neurological signs. This study was the first to assess the relationship between oxidative stress, selected genetic polymorphisms, and psychiatric symptoms in WD. A total of 464 patients under the care of the Institute of Psychiatry and Neurology in Warsaw were studied. Genotyping for GPX1 (rs1050450), SOD2 (rs4880), and CAT (rs1001179) was performed, along with biochemical analyses of copper metabolism, oxidative DNA, lipid and protein damage, and systemic antioxidant capacity. Among the most important observations are the following: the homozygous GPX1 rs1050450 TT and SOD2 rs4880 CC genotypes were associated with the lowest prevalence of psychiatric symptoms. The CAT rs1001179 TT genotype was linked to a delayed onset of psychiatric symptoms by 6.0–8.5 years. Patients with or without psychiatric symptoms did not differ significantly in saliva 8-OHdG, total antioxidant capacity, serum glutathione (GSH), catalase, and MnSOD; however, patients reporting psychiatric symptoms had significantly higher prostaglandin F2α 8-epimer (8-iso-PGF2α) concentrations and tended to have lower serum glutathione peroxidase (Gpx) concentrations compared to those without such symptoms. Our data firstly provide consistent evidence that oxidative stress balance associated with copper overload in the CNS may be associated with CNS damage and the development of psychiatric symptoms of WD. In particular, our findings of increased oxidative lipid damage together with decreased Gpx activity indirectly suggest that damage to neuronal membrane lipids, which may be potentially related to abnormalities in GSH metabolism, may have an etiological role in CNS damage and related symptoms. Full article

Vitamin D is a key micronutrient in the function of the skeletomuscular system. Athletes are at increased risk of developing vitamin D deficiency during the execution of very demanding disciplines such as CrossFit^®. Single-nucleotide polymorphisms (SNPs) may influence circulating 25-hydroxy-vitamin D (25(OH)D) levels. An observational, longitudinal pilot study was conducted with 50 trained males according to specific inclusion criteria. Blood samples were obtained to determine 25(OH)D, vitamin D-binding protein (VDBP), vitamin D-receptor (VDR)circulating levels, and the presence of SNPs after DNA isolation and genotyping: rs10741657 to CYP2R1, rs2282679 to GC and rs2228570 to VDR genes. Significant differences (p < 0.05) in 25(OH)D concentration were determined between the biallelic combinations of rs228679 (GC) and rs228570 (VDR). The VDBP and VDR proteins did not show different levels in the case of the rs10741657 (CYP2R1) alleles. Statistically significant weak positive correlations (p < 0.05) were observed between 25(OH)D and AA-alleles of the CYP2R1 and VDR genes, and TT-alleles of the GC gene. Additionally, AA (rs10741657 and rs2228570) and TT (rs2282679) have a probability between 2 and 4 of having major effects on the concentration of 25(OH)D. Conversely, GG alleles present a probability of suboptimal values of 25(OH)D of 69%, 34%, and 24% for VDR, GC, and CYP2R1, respectively, showing a strong moderate positive correlation (r = 0.41) between the degrees of sports performance and 25(OH)D plasma levels. CYP2R1 (rs10741657), GC (rs2282679), and VDR (rs2228570) affect the concentration of serum 25(OH)D, as an indicator of vitamin D status and play a critical role in the sports performance of CrossFit^® practitioners. Full article

Lung adenocarcinoma (LUAD) is driven by epidermal growth factor receptor (EGFR) mutations, making it a key therapeutic target. ADAM9, a member of the A disintegrin and metalloproteinase (ADAM) family, facilitates the release of growth factors and was implicated in activating the EGFR-mediated progression in several cancer types. In this study, we explored potential associations among ADAM9 single-nucleotide polymorphisms (SNPs), the EGFR mutation status, and the clinicopathological progression of LUAD in a Taiwanese population. In total, 535 LUAD patients with various EGFR statuses were enrolled, and allelic distributions of ADAM9 SNPs—located in promoter and intron regions, including rs78451751 (T/C), rs6474526 (T/G), rs7006414 (T/C), and rs10105311 (C/T)—were analyzed using a TaqMan allelic discrimination assay. We found that LUAD patients with at least one polymorphic G allele in ADAM9 rs6474526 had a lower risk of developing EGFR mutations compared to those with the wild-type (WT) TT genotype. Furthermore, G-allele carriers (TG + GG) of rs6474526 were associated with an increased likelihood of developing larger tumors (T3 or T4), particularly among patients with mutant EGFR. Conversely, in patients with WT EGFR, carriers of the T allele in rs10105311 had a lower risk of progressing to advanced stages (stage III or IV). Among females or non-smokers, G-allele carriers of rs6474526 demonstrated a higher risk of advanced tumor stages and distant metastases. In clinical data from the Genotype-Tissue Expression (GTEx) database, individuals with the polymorphic T allele in rs6474526 showed reduced ADAM9 expression in lung and whole blood tissues. Screening the genotype of rs6474526 in a set of LUAD cell lines revealed that cells carrying at least one minor G allele exhibited higher ADAM9 levels compared to those with the TT genotype. Additionally, analyses using TCGA and CPTAC databases revealed elevated ADAM9 expression in LUAD specimens compared to normal tissues. Elevated protein levels were correlated with advanced T stages, pathological stages, and worse prognoses. In summary, our results suggest that ADAM9 genetic variants of rs6474526 may affect ADAM9 expression and are associated with the EGFR mutation status. Both rs6474526 and rs10105311 were correlated with disease progression in LUAD patients. These variants could serve as potential biomarkers for predicting clinical outcomes. Full article