Search Results (1,711)

Background/Objectives: Glycogen storage disease type II, also known as Pompe disease (PD), is a rare autosomal recessive genetic disorder triggered by a deficiency in lysosomal acid α-glucosidase (GAA). Recently, we discovered two deleterious missense variants of the GAA gene, c.1799G>A (p.Arg600His) (a pathogenic mutation) and c.55G>A (p.Val19Met), in a domestic short-haired cat with PD. This study aimed to design genotyping assays for these two variants and ascertain their allele frequencies in Japanese cat populations. Methods: We developed fluorescent probe-based real-time polymerase chain reaction assays to genotype the c.1799G>A and c.55G>A variants. A total of 738 cats, comprising 99 purebred cats from 20 breeds and 540 mixed-breed cats, were screened using these assays. Results: Genotyping assays clearly differentiated all known genotypes of the two variants. None of the 738 cats tested carried the c.1799G>A variant. However, we identified cats with c.55G/A and c.55A/A genotypes in the purebred (A allele frequency: 0.081) and mixed-breed cats (0.473). A significant difference (p < 0.001) was observed in the A allele frequency between the two groups. Conclusions: The c.1799G>A mutation appears rare in cat populations, suggesting it may be confined to specific pedigree Japanese mixed-breed cats. The c.55G>A variant was detected in purebred and mixed-breed cats, suggesting that it may not be directly linked to feline PD. However, additional studies are required to elucidate the precise relationship between this variant and cardiac function. Genotyping assays will serve as valuable tools for diagnosing and genotyping feline PD. Full article

Multiple sclerosis (MS) is a chronic autoimmune disease characterized by the immune system attacking the central nervous system, leading to demyelination and neurodegeneration. This work investigates the relationship between specific human leukocyte antigen (HLA) polymorphisms and MS, aiming to reveal the immunogenetic background of this disease for more individualized management approaches. This study employed a case–control design, analyzing HLA allele frequencies in 179 MS patients and 200 control subjects using next-generation sequencing, The key findings indicate significant associations between several HLA Class I and II alleles and MS, including HLA-B*35:03:01:03, HLA-C*04:01:01:14, HLA-DRB1*15:01:01:26, and HLA-DQA1*05:05:01:02. These findings emphasize the critical role of HLA molecules in MS Romanian patients. Full article

This study examined the distribution and disease associations of non-HLA-B*27 HLA-B alleles in Romanian spondyloarthritis (SpA) patients, aiming to address the underrepresentation of Eastern European populations in immunogenetic research. Methods: We analyzed 263 HLA-B*27-negative patients from Northeastern Romania fulfilling ASAS criteria. HLA-B genotyping was performed at two-digit resolution, and allele distributions were compared with two Romanian HLA-B*27-negative control groups (n = 335 and n = 1705 cases), using chi-square testing and logistic regression. Compared to controls, HLA-B*47 (p = 0.0007) and HLA-B*54 (p = 0.0013) were significantly enriched, while HLA-B*40 was underrepresented (p = 0.0287). Notably, HLA-B*54 was observed exclusively in axial SpA. Within the cohort, both HLA-B*13 and HLA-B*57 alleles were associated with psoriasis, while HLA-B*37 and HLA-B*41 alleles were clustered within the reactive arthritis group. The HLA-B*35 and HLA-B*18 alleles were the most frequently observed alleles across most clinical phenotypes. When comparing the frequency of HLA-B associations, the most common genotypes among SpA patients were B*08-B*18, B*13-B*35, and B*35-B*51. Notably, B*08-B*18 was more frequent in patients with radiographic sacroiliitis grade ≥ 2, while B*35-B*51 was more frequent in those with confirmed systemic inflammation, as indicated by elevated CRP or ESR levels. Analysis of peptide-binding patterns revealed a cluster of risk alleles, HLA-B*08, B*18, B*35, B*40, and B*54, sharing similar features, distinct from the canonical profile of B*27. These findings highlight the contribution of non-B*27 HLA-B alleles to SpA susceptibility in an Eastern European population and support the notion that HLA-B*27-negative SpA may represent a distinct clinical and immunological entity, driven by alternative pathogenic mechanisms. They also emphasize the importance of population-specific immunogenetic profiling and support expanding genetic characterization in HLA-B*27-negative patients. Full article

The frequency of specific variants associated with the risk of developing cardiovascular diseases has been extensively studied through genome-wide association studies (GWASs). Differences between populations may be caused by the interaction of several factors, such as environmental and genetic backgrounds. Here, we studied 19 SNPs involved in atherosclerosis (AT) and venous thromboembolism (VTE) risk in the Azorean and mainland Portuguese populations and compared their frequencies with other European, Asian, and African populations. Results revealed that, although there was no difference between Azorean and mainland populations, eight SNPs in ADAMTS7, PCSK9, APOE, and LDLR genes showed significant statistical differences (χ², p < 0.05) when compared with the European population. The multilocus genetic profile (MGP) analysis demonstrated that 7.4% of mainlanders and 11.2% of Azoreans have a high-risk of developing atherosclerosis. The opposite tendency was observed for venous thromboembolism risk, where the mainland population presented a higher risk (6.5%) than the Azorean population (4.1%). Significant differences in VTE-MGP distribution were found among the Azorean geographic groups (p < 0.05), with the Eastern group showing the highest VTE risk. Conversely, for the risk AT-MGP, the Central group shows the highest risk (12.9%). Taken together, the data suggest a risk of developing a cardiovascular disease consistent with the European population. However, the Azorean-specific genetic background and socio-cultural habits (dietary and sedentary) may explain the differences observed, validating the need to assess the allelic and genotypic frequencies between different populations, especially in small geographical locations, such as the Azores archipelago. In conclusion, these findings can improve the prevention, diagnosis, and treatment of high-risk individuals, and contribute to reducing the lifelong burden of cardiovascular diseases in the Azorean population. Full article

The P1104A variant in the TYK2 gene is recognized as the first common monogenic cause of tuberculosis, and recent studies also suggest a potential role in COVID-19 severity. However, its frequency and impact in admixed Latin American populations remain underexplored. Therefore, we investigated the P1104A/TYK2 variant in a cohort comprising 1826 RT-PCR-confirmed COVID-19 patients from Southern Brazil. Cases were stratified by severity into non-severe (n = 1190) and severe (n = 636). Three homozygous individuals were identified—one non-severe and two severe cases—although no statistically significant association with disease severity was observed. The frequency of the C allele in the COVID-19 cohort (2.85%) was significantly higher than in Brazilian population databases, including “DNA do Brasil” (1.81%, p < 0.001) and ABraOM (2.34%, p = 0.03), but lower than in the multi-ancestry gnomAD database (3.71%, p = 0.01), possibly reflecting ancestry bias. We also observed associations between COVID-19 severity and sex (p = 0.003), age (p < 0.001), obesity (p < 0.001), diabetes (p < 0.001), and hypertension (p < 0.001). Future studies in larger and more diverse cohorts are needed to characterize the prevalence of the variant in admixed populations and assess its contribution to COVID-19 susceptibility. Full article

Wool has distinctive biological, physical, and chemical properties that contribute to its value both for the sheep and in global fibre and textile markets. Its fibres are primarily composed of proteins, principally keratin and keratin-associated proteins (KAPs). To better comprehend the genes that underpin key wool traits, this study examined the keratin-associated protein 36-1 gene (KRTAP36-1) in Chinese Tan lambs. We identified three previously reported alleles of the gene (named A, B and C) that were present in the lambs studied, with genotype frequencies as follows: 2.0% (n = 5; AA), 6.9% (n = 17; AB), 13.8% (n = 34; AC), 8.9% (n = 22; BB), 33.4% (n = 82; BC) and 35.0% (n = 86; CC). The frequencies of the individual alleles in the Chinese Tan lambs were 12.4%, 29.1% and 58.5% for alleles A, B and C, respectively. The three alleles were in Hardy–Weinberg Equilibrium. In an association analysis, it was revealed that allele C was associated with variation in the mean fibre curvature of the fine wool of the Chinese Tan lambs, but this association was not observed in their heterotypic hair fibres. This finding suggests that KRTAP36-1 might be differentially expressed in the wool follicles that produce the two fibre types, and that along with other KRTAP genes, it may be involved in determining fibre curvature and the distinctive curly coat of the lambs. Full article

Background/Objectives: Papillary thyroid microcarcinoma (MPTC), a subset of papillary thyroid carcinoma (PTC), is increasingly detected with advanced imaging. While most MPTCs are indolent, some exhibit aggressive behavior, complicating clinical management. The BRAF V600E mutation, common in PTC, is linked to aggressive features, and its allele frequency (AF) may serve as a biomarker for tumor aggressiveness. This study explored the association between BRAF V600E AF and aggressive histopathological features in MPTC. Methods: Data from 1 January 2016 to 23 December 2023 were retrieved from two McGill University teaching hospitals. Inclusion criteria comprised patients aged ≥ 18 years with thyroid nodules ≤ 1 cm, documented BRAF V600E mutation and AF results, and available surgical pathology reports. Tumor aggressiveness was defined as the presence of lymph node metastasis, aggressive histological subtype (tall cell, hobnail, columnar, solid/trabecular or diffuse sclerosing), extra thyroidal extension, or extensive lymphovascular extension. Associations were explored using t-tests. Results: Among 1564 records, 34 met the inclusion criteria and were included in analyses. The mean BRAF V600E AF was significantly higher in aggressive tumors (23.58) compared to non-aggressive tumors (13.73) (95% CI: −18.53 to −1.16, p = 0.03). Although not statistically significant, trends were observed for higher BRAF V600E AF in tumors with lymph node metastasis (mean AF: 25.4) compared to those without (mean AF: 16.67, p = 0.08). No significant difference was noted in BRAF V600E AF by histological subtype (mean AF for aggressive: 19.57; non-aggressive: 19.15, p = 0.94). Conclusions: Elevated BRAF V600E AF is associated with aggressive behavior in MPTC, highlighting its potential as a biomarker to inform treatment strategies. Larger studies are warranted to validate these findings and enhance clinical management of MPTC patients. Full article

Background: This study aimed to determine the association between PNPLA3 rs738409, rs2896019, and FTO rs9939609, rs17817449 single-nucleotide polymorphisms and the risk of metabolic dysfunction-associated steatotic liver disease (MASLD) in Mongolian individuals. Methods: We conducted a case-control study, enrolling 100 MASLD patients and 50 subjects without MASLD. We used the PCR-RFLP technique on three genotype SNPs (rs738409, rs2896019 in PNPLA3, and rs9939609 in FTO). We analyzed liver function and lipid metabolism parameters in the peripheral blood of study participants. A p-value below 0.05 was considered a statistically significant result. Results: This study, which included 150 participants aged 23 to 75, had a mean age of 46.73 ± 11.45 years, with 40% of participants being male (60 individuals). We observed the rs738409 (G), rs2896019 (G), and rs9939609 (A) alleles at a statistically significantly enhanced frequency in the case group (32.5%, 33%, and 21%) compared to the control group (19%, 25%, and 19%), indicating an increased risk of MASLD. The FTO rs17817449 SNP did not show a significant difference between groups. PNPLA3 rs738409 GC/GG genotype (OR = 2.39, p = 0.019) and FTO rs9939609 AT/AA (OR = 2.55, p = 0.025) genotype showed a significant association with MASLD. In the evaluation of the FTO rs9939609, rs17817449, and PNPLA3 rs738409, rs2896019 single-nucleotide polymorphisms among the research individuals, 18.7% had no SNPs, 15.3% had one SNP, 29.3% had two SNPs, 25.3% had three SNPs, and 11.3% had four SNPs. The risk of MASLD increased significantly for individuals having four SNPs (OR = 4.23, p = 0.007). Conclusions: We found that PNPLA3 rs738409 GC/GG genotype and FTO rs9939609 AT/AA genotype are strongly associated with an increased risk of MASLD. Notably, individuals with a higher rate of SNP number, had a significantly higher risk of MASLD. Full article

Background/Objectives: Variations in hair length are observed in many dog breeds, as determined by the canine FGF5 gene. Long-haired Akitas, which are disqualified under breeding standards of Akitas, are sometimes born to short-haired parents and may have been subjected to treatments compromising animal welfare. Here, we aimed to identify an FGF5 variant associated with hair coat variations in Akitas in Japan, and to assess how welfare of this breed can be improved by carefully planned breeding. Methods: DNA samples were obtained from 60 Akitas in 2021 (modern Akitas) and 73 Akitas in the 1970s and the 1980s (classic Akitas). Sanger sequencing was performed on all exons and exon–intron junctions of the FGF5 gene to determine the causative variant of long hair in Akitas. A real-time PCR assay was developed to genotype FGF5:c.578C>T in modern and classic Akitas. Using 54 dogs from modern Akitas, scores (1 to 10) of hair length were compared among the three genotypes (C/C, C/T, and T/T). Results: Sanger sequencing revealed that the canine FGF5:c.578C>T variant was associated with long hair in Akitas in Japan. Genotyping revealed that the frequency of the mutant T allele was 0.350 in modern Akitas, which was significantly higher (p < 0.001) than in classic Akitas (0.212). The three genotypes were not in Hardy–Weinberg equilibrium (HWE) in modern Akitas but were in HWE in classic Akitas. There were significant differences in hair length scores among the three genotypes (p < 0.001) and between the C/C and C/T genotypes (p < 0.005). There was no significant difference in the scores between male and female dogs. Conclusions: This study revealed that a causative variant that determines the long hair trait of Akitas in Japan was the FGF5:c.578C>T variant, which was inherited in an incompletely dominant manner. Akita dog breeders were more likely to select heterozygous C/T dogs based on the appearance of the hair coat for breeding dogs with an ideal fluffy hair coat. This might result in a high mutant T allele frequency and the production of undesired long-haired Akitas with T/T, which may create welfare problems. Genetic testing for this variant is necessary to improve welfare and conserve the Akita breed. Full article

Fragile X syndrome (FXS) is the most common form of X-linked intellectual disability (ID). This study aimed to share 30 years of experience in diagnosing FXS and determine its frequency in Thailand. We retrospectively reviewed 1480 unrelated patients (1390 males and 90 females) with ID, developmental delay, or autism spectrum disorder, or individuals referred for FXS DNA testing at Songklanagarind Hospital, Thailand, over a 30-year period. The samples were analyzed using cytogenetic methods, PCR-based techniques, and/or Southern blot analysis. Full mutations (>200 CGG repeats) were identified in 100 males (7.2%) and three females (3.3%). An intermediate allele was detected in one male, while no premutation was found in the index cases. Two males were suspected to have FMR1 gene deletions. Twelve families underwent prenatal testing during this study. Most families undergoing prenatal FXS diagnosis involved mothers who were premutation carriers and had given birth to children affected by FXS. This study represents the largest series of molecular genetic FXS testing cases reported in Thailand. The frequency of FXS identified in different cohorts of Thai patients across various periods was approximately 7%. This study enhances public awareness of at-risk populations and highlights the importance of prenatal testing and genetic counseling for vulnerable families. Full article

Background: Population persistence for organisms to survive in a world with a rapidly changing climate will require either dispersal to suitable areas, evolutionary adaptation to altered conditions and/or sufficient phenotypic plasticity to withstand it. Given the slow growth and geographically isolated populations of many tree species, there is a high likelihood of local adaption or the acclimation of functional traits in these populations across the UK. Objectives: Given the slow growth and often isolated populations of Tilia cordata (lime tree), we hypothesised that there is a high likelihood of local adaptation or the acclimation of metabolic traits in these populations across the UK. Our aim was to test if the functional metabolomic traits of Tilia cordata (lime tree), collected in situ from natural populations, varied within and between populations and to compare this to neutral allele variation in the population. Methods: We used a metabolic fingerprinting approach to obtain a snapshot of the metabolic status of leaves collected from T. cordata from six populations across the UK. Environmental metadata, longer-term functional traits (specific leaf area) and neutral allelic variation in the population were also measured to assess the plastic capacity and local adaptation of the species. Results: The metabolic fingerprints derived from leaf material collected and fixed in situ from individuals in six populations of T. cordata across its UK range were similar, despite contrasting environmental conditions during sampling. Neutral allele frequencies showed almost no significant group structure, indicating low differentiation between populations. The specific leaf area did vary between sites. Conclusions: The low metabolic variation between UK populations of T. cordata despite contrasting environmental conditions during sampling indicates high levels of phenotypic plasticity. Full article

Background/Objectives: Global warming and rising CO₂ concentrations pose significant challenges to plant systems. Amid these pressures, this study contributes to understanding how tropical species respond by simultaneously evaluating reproductive and genetic traits. It specifically investigates the effects of maternal exposure to warming and elevated CO₂ on progeny physiology, genetic diversity, and population structure in Stylosanthes capitata, a resilient forage legume native to Brazil. Methods: Maternal plants were cultivated under controlled treatments, including ambient conditions (control), elevated CO₂ at 600 ppm (eCO₂), elevated temperature at +2 °C (eTE), and their combined exposure (eTEeCO₂), within a Trop-T-FACE field facility (Temperature Free-Air Controlled Enhancement and Free-Air Carbon Dioxide Enrichment). Seed traits (seeds per inflorescence, hundred-seed mass, abortion, non-viable seeds, coat color, germination at 32, 40, 71 weeks) and abnormal seedling rates were quantified. Genetic diversity metrics included the average (A) and effective (Ae) number of alleles, observed (Ho) and expected (He) heterozygosity, and inbreeding coefficient (Fis). Population structure was assessed using Principal Coordinates Analysis (PCoA), Analysis of Molecular Variance (AMOVA), number of migrants per generation (Nm), and genetic differentiation index (Fst). Two- and three-way Analysis of Variance (ANOVA) were used to evaluate factor effects. Results: Compared to control conditions, warming increased seeds per inflorescence (+46%), reduced abortion (−42.9%), non-viable seeds (−57%), and altered coat color. The germination speed index (GSI +23.5%) and germination rate (Gr +11%) improved with warming; combined treatments decreased germination time (GT −9.6%). Storage preserved germination traits, with warming enhancing performance over time and reducing abnormal seedlings (−54.5%). Conversely, elevated CO₂ shortened GSI in late stages, impairing germination efficiency. Warming reduced Ae (−35%), He (−20%), and raised Fis (maternal 0.50, progeny 0.58), consistent with the species’ mixed mating system; A and Ho were unaffected. Allele frequency shifts suggested selective pressure under eTE. Warming induced slight structure in PCoA, and AMOVA detected 1% (maternal) and 9% (progeny) variation. Fst = 0.06 and Nm = 3.8 imply environmental influence without isolation. Conclusions: Warming significantly shapes seed quality, reproductive success, and genetic diversity in S. capitata. Improved reproduction and germination suggest adaptive advantages, but higher inbreeding and reduced diversity may constrain long-term resilience. The findings underscore the need for genetic monitoring and broader genetic bases in cultivars confronting environmental stressors. Full article

Background: In recent years, comprehensive analyses using a genome-wide association study (GWAS) have been conducted to identify genetic factors related to athletic performance. In this study, we investigated the association between genetic variants and elite wrestling status across multiple ethnic groups using a genome-wide genotyping approach. Methods: This study included 168 elite wrestlers (64 Japanese, 67 Turkish, and 36 Russian), all of whom had competed in international tournaments, including the Olympic Games. Control groups consisted of 306 Japanese, 137 Turkish, and 173 Russian individuals without elite athletic backgrounds. We performed a GWAS comparing allele frequencies of single-nucleotide polymorphisms (SNPs) between elite wrestlers and controls in each ethnic cohort. Cross-population analysis comprised (1) identifying SNPs with nominal significance (p < 0.05) in all three groups, then (2) meta-analyzing overlapped SNPs to assess effect consistency and combined significance. Finally, we investigated whether the most significant SNPs were associated with gene expression in skeletal muscle in 23 physically active men. Results: The GWAS identified 328,388 (Japanese), 23,932 (Turkish), and 30,385 (Russian) SNPs reaching nominal significance. Meta-analysis revealed that the ATP2A3 rs6502758 and UNC5C rs265061 polymorphisms were associated (p < 0.0001) with elite wrestling status across all three populations. Both variants are located in intronic regions and influence the expression of their respective genes in skeletal muscle. Conclusions: This is the first study to investigate gene polymorphisms associated with elite wrestling status in a multi-ethnic cohort. ATP2A3 rs6502758 and UNC5C rs265061 polymorphisms may represent important genetic factors associated with achieving an elite status in wrestling, irrespective of ethnicity. Full article

FMC63-CAR T cell therapy targeting CD19 protein on malignant B-cells is effective in patients with relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL), with complete response rates of 43–54%. Common germline variants of the immune-checkpoint regulator CTLA-4 may elicit different responses to CAR-T cell therapy. The CTLA4 gene single-nucleotide polymorphism rs231775 coding threonine or alanine at amino acid position 17 of the CTLA-4 protein was prevalent in 55% of the studied DLBCL patients. In a retrospective comparative analysis of clinical outcome, there were significant differences in CTLA4 A17hom vs. T17Ahet and T17hom carriers with four-year progression-free survival at 77%, 59%, and 30% (p = 0.019), four-year overall survival was 79%, 41%, and 33% (p = 0.049), the relapse rates were 20%, 37%, and 56% (p = 0.025), and the death rates 20%, 54%, and 52% (p = 0.049). Conclusions: CTLA4 rs231775 polymorphism may impact the treatment outcome in FMC63-anti-CD19 CAR-T cell therapy, with an association of the CTLA4 minor allele A17 to favorable treatment outcome. Full article

Background/Objectives: Cystic fibrosis (CF) is a rare autosomal recessive genetic disease that has a progressive and multisystemic course. The spectrum and frequency of mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) vary both in European countries and in other geographical regions. The aim of our retrospective study was to present the genetic variants identified in a group of 48 CF patients from the Moldova region (Romania), as well as to establish genotype–phenotype correlations. Methods: Genetic testing was initially performed for 38 CFTR mutations, and in heterozygous patients or those in whom no mutation was detected, CFTR gene sequencing (NGS) was performed. Results: The compound heterozygous genotype was identified in 26 (54.16%) of the patients (with one of the alleles being F508del), while 22 (45.83%) patients had the homozygous F508del genotype. The F508del variant was the most frequent (69.79%), followed by G542X (6.25%, 6/96). Several new variants were also identified that had not been reported in other studies from Romania (R1158X, K598*, R347H, c.2589_2599del, R496H, and CFTRdele2). Phenotypic manifestations in patients with CFTR class I, II, III and VII variants (homozygous and compound heterozygous) were more severe compared to those in patients with CFTR class IV, V and VI mutations, with the data obtained being consistent with those in the literature. Respiratory tract involvement was present in 77.08% of the patients, being more frequent in patients with the compound heterozygous genotype compared to the homozygous F508del genotype. Most patients had exocrine pancreatic insufficiency (EPI) (85.41%). Gastrointestinal manifestations included hepatocytolysis (66.66%) and biliary cirrhosis (0.41%). Meconium ileus was detected in 18.75% of patients, all with a compound heterozygous genotype. Conclusions: We compared the results obtained with data from the literature and correlated the detected CFTR variant (genotype) with the phenotypic manifestations, highlighting certain particularities present in some patients. Genetic testing allows for early diagnosis and adapted management, including personalized treatment for each patient. Identification of novel unclassified CFTR variants still remains a challenge for clinicians. NGS-based screening of heterozygous healthy carriers is important for both genetic counseling and prenatal diagnosis. Full article