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Comparative Study
. 2013 May;45(5):518-21.
doi: 10.1038/ng.2581. Epub 2013 Mar 17.

"V体育官网入口" Genome-wide association analysis identifies a susceptibility locus for pulmonary arterial hypertension

Marine Germain  1 , Mélanie Eyries, David Montani, Odette Poirier, Barbara Girerd, Peter Dorfmüller, Florence Coulet, Sophie Nadaud, Svetlana Maugenre, Christophe Guignabert, Wassila Carpentier, Anton Vonk-Noordegraaf, Marilyne Lévy, Ari Chaouat, Jean-Charles Lambert, Marion Bertrand, Anne-Marie Dupuy, Luc Letenneur, Mark Lathrop, Philippe Amouyel, Thomy J L de Ravel, Marion Delcroix, Eric D Austin, Ivan M Robbins, Anna R Hemnes, James E Loyd, Erika Berman-Rosenzweig, Robyn J Barst, Wendy K Chung, Gerald Simonneau, David A Trégouët, Marc Humbert, Florent Soubrier
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Comparative Study

Genome-wide association analysis identifies a susceptibility locus for pulmonary arterial hypertension

"V体育官网入口" Marine Germain et al. Nat Genet. 2013 May.

Abstract

Pulmonary arterial hypertension (PAH) is a rare, severe disease resulting from progressive obliteration of small-caliber pulmonary arteries by proliferating vascular cells. PAH can occur without recognized etiology (idiopathic PAH), be associated with a systemic disease or occur as a heritable form, with BMPR2 mutated in approximately 80% of familial and 15% of idiopathic PAH cases. We conducted a genome-wide association study (GWAS) based on 2 independent case-control studies for idiopathic and familial PAH (without BMPR2 mutations), including a total of 625 cases and 1,525 healthy individuals. We detected a significant association at the CBLN2 locus mapping to 18q22. 3, with the risk allele conferring an odds ratio for PAH of 1. 97 (1. 59-2. 45; P = 7 VSports手机版. 47 × 10(-10)). CBLN2 is expressed in the lung, and its expression is higher in explanted lungs from individuals with PAH and in endothelial cells cultured from explanted PAH lungs. .

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Figure 1
Figure 1. CBLN2 mRNA levels are increased in lungs from PAH patients
CBLN2 mRNA levels were measured by real time RT-PCR in lungs from control (CTL, white bars, n = 9) and PAH patients (PAH, black bars, n = 6) and normalized to GAPDH mRNA levels. *** P < 0.001 vs controls.
Figure 2
Figure 2. Immunostaining of pulmonary arteries with a cerebellin 2 antibody
A/ Endothelial labeling of a pulmonary artery with intimal fibrosis (see arrows) B/ Endothelial labeling of a plexiform lesion (red arrows), labeling of intravascular cellular elements (erythrocytes, leukocytes) (green arrow), background-staining in some areas (black arrow); C/ Pulmonary artery from a control patient without labeling. Scattered bronchial cells are labeled (black arrows).
Figure 3
Figure 3. CBLN2 mRNA levels in pulmonary vascular cells from PAH patients
CBLN2 mRNA levels were measured by real time RT-PCR in cultured pulmonary artery endothelial cells (PA-EC) and pulmonary artery smooth muscle cells (PA-SMC) from controls (CTL, white bars, n = 10 for PA-EC and n = 10 for PA-SMC) and PAH patients (PAH, black bars, n = 8 for PA-EC and n = 5 for PA-SMC) and normalized to GAPDH mRNA levels. * P < 0.05 vs controls.
Figure 4
Figure 4. Cell proliferation in pulmonary artery smooth muscle cells (PA-SMC) treated with CBLN2
Cell proliferation was measured by BrdU incorporation in PA-SMC cultured in complete medium with 5 % fetal calf serum (FCS) or depleted medium (0.2 % FCS) and treated with CBLN2 peptide at concentrations ranging from 0 to 10 nM. A significant decrease in the proliferation of PA-SMC was observed when cells were treated with increasing doses of CBLN2 peptide. Each symbol represents the value for one experiment. The log-linear regression line is indicated (n = 4, log-linear regression test, P = 6.33 x 10−4).
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VSports在线直播 - References

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