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
AIMS/HYPOTHESIS: Type 2 diabetes increases the risk of cardiovascular and renal complications, but early risk prediction could lead to timely intervention and better outcomes. Genetic information can be used to enable early detection of risk. METHODS: We developed a multi-polygenic risk score (multiPRS) that combines ten weighted PRSs (10 wPRS) composed of 598 SNPs associated with main risk factors and outcomes of type 2 diabetes, derived from summary statistics data of genome-wide association studies. The 10 wPRS, first principal component of ethnicity, sex, age at onset and diabetes duration were included into one logistic regression model to predict micro- and macrovascular outcomes in 4098 participants in the ADVANCE study and 17,604 individuals with type 2 diabetes in the UK Biobank study. RESULTS: The model showed a similar predictive performance for cardiovascular and renal complications in different cohorts. It identified the top 30% of ADVANCE participants with a mean of 3.1-fold increased risk of major micro- and macrovascular events (p = 6.3 × 10-21 and p = 9.6 × 10-31, respectively) and a 4.4-fold (p = 6.8 × 10-33) higher risk of cardiovascular death. While in ADVANCE overall, combined intensive blood pressure and glucose control decreased cardiovascular death by 24%, the model identified a high-risk group in whom it decreased the mortality rate by 47%, and a low-risk group in whom it had no discernible effect. High-risk individuals had the greatest absolute risk reduction with a number needed to treat of 12 to prevent one cardiovascular death over 5 years. CONCLUSIONS/INTERPRETATION: This novel multiPRS model stratified individuals with type 2 diabetes according to risk of complications and helped to target earlier those who would receive greater benefit from intensive therapy.
- MeSH
- celogenomová asociační studie MeSH
- diabetes mellitus 2. typu * komplikace genetika MeSH
- komplikace diabetu * komplikace MeSH
- krevní glukóza MeSH
- krevní tlak genetika MeSH
- lidé MeSH
- multifaktoriální dědičnost * MeSH
- rizikové faktory MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- MeSH
- genetická predispozice k nemoci * MeSH
- lékařská genetika MeSH
- lidé MeSH
- Check Tag
- lidé 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: The mechanism explaining the inverse association between renal urate and albumin excretion remains unclear. First, we evaluated the impact of candidate variants in the main urate transporter genes (i.e., SLC2A9, SLC22A12, ABCG2) on the association between fractional excretion of uric acid (FEUA) and urinary albumin/creatinine ratio (uACR). Second, we examined uromodulin and sodium excretion as mediators of the association between FEUA and uACR. METHODS: We performed cross-sectional analysis of 737 French Canadians from the CARTaGENE cohort, a random sample of the Quebec population aged 40-69 years (a total of 20,004 individuals). Individuals with available genotyping and urinary data were obtained from a sub-study including gender-matched pairs with high and low Framingham Risk Score and vascular rigidity index. We further excluded individuals with an estimated glomerular filtration rate <60 ml/min/1.73 m2, glycosuria, and use of confounding medication. A spot urine sample was analyzed. Genotyping was performed using the Illumina Omni2.5-8 BeadChips. Genetic variants were analyzed using an additive model. RESULTS: Final analyses included 593 individuals (45.5% of men; mean age 54.3 ± 8.6). We observed an antagonistic interaction between rs13129697 variant of the SLC2A9 gene and FEUA tertiles on uACR (P = 0.002). Using the mediation analysis, uromodulin explained 32%, fractional excretion of sodium (FENa) 44%, and uromodulin together with FENa explained 70% of the inverse relationship between FEUA and uACR. Bootstrapping process confirmed the role of both mediators. CONCLUSIONS: Our data suggest that the association of albuminuria with decreased renal urate excretion may be modified by the transporter SLC2A9, and mediated by uromodulin and sodium handling.
- MeSH
- albuminurie genetika patofyziologie moč MeSH
- biologické markery moč MeSH
- dospělí MeSH
- eliminace ledvinami * MeSH
- genotyp MeSH
- hodnoty glomerulární filtrace fyziologie MeSH
- kyselina močová moč MeSH
- lidé středního věku MeSH
- lidé MeSH
- proteiny usnadňující transport glukosy genetika metabolismus MeSH
- průřezové studie MeSH
- retrospektivní studie MeSH
- senioři MeSH
- uromodulin moč MeSH
- vyšetření funkce ledvin MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- MeSH
- dějiny lékařství MeSH
- etický kodex zákonodárství a právo MeSH
- experimenty na lidech * MeSH
- genetika etika normy zákonodárství a právo MeSH
- Helsinská deklarace dějiny MeSH
- informovaný souhlas pacienta * normy zákonodárství a právo MeSH
- lidé MeSH
- lidská práva zákonodárství a právo MeSH
- mezinárodní agentury zákonodárství a právo MeSH
- placebo efekt MeSH
- směrnice jako téma MeSH
- výzkum * normy zákonodárství a právo MeSH
- zákonodárství lékařské MeSH
- Check Tag
- lidé MeSH
OBJECTIVE: We have previously reported the genetic determinants of unmet renal needs in Type 2 Diabetic (T2D) patients of the ADVANCE study (Abstract 0105-PD, IDF - World Diabetes Congress, Vancouver, 2015). We report here the external validation of several of these loci. An improved knowledge of the genetics linked to worsening diabetic nephropathy will offer insights on how to better manage this complication of diabetes and hypertension in T2D patients. DESIGN AND METHOD: We investigated 3,500 T2D patients of Caucasian origin included in the ADVANCE trial who were all treated with current standard therapies. These patients were genotyped with Affymetrix Human Genome-Wide SNP arrays 5.0 or 6.0. Renal phenotypes were defined as increasing albuminuria (non-responders) or decreasing albuminuria (responders) and declining eGFR (non-responders) or increasing eGFR (responders) during the 5-year follow-up of ADVANCE. Genome wide association studies (GWAS) were performed using PLINK (v.1.9) for albuminuria and eGFR separately both in ADVANCE and in the Czech Post-MONICA cohort. Significant SNPs (p-value of 9x10) were then catalogued, and a literature search was conducted to validate genes associated with these SNPs. RESULTS: GWAS analyses showed associations with 47 genes for eGFR non-responders. Five of these, (ERC2, ZNF385D, TRAM1L1, SHANK2, and UMOD) were previously associated with GFR or kidney failure in the literature. In addition, eight of these (CACNA2D3, NOL10, ZNF385D, TENM2, CTB-7E3.1, CDH18, LMBR1 and LOC339166) are associated with GFR in Post-MONICA cohort. For albuminuria non-responders, GWAS analysis identified 57 genes. Two of these, (CERS6 and NRXN3) were previously reported in the literature as being associated with diabetic nephropathies and four of these (CERS6, STK39, DGKB and NRXN3) are associated with uric acid (which correlates with albuminuria) in Post-MONICA. CONCLUSIONS: Literature review and analysis of Post-MONICA data has enabled the validation of genes associated with renal non-response to standard therapy in the ADVANCE study.
- Publikační typ
- časopisecké články MeSH
