| 81. |
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- Okada, Yukinori, et al.
(författare)
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Genetics of rheumatoid arthritis contributes to biology and drug discovery
- 2014
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Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 506:7488, s. 376-381
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Tidskriftsartikel (refereegranskat)abstract
- A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological data sets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA)(1). Here we performed a genome-wide association study meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating similar to 10 million single-nucleotide polymorphisms. We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 101 (refs 2-4). We devised an in silico pipeline using established bioinformatics methods based on functional annotation(5), cis-acting expression quantitative trait loci(6) and pathway analyses(7-9)-as well as novel methods based on genetic overlap with human primary immunodeficiency, haematological cancer somatic mutations and knockout mouse phenotypes-to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery.
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- Ramos-Maqueda, J, et al.
(författare)
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Lifestyle physical activity and rapid-rate non-sustained ventricular tachycardia in arrhythmogenic cardiomyopathy
- 2023
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Ingår i: Heart (British Cardiac Society). - : BMJ. - 1468-201X .- 1355-6037. ; 109:13, s. 992-999
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Tidskriftsartikel (refereegranskat)abstract
- To investigate the association of accelerometer-measured lifestyle physical activity with rapid-rate non-sustained ventricular tachycardias (RR-NSVTs) in patients with arrhythmogenic cardiomyopathy (AC).MethodsThis multicentre, observational study enrolled 72 patients with AC, including right, left and biventricular forms of the disease, with underlying desmosomal and non-desmosomal mutations. Lifestyle physical activity, objectively monitored with accelerometers (ie, movement sensors) and RR-NSVT, identified as >188 bpm and >18 beats from a textile Holter ECG for 30 days.ResultsSixty-three patients with AC (38±17.6 years, 57% men) were included. A total of 17 patients experienced ≥1 RR-NSVTs, and a total of 35 events were recorded. The odds of occurrence of ≥1 RR-NSVT during the recording did not increase as a function of either total physical activity (OR 0.95, 95% CI (CI95%) 0.68 to 1.30 for 60 min increase) or moderate-to-vigorous activities (OR 0.89, CI95%0.71 to 1.08 for 5 min increase). Participants presenting RR-NSVTs during the recording (n=17) did not present greater odds of RR-NSVT in the days with more time either in total physical activity (OR 1.05, CI95%0.84 to 1.29 for additional 60 min) or moderate-to-vigorous activities (OR 1.05, CI95%0.97 to 1.12 for additional 5 min). Physical activity levels were neither different between the patients with and without RR-NSVTs during the recording period nor in the days of occurrence of RR-NSVT compared with the rest of the days. Finally, 4 of the 35 RR-NSVTs recorded in the 30 days occurred during physical activity (3 during moderate-to-vigorous intensity and 1 during light-intensity activities).ConclusionsThese findings suggest that lifestyle physical activity is not associated with RR-NSVTs in patients with AC.
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