X-chromosomal genetic variants are understudied but can yield valuable insights into sexually dimorphic human traits and diseases. We performed a sex-stratified cross-ancestry X-chromosome-wide association meta-analysis of seven kidney-related traits (n = 908,697), identifying 23 loci genome-wide significantly associated with two of the traits: 7 for uric acid and 16 for estimated glomerular filtration rate (eGFR), including four novel eGFR loci containing the functionally plausible prioritized genes ACSL4, CLDN2, TSPAN6 and the female-specific DRP2. Further, we identified five novel sex-interactions, comprising male-specific effects at FAM9B and AR/EDA2R, and three sex-differential findings with larger genetic effect sizes in males at DCAF12L1 and MST4 and larger effect sizes in females at HPRT1. All prioritized genes in loci showing significant sex-interactions were located next to androgen response elements (ARE). Five ARE genes showed sex-differential expressions. This study contributes new insights into sex-dimorphisms of kidney traits along with new prioritized gene targets for further molecular research.
- MeSH
- androgeny * genetika MeSH
- celogenomová asociační studie * MeSH
- genetická predispozice k nemoci MeSH
- jednonukleotidový polymorfismus MeSH
- ledviny MeSH
- lidé MeSH
- lidské chromozomy X genetika MeSH
- responzivní elementy MeSH
- tetraspaniny genetika MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- metaanalýza MeSH
The tegument, as the surface layer of adult male and female Schistosoma spp. represents the protective barrier of the worms to the hostile environment of the host bloodstream. Here we present the first comparative analysis of sex-specific tegument proteins of paired or virgin Schistosoma mansoni. We applied a new and highly sensitive workflow, allowing detection of even low abundance proteins. Therefore, a streptavidin-biotin affinity purification technique in combination with single pot solid-phase enhanced sample preparation was established for subsequent LC-MS/MS analysis. We were able to identify 1519 tegument proteins for male and female virgin and paired worms and categorized them by sex. Bioinformatic analysis revealed an involvement of female-specific tegument proteins in signaling pathways of cellular processes and antioxidant mechanisms. Male-specific proteins were found to be enriched in processes linked to phosphorylation and signal transduction. This suggests a task sharing between the sexes that might be necessary for survival in the host. Our datasets provide a basis for further studies to understand and ultimately decipher the strategies of the two worm sexes to evade the immune system.
- MeSH
- chromatografie kapalinová MeSH
- proteiny červů metabolismus MeSH
- proteom * metabolismus MeSH
- Schistosoma mansoni * metabolismus MeSH
- tandemová hmotnostní spektrometrie MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
BACKGROUND: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk. METHODS: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH. RESULTS: Across disorders, genome-wide significant single nucleotide polymorphism-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10-8), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10-6) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10-7; rs73033497, p = 8.8 × 10-7; rs7914279, p = 6.4 × 10-7), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10-7) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10-7), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10-7) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05). CONCLUSIONS: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels.
- MeSH
- bipolární porucha genetika MeSH
- celogenomová asociační studie MeSH
- depresivní porucha unipolární * genetika MeSH
- endoteliální buňky MeSH
- genetická predispozice k nemoci MeSH
- jednonukleotidový polymorfismus MeSH
- lidé MeSH
- pohlavní dimorfismus * MeSH
- psychotické poruchy * genetika MeSH
- receptory vaskulárního endoteliálního růstového faktoru MeSH
- schizofrenie genetika MeSH
- sulfurtransferasy MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Research Support, N.I.H., Extramural MeSH
Reproductive longevity is essential for fertility and influences healthy ageing in women1,2, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations3. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.
- MeSH
- alely MeSH
- celogenomová asociační studie MeSH
- checkpoint kinasa 1 genetika MeSH
- checkpoint kinasa 2 genetika MeSH
- diabetes mellitus 2. typu MeSH
- dieta MeSH
- dlouhověkost genetika MeSH
- dospělí MeSH
- fertilita genetika MeSH
- genetická predispozice k nemoci MeSH
- kosti a kostní tkáň metabolismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- menopauza genetika MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- ovarium metabolismus MeSH
- předčasná menopauza genetika MeSH
- primární ovariální insuficience genetika MeSH
- protein FMRP genetika MeSH
- stárnutí genetika MeSH
- uterus MeSH
- zdravé stárnutí genetika MeSH
- zvířata MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Dálný východ MeSH
- Evropa MeSH
B. pertussis is the etiological agent of whooping cough, a highly contagious respiratory disease which remains uncontrolled worldwide. Understanding how this pathogen responds to the environmental changes and adapts to different niches found inside the host might contribute to gain insight into bacterial pathogenesis. Comparative analyses of previous transcriptomic and proteomic data suggested that post-transcriptional regulatory mechanisms modulate B. pertussis virulence in response to iron availability. Iron scarcity represents one of the major stresses faced by bacterial pathogens inside the host. In this study, we used gel-free nanoLC-MS/MS-based proteomics to investigate whether Hfq, a highly conserved post-transcriptional regulatory protein, is involved in B. pertussis adaptation to low iron environment. To this end, we compared the protein profiles of wild type B. pertussis and its isogenic hfq deletion mutant strain under iron-replete and iron-depleted conditions. Almost of 33% of the proteins identified under iron starvation was found to be Hfq-dependent. Among them, proteins involved in oxidative stress tolerance and virulence factors that play a key role in the early steps of host colonization and bacterial persistence inside the host cells. Altogether these results suggest that Hfq shapes the infective phenotype of B. pertussis. SIGNIFICANCE: In the last years, it became evident that post-transcriptional regulation of gene expression in ba cteria plays a central role in host-pathogen interactions. Hfq is a bacterial protein that regulates gene expression at post-transcriptional level found pivotal in the establishment of successful infections. In this study, we investigated the role of Hfq in Bordetella pertussis response to iron starvation, one of the main stresses imposed by the host. The data demonstrate that Hfq regulates the abundance of a significant number of B. pertussis proteins in response to iron starvation. Among them, virulence factors and proteins involved in oxidative stress tolerance, key players in host colonization and intracellular bacterial survival. Altogether, our results suggest a relevant role of Hfq in B. pertussis adaptation to the different niches found inside the host eventually granting bacterial pathogenesis.
BACKGROUND: We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. METHODS: Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration. RESULTS: The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer's disease - outcomes for which large-scale trial data were unavailable. CONCLUSIONS: Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.
- MeSH
- anticholesteremika škodlivé účinky terapeutické užití MeSH
- biologické markery krev MeSH
- celogenomová asociační studie MeSH
- cévní mozková příhoda epidemiologie prevence a kontrola MeSH
- down regulace MeSH
- dyslipidemie krev farmakoterapie epidemiologie genetika MeSH
- hodnocení rizik MeSH
- infarkt myokardu epidemiologie prevence a kontrola MeSH
- inhibitory serinových proteinas škodlivé účinky terapeutické užití MeSH
- ischemie mozku epidemiologie prevence a kontrola MeSH
- jednonukleotidový polymorfismus * MeSH
- LDL-cholesterol krev MeSH
- lidé MeSH
- PCSK9 inhibitory MeSH
- proproteinkonvertasa subtilisin/kexin typu 9 genetika MeSH
- randomizované kontrolované studie jako téma MeSH
- rizikové faktory MeSH
- výsledek terapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
Elevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardiometabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci and colocalization with gene expression in 47 tissues implicated the kidney and liver as the main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in the liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A transactivated the promoter of ABCG2, encoding a major urate transporter, in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardiometabolic traits.
- MeSH
- ABC transportér z rodiny G, člen 2 genetika MeSH
- celogenomová asociační studie MeSH
- dna (nemoc) krev epidemiologie genetika MeSH
- genetická predispozice k nemoci MeSH
- genetické lokusy MeSH
- genetické markery * MeSH
- hepatocytární jaderný faktor 1-alfa genetika MeSH
- hepatocytární jaderný faktor 4 genetika MeSH
- játra metabolismus patologie MeSH
- jednonukleotidový polymorfismus * MeSH
- kardiovaskulární nemoci krev epidemiologie genetika MeSH
- kohortové studie MeSH
- kyselina močová krev MeSH
- ledviny metabolismus patologie MeSH
- lidé MeSH
- metabolické nemoci krev epidemiologie genetika MeSH
- nádorové proteiny genetika MeSH
- orgánová specificita MeSH
- signální transdukce * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
- MeSH
- běloši MeSH
- celogenomová asociační studie MeSH
- chronická renální insuficience genetika patofyziologie moč MeSH
- fenotyp MeSH
- genetická predispozice k nemoci * MeSH
- genetické asociační studie metody MeSH
- hodnoty glomerulární filtrace MeSH
- jednonukleotidový polymorfismus MeSH
- kvantitativní znak dědičný * MeSH
- lidé MeSH
- lokus kvantitativního znaku * MeSH
- mapování chromozomů MeSH
- typy dědičnosti MeSH
- uromodulin moč MeSH
- vyšetření funkce ledvin MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- metaanalýza MeSH
- práce podpořená grantem MeSH
BACKGROUND: Statin treatment and variants in the gene encoding HMG-CoA reductase are associated with reductions in both the concentration of LDL cholesterol and the risk of coronary heart disease, but also with modest hyperglycaemia, increased bodyweight, and modestly increased risk of type 2 diabetes, which in no way offsets their substantial benefits. We sought to investigate the associations of LDL cholesterol-lowering PCSK9 variants with type 2 diabetes and related biomarkers to gauge the likely effects of PCSK9 inhibitors on diabetes risk. METHODS: In this mendelian randomisation study, we used data from cohort studies, randomised controlled trials, case control studies, and genetic consortia to estimate associations of PCSK9 genetic variants with LDL cholesterol, fasting blood glucose, HbA1c, fasting insulin, bodyweight, waist-to-hip ratio, BMI, and risk of type 2 diabetes, using a standardised analysis plan, meta-analyses, and weighted gene-centric scores. FINDINGS: Data were available for more than 550 000 individuals and 51 623 cases of type 2 diabetes. Combined analyses of four independent PCSK9 variants (rs11583680, rs11591147, rs2479409, and rs11206510) scaled to 1 mmol/L lower LDL cholesterol showed associations with increased fasting glucose (0·09 mmol/L, 95% CI 0·02 to 0·15), bodyweight (1·03 kg, 0·24 to 1·82), waist-to-hip ratio (0·006, 0·003 to 0·010), and an odds ratio for type diabetes of 1·29 (1·11 to 1·50). Based on the collected data, we did not identify associations with HbA1c (0·03%, -0·01 to 0·08), fasting insulin (0·00%, -0·06 to 0·07), and BMI (0·11 kg/m2, -0·09 to 0·30). INTERPRETATION: PCSK9 variants associated with lower LDL cholesterol were also associated with circulating higher fasting glucose concentration, bodyweight, and waist-to-hip ratio, and an increased risk of type 2 diabetes. In trials of PCSK9 inhibitor drugs, investigators should carefully assess these safety outcomes and quantify the risks and benefits of PCSK9 inhibitor treatment, as was previously done for statins. FUNDING: British Heart Foundation, and University College London Hospitals NHS Foundation Trust (UCLH) National Institute for Health Research (NIHR) Biomedical Research Centre.
- MeSH
- diabetes mellitus 2. typu krev diagnóza genetika MeSH
- genetická predispozice k nemoci genetika MeSH
- genetická variace genetika MeSH
- kohortové studie MeSH
- krevní glukóza metabolismus MeSH
- LDL-cholesterol krev genetika MeSH
- lidé MeSH
- mendelovská randomizace metody MeSH
- proproteinkonvertasa subtilisin/kexin typu 9 genetika MeSH
- randomizované kontrolované studie jako téma metody MeSH
- studie případů a kontrol MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
UNLABELLED: Previous studies have shown that B. pertussis survives inside human macrophages in non-acidic compartments with characteristics of early endosomes. In order to gain new insight into the biology of B. pertussis survival in host cells, we have analyzed the adaptation of the bacterial proteome during intracellular infection. The proteome of B. pertussis 3 h and 48 h after infection of human macrophage-like THP-1 cells was examined by nano-liquid chromatography combined with tandem MS and compared to the protein profile of extracellular B. pertussis growing in the same cell culture medium. Compared with extracellular bacteria, almost 300 proteins out of 762 identified proteins displayed altered levels in intracellular B. pertussis. Functional analyses of the proteins displaying altered abundance revealed enrichment of proteins involved in stress response, iron uptake, cellular metabolism, transcriptional regulation, and virulence. To our knowledge, this is the first analysis of the B. pertussis proteome during adaptation to the intramacrophage environment and the data provide new clues for understanding B. pertussis adaptation and pathogenesis. BIOLOGICAL SIGNIFICANCE: B. pertussis is a respiratory pathogen that has adapted exclusively to the human host. Despite high vaccination rates, whooping cough remains a serious threat to human health and its incidence has been increasing in recent years in vaccinated populations. The mechanisms that allow this pathogen to evade immune clearance, persist in the host, and cause a prolonged paroxysmal cough are still poorly understood. Recent studies regarding B. pertussis survival inside host cells and the cellular response to this bacterial infection indicate that B. pertussis may have an intracellular phase during infection which probably contributes to persistence and vaccine failure. In this study we provide the first global proteome profile of B. pertussis within macrophages. The data provide novel insights into the adaptive responses elicited by these bacteria for physiological adaptation to the host environment.
