IgA nephropathy (IgAN) is a progressive form of kidney disease defined by glomerular deposition of IgA. Here we performed a genome-wide association study of 10,146 kidney-biopsy-diagnosed IgAN cases and 28,751 controls across 17 international cohorts. We defined 30 genome-wide significant risk loci explaining 11% of disease risk. A total of 16 loci were new, including TNFSF4/TNFSF18, REL, CD28, PF4V1, LY86, LYN, ANXA3, TNFSF8/TNFSF15, REEP3, ZMIZ1, OVOL1/RELA, ETS1, IGH, IRF8, TNFRSF13B and FCAR. The risk loci were enriched in gene orthologs causing abnormal IgA levels when genetically manipulated in mice. We also observed a positive genetic correlation between IgAN and serum IgA levels. High polygenic score for IgAN was associated with earlier onset of kidney failure. In a comprehensive functional annotation analysis of candidate causal genes, we observed convergence of biological candidates on a common set of inflammatory signaling pathways and cytokine ligand-receptor pairs, prioritizing potential new drug targets.

• MeSH
• celogenomová asociační studie MeSH
• IgA nefropatie * farmakoterapie   genetika   diagnóza   MeSH
• imunoglobulin A genetika   MeSH
• myši MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH
• Názvy látek
• imunoglobulin A MeSH

Membranous Nephropathy (MN) is a rare autoimmune cause of kidney failure. Here we report a genome-wide association study (GWAS) for primary MN in 3,782 cases and 9,038 controls of East Asian and European ancestries. We discover two previously unreported loci, NFKB1 (rs230540, OR = 1.25, P = 3.4 × 10-12) and IRF4 (rs9405192, OR = 1.29, P = 1.4 × 10-14), fine-map the PLA2R1 locus (rs17831251, OR = 2.25, P = 4.7 × 10-103) and report ancestry-specific effects of three classical HLA alleles: DRB1*1501 in East Asians (OR = 3.81, P = 2.0 × 10-49), DQA1*0501 in Europeans (OR = 2.88, P = 5.7 × 10-93), and DRB1*0301 in both ethnicities (OR = 3.50, P = 9.2 × 10-23 and OR = 3.39, P = 5.2 × 10-82, respectively). GWAS loci explain 32% of disease risk in East Asians and 25% in Europeans, and correctly re-classify 20-37% of the cases in validation cohorts that are antibody-negative by the serum anti-PLA2R ELISA diagnostic test. Our findings highlight an unusual genetic architecture of MN, with four loci and their interactions accounting for nearly one-third of the disease risk.

• MeSH
• alely MeSH
• Asijci genetika   MeSH
• běloši genetika   MeSH
• celogenomová asociační studie * MeSH
• interferonové regulační faktory genetika   MeSH
• jednonukleotidový polymorfismus MeSH
• lidé MeSH
• membranózní glomerulonefritida diagnóza   genetika   imunologie   MeSH
• molekulární modely MeSH
• NF-kappa B - podjednotka p50 genetika   MeSH
• receptory pro fosfolipasy A2 genetika   MeSH
• sekvence aminokyselin MeSH
• studie případů a kontrol MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• interferon regulatory factor-4 MeSH Prohlížeč
• interferonové regulační faktory MeSH
• NF-kappa B - podjednotka p50 MeSH
• NFKB1 protein, human MeSH Prohlížeč
• PLA2R1 protein, human MeSH Prohlížeč
• receptory pro fosfolipasy A2 MeSH

ISSUES: Smoking prevalence in European countries is high. Adequately trained physicians can play a key role in reducing smoking rates in Europe. This paper provides an overview of postgraduate smoking cessation training for physicians in Europe. APPROACH: Two methods were used: (i) a review of the Europe-based published and grey literature between 1999 and 2009 on postgraduate education programs for physicians in smoking cessation; and (ii) a survey of key informants identified through two European tobacco control list serves. KEY FINDINGS: A total of nine relevant articles were identified through the literature search which showed over 170 postgraduate training programs offered in Europe in smoking cessation. The survey resulted in a 100% response rate from 38 key informants from 28 European countries. Respondents from all countries except Latvia reported knowledge of the existence of smoking cessation training programs. Course content included brief intervention training (93%), pharmacotherapy (96%), motivational interviewing skills (85%) and training in the stages of change (89%). Participation by physicians in these courses was reported to be low (ranging in total participation estimates from 15 to 1100 per country). IMPLICATIONS: The study showed numerous training opportunities for physicians in Europe. However, postgraduate training in smoking cessation might not be reaching physicians and might not be rigorously evaluated. CONCLUSIONS: It is imperative that the effectiveness of the programs in changing provider practices and patient smoking outcomes is adequately evaluated. Further research is also indicated for methods of disseminating effective educational activities throughout Europe with the intention of increasing participation.

• MeSH
• kontinuální vzdělávání lékařů metody   trendy   MeSH
• kouření terapie   MeSH
• lékaři * trendy   MeSH
• lidé MeSH
• odvykání kouření metody   MeSH
• poruchy vyvolané užíváním tabáku epidemiologie   prevence a kontrola   terapie   MeSH
• prevence kouření MeSH
• role lékaře MeSH
• sběr dat metody   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Geografické názvy
• Evropa epidemiologie   MeSH