BACKGROUND: This cross-sectional study investigated the relationship between genetic variations in monocarboxylate transporter genes and blood lactate production and removal after high-intensity efforts in humans. The study was conducted to explore how genetic variations in the MCT1, MCT2, and MCT4 genes influenced lactate dynamics and to advance the field of sports genetics by pinpointing critical genetic markers that can enhance athletic performance and recovery. METHODS: 337 male athletes from Poland and the Czech Republic underwent two intermittent all-out Wingate tests. Before the tests, DNA samples were taken from each participant, and SNP (single nucleotide polymorphism) analysis was carried out. Two intermittent all-out tests were implemented, and lactate concentrations were assessed before and after these tests. RESULTS: Sprinters more frequently exhibited the haplotype TAC in the MCT2 gene, which was associated with an increase in the difference between maximum lactate and final lactate concentration. Additionally, this haplotype was linked to higher maximum lactate concentration and was more frequently observed in sprinters. The genotypic interactions AG/T- and GGxT- (MCT1 rs3789592 x MCT4 rs11323780), TTxTT (MCT1 rs12028967 x MCT2 rs3763979), and MCT1 rs7556664 x MCT4 rs11323780 were all associated with an increase in the difference between maximum lactate concentration and final lactate concentration. Conversely, the AGxGG (MCT1 rs3789592 x MCT2 rs995343) interaction was linked to a decrease in this difference. The relationship between maximum lactate concentration and genotypic interactions can be observed as follows: when ATxTT (MCT2 rs3763980 x MCT4 rs11323780) or CTxCT (MCT1 rs10857983 x MCT2 rs3763979) genotypic combinations are present, it leads to a decrease in maximum lactate concentration. Similarly, the combination of CTxCT (MCT1 rs4301628 x MCT2 rs3763979), CT x TT (MCT1 rs4301628 x MCT4 rs11323780), and CTxTT (MCT1 rs4301628 x MCT2 rs3763979) results in decreased maximum lactate concentration. CONCLUSIONS: The TAC haplotype (rs3763980, rs995343, rs3763979) in the MCT2 gene is associated with altered lactate clearance in sprinters, potentially affecting performance and recovery by elevating post-exercise lactate concentrations. While MCT4 rs11323780 is also identified as a significant variant in lactate metabolism, suggesting its role as a biomarker for sprinting performance, further investigation is necessary to clarify underlying mechanisms and consider additional factors. Based on elite male athletes from Poland and the Czech Republic, the study may not generalize to all sprinters or diverse athletic populations. Although genetic variants show promise as biomarkers for sprinting success, athletic performance is influenced by a complex interplay of genetics, environment, and training extending beyond MCT genes.
- MeSH
- dospělí MeSH
- genotyp MeSH
- haplotypy * MeSH
- jednonukleotidový polymorfismus * MeSH
- kinetika MeSH
- kyselina mléčná * krev metabolismus MeSH
- lidé MeSH
- mladý dospělý MeSH
- přenašeče monokarboxylových kyselin * genetika metabolismus MeSH
- průřezové studie MeSH
- sportovci MeSH
- svalové proteiny * genetika metabolismus MeSH
- symportéry * genetika metabolismus MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: The highest mortality and morbidity worldwide is associated with atherosclerotic cardiovascular disease (ASCVD), which has in background both environmental and genetic risk factors. Apolipoprotein L1 (APOL1) variability influences the risk of ASCVD in Africans, but little is known about the APOL1 and ASCVD in other ethnic groups. METHODS: To investigate the role of APOL1 and ASCVD, we have genotyped four (rs13056427, rs136147, rs10854688 and rs9610473) APOL1 polymorphisms in a group of 1541 male patients with acute coronary syndrome (ACS) and 1338 male controls. RESULTS: Individual APOL1 polymorphisms were not associated with traditional CVD risk factors such as smoking, hypertension or diabetes prevalence, with BMI values or plasma lipid levels. Neither individual polymorphisms nor haplotypes were associated with an increased risk of ACS nor did they predict total or cardiovascular mortality over the 10.2 ± 3.9 years of follow-up. CONCLUSIONS: We conclude that APOL1 genetic variability has no major effect on risk of ACS in Caucasians.
- MeSH
- akutní koronární syndrom * genetika MeSH
- apolipoprotein L1 * genetika MeSH
- apolipoproteiny genetika MeSH
- běloši genetika MeSH
- genetická predispozice k nemoci MeSH
- haplotypy MeSH
- jednonukleotidový polymorfismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- lipoproteiny HDL genetika MeSH
- rizikové faktory MeSH
- senioři MeSH
- studie případů a kontrol MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Česká republika MeSH
Metabolic syndrome is a growing concern in developed societies and due to its polygenic nature, the genetic component is only slowly being elucidated. Common mitochondrial DNA sequence variants have been associated with symptoms of metabolic syndrome and may, therefore, be relevant players in the genetics of metabolic syndrome. We investigate the effect of mitochondrial sequence variation on the metabolic phenotype in conplastic rat strains with identical nuclear but unique mitochondrial genomes, challenged by high-fat diet. We find that the variation in mitochondrial rRNA sequence represents risk factor in the insulin resistance development, which is associated with diacylglycerols accumulation, induced by tissue-specific reduction of the oxidative capacity. These metabolic perturbations stem from the 12S rRNA sequence variation affecting mitochondrial ribosome assembly and translation. Our work demonstrates that physiological variation in mitochondrial rRNA might represent a relevant underlying factor in the progression of metabolic syndrome.
- MeSH
- dieta s vysokým obsahem tuků škodlivé účinky MeSH
- genetická predispozice k nemoci MeSH
- haplotypy * MeSH
- inzulinová rezistence genetika MeSH
- krysa rodu rattus MeSH
- metabolický syndrom * genetika metabolismus MeSH
- mitochondriální DNA genetika metabolismus MeSH
- mitochondrie metabolismus genetika MeSH
- RNA mitochondriální genetika metabolismus MeSH
- RNA ribozomální * genetika metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Genome-wide association studies (GWASs) based on common single nucleotide polymorphisms (SNPs) have identified several loci associated with the risk of monoclonal gammopathy of unknown significance (MGUS), a precursor condition for multiple myeloma (MM). We hypothesized that analyzing haplotypes might be more useful than analyzing individual SNPs, as it could identify functional chromosomal units that collectively contribute to MGUS risk. To test this hypothesis, we used data from our previous GWAS on 992 MGUS cases and 2910 controls from three European populations. We identified 23 haplotypes that were associated with the risk of MGUS at the genome-wide significance level (p < 5 × 10-8) and showed consistent results among all three populations. In 10 genomic regions, strong promoter, enhancer and regulatory element-related histone marks and their connections to target genes as well as genome segmentation data supported the importance of these regions in MGUS susceptibility. Several associated haplotypes affected pathways important for MM cell survival such as ubiquitin-proteasome system (RNF186, OTUD3), PI3K/AKT/mTOR (HINT3), innate immunity (SEC14L1, ZBP1), cell death regulation (BID) and NOTCH signaling (RBPJ). These pathways are important current therapeutic targets for MM, which may highlight the advantage of the haplotype approach homing to functional units.
- MeSH
- celogenomová asociační studie * MeSH
- genetická predispozice k nemoci * MeSH
- haplotypy * MeSH
- jednonukleotidový polymorfismus * MeSH
- lidé MeSH
- mnohočetný myelom genetika MeSH
- monoklonální gamapatie nejasného významu * genetika MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Human leukocyte antigen G (HLA-G) belongs to non-classical MHC class I molecules that is involved in the suppression of immune response. As HLA-G plays important role in the maintenance of fetal tolerance, its overexpression has been associated with tumor progression. For the regulation of HLA-G levels, genetic variants within the 5' upstream regulatory region (5'URR) are of crucial importance. Our study aimed to analyze the association between 16 HLA-G 5'URR variants, sHLA-G level and clinical variables in glioma patients. METHODS: We investigated 59 patients with gliomas (mean age 54.70 ± 15.10 years) and 131 healthy controls (mean age 41.45 ± 9.75 years). Patient's blood was obtained on the day of surgical treatment. The HLA-G 5'URR polymorphisms were typed by direct sequencing and the plasma level of sHLA-G assessed by ELISA. RESULTS: Haploblock within HLA-G 5'URR consisting of -762T, -716G, -689G, -666T, -633A, followed by -486C and -201A alleles were significantly more frequent in patients with gliomas than in the controls (p < 0.05). No correlation of HLA-G 5'URR variants with sHLA-G plasma level was found. Analysis of HLA-G 5'URR variants with main clinical variables in patients with grade IV gliomas revealed that haploblock carriers of -762CT, -716TG, -689AG, -666GT, -633GA, -486AC, -477GC, -201GA followed by -369AC carriers tend to have lower age at onset as compared to other genotype carriers (p = 0.04). CONCLUSION: Our results suggest genetic association of HLA-G 5'URR variants with risk of developing gliomas and possible contribution of HLA-G to disease pathology.
BACKGROUND: In patients with idiopathic inflammatory myopathies (IIM), autoantibodies are associated with specific clinical phenotypes suggesting a pathogenic role of adaptive immunity. We explored if autoantibody profiles are associated with specific HLA genetic variants and clinical manifestations in IIM. METHODS: We included 1348 IIM patients and determined the occurrence of 14 myositis-specific or -associated autoantibodies. We used unsupervised cluster analysis to identify autoantibody-defined subgroups and logistic regression to estimate associations with clinical manifestations, HLA-DRB1, HLA-DQA1, HLA-DQB1 alleles, and amino acids imputed from genetic information of HLA class II and I molecules. FINDINGS: We identified eight subgroups with the following dominant autoantibodies: anti-Ro52, -U1RNP, -PM/Scl, -Mi2, -Jo1, -Jo1/Ro52, -TIF1γ or negative for all analysed autoantibodies. Associations with HLA-DRB1∗11, HLA-DRB1∗15, HLA-DQA1∗03, and HLA-DQB1∗03 were present in the anti-U1RNP-dominated subgroup. HLA-DRB1∗03, HLA-DQA1∗05, and HLA-DQB1∗02 alleles were overrepresented in the anti-PM/Scl and anti-Jo1/Ro52-dominated subgroups. HLA-DRB1∗16, HLA-DRB1∗07 alleles were most frequent in anti-Mi2 and HLA-DRB1∗01 and HLA-DRB1∗07 alleles in the anti-TIF1γ subgroup. The HLA-DRB1∗13, HLA-DQA1∗01 and HLA-DQB1∗06 alleles were overrepresented in the negative subgroup. Significant signals from variations in class I molecules were detected in the subgroups dominated by anti-Mi2, anti-Jo1/Ro52, anti-TIF1γ, and the negative subgroup. INTERPRETATION: Distinct HLA class II and I associations were observed for almost all autoantibody-defined subgroups. The associations support autoantibody profiles use for classifying IIM which would likely reflect underlying pathogenic mechanisms better than classifications based on clinical symptoms and/or histopathological features. FUNDING: See a detailed list of funding bodies in the Acknowledgements section at the end of the manuscript.
- MeSH
- alely MeSH
- autoprotilátky * genetika MeSH
- fenotyp MeSH
- genetická predispozice k nemoci MeSH
- haplotypy MeSH
- HLA-DRB1 řetězec genetika MeSH
- lidé MeSH
- myozitida * genetika imunologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Pediatric steroid-sensitive nephrotic syndrome (pSSNS) is the most common childhood glomerular disease. Previous genome-wide association studies (GWAS) identified a risk locus in the HLA Class II region and three additional independent risk loci. But the genetic architecture of pSSNS, and its genetically driven pathobiology, is largely unknown. Here, we conduct a multi-population GWAS meta-analysis in 38,463 participants (2440 cases). We then conduct conditional analyses and population specific GWAS. We discover twelve significant associations-eight from the multi-population meta-analysis (four novel), two from the multi-population conditional analysis (one novel), and two additional novel loci from the European meta-analysis. Fine-mapping implicates specific amino acid haplotypes in HLA-DQA1 and HLA-DQB1 driving the HLA Class II risk locus. Non-HLA loci colocalize with eQTLs of monocytes and numerous T-cell subsets in independent datasets. Colocalization with kidney eQTLs is lacking but overlap with kidney cell open chromatin suggests an uncharacterized disease mechanism in kidney cells. A polygenic risk score (PRS) associates with earlier disease onset. Altogether, these discoveries expand our knowledge of pSSNS genetic architecture across populations and provide cell-specific insights into its molecular drivers. Evaluating these associations in additional cohorts will refine our understanding of population specificity, heterogeneity, and clinical and molecular associations.
- MeSH
- celogenomová asociační studie * MeSH
- dítě MeSH
- genetická predispozice k nemoci MeSH
- haplotypy MeSH
- jednonukleotidový polymorfismus MeSH
- lidé MeSH
- nefrotický syndrom * genetika MeSH
- rizikové faktory MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- metaanalýza MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
OBJECTIVE: The idiopathic inflammatory myopathies (IIMs) are heterogeneous diseases thought to be initiated by immune activation in genetically predisposed individuals. We imputed variants from the ImmunoChip array using a large reference panel to fine-map associations and identify novel associations in IIM. METHODS: We analyzed 2,565 Caucasian IIM patient samples collected through the Myositis Genetics Consortium (MYOGEN) and 10,260 ethnically matched control samples. We imputed 1,648,116 variants from the ImmunoChip array using the Haplotype Reference Consortium panel and conducted association analysis on IIM and clinical and serologic subgroups. RESULTS: The HLA locus was consistently the most significantly associated region. Four non-HLA regions reached genome-wide significance, SDK2 and LINC00924 (both novel) and STAT4 in the whole IIM cohort, with evidence of independent variants in STAT4, and NAB1 in the polymyositis (PM) subgroup. We also found suggestive evidence of association with loci previously associated with other autoimmune rheumatic diseases (TEC and LTBR). We identified more significant associations than those previously reported in IIM for STAT4 and DGKQ in the total cohort, for NAB1 and FAM167A-BLK loci in PM, and for CCR5 in inclusion body myositis. We found enrichment of variants among DNase I hypersensitivity sites and histone marks associated with active transcription within blood cells. CONCLUSION: We found novel and strong associations in IIM and PM and localized signals to single genes and immune cell types.
NK buňky hrají u alogenní transplantace kostní dřeně významnou roli, nejen při eradikaci zbývajících nádorových buněk, ale ovlivňují i rozvoj reakce štěpu proti hostiteli. Je tedy třeba porozumět jejich regulaci a tomu, jakým způsobem může reakce imunitního systému pacienta NK buňky dárce ovlivňovat. Inhibice a aktivace NK buněk je řízena celou řadou receptorů, které reagují na široké spektrum ligandů. Ať už inhibičních, které signalizují NK buňkám, že je cílová buňka v pořádku nebo aktivačních, které vyjadřují nějaké poškození cílové buňky. Mezi nejprozkoumanější receptory patří KIR a dále NKG2D se svými ligandy MICA a MICB. Přehledu jejich role v transplantaci kostní dřeně se věnuje tato práce.
NK cells play an important role in allogeneic stem cell transplantation; not only as effector cells in the eradication of remaining cancer cells but also as potential inducers of graft versus host disease. Hence, it is important to understand their regulation and how the patient’s immune system affects donor NK cells. NK cell inhibition or activation is directed by many receptors which interact with a broad spectrum of ligands. Inhibition ligands signal that the target cell is healthy, and activating ligands reflect that the cell is damaged. The most investigated receptors are KIR together with the NKG2D receptor with its ligands MICA and MICB. This work describes their role in stem cell transplantation.
- MeSH
- akutní myeloidní leukemie * imunologie terapie MeSH
- haplotypy genetika MeSH
- HLA antigeny MeSH
- homologní transplantace MeSH
- lektinové receptory NK-buněk - podrodina K analýza genetika MeSH
- lidé MeSH
- ligandy MeSH
- polymorfismus genetický MeSH
- receptory buněk NK * imunologie klasifikace MeSH
- receptory KIR analýza genetika MeSH
- transplantace kostní dřeně MeSH
- transplantační imunologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
The human dopamine transporter gene SLC6A3 has been consistently implicated in several neuropsychiatric diseases but the disease mechanism remains elusive. In this risk synthesis, we have concluded that SLC6A3 represents an increasingly recognized risk with a growing number of familial mutants associated with neuropsychiatric and neurological disorders. At least five loci were related to common and severe diseases including alcohol use disorder (high activity variant), attention-deficit/hyperactivity disorder (low activity variant), autism (familial proteins with mutated networking) and movement disorders (both regulatory variants and familial mutations). Association signals depended on genetic markers used as well as ethnicity examined. Strong haplotype selection and gene-wide epistases support multimarker assessment of functional variations and phenotype associations. Inclusion of its promoter region's functional markers such as DNPi (rs67175440) and 5'VNTR (rs70957367) may help delineate condensate-based risk action, testing a locus-pathway-phenotype hypothesis for one gene-multidisease etiology.
