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Variants of PBEF predispose to systemic sclerosis and pulmonary arterial hypertension development
Journal of Translational Medicine volume 8, Article number: P46 (2010)
Pre B-cell colony-enhancing factor (PBEF) is intricately involved in inflammation and fibrosis, functional polymorphisms of PBEF have been previously shown to influence PBEF expression and pulmonary damage. Systemic sclerosis (SSc) is a disease in which inflammation, fibrosis and pulmonary deterioration are prominent hallmarks. Therefore we here investigate the role of the PBEF -1001T>G and PBEF -1543C>T polymorphisms in the genetic predisposition to systemic sclerosis (SSc) susceptibility and pulmonary involvement.
Patients and methods
We genotyped DNA from 2737 SSc patients and 1913 matched healthy controls, both from 8 different ethnic populations. Genotyping was performed using custom Taqman 5´allelic discrimination assays. In addition, PBEF serum expression levels were measured by ELISA and correlated with genotypes.
In two separate populations and in a meta-analysis, the combined PBEF -1543CC -1001TT genotype, hence carrying no minor alleles, was found associated with SSc susceptibility (P=0.009 OR 1.20 (95% CI 1.05-1.37). In addition, these subjects showed an increased decline in forced vital capacity (FVC) over 15 years follow-up (P=0.02) (HR 1.64, 95%CI: 1.02-2.64) and a higher PBEF serum concentration (P<0.01), compared to carriers of minor alleles. On the other hand, patients with genotype PBEF -1001TT were at lower risk for PAH development within 15 years of disease onset compared to the carriers with genotypes PBEF-1001GG and PBEF-1001TG (P<0.001) (HR 3.29, 95%CI: 1.52-7.12).
Our data identify PBEF as a novel candidate gene that influences SSc susceptibility, pulmonary function and the development of PAH.
JCA Broen, P Gourh, M C Vonk, F C Arnett, J Martin and TRDJ Radstake contributed equally to this work.
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Broen, J., Gourh, P., Vonk, M.C. et al. Variants of PBEF predispose to systemic sclerosis and pulmonary arterial hypertension development. J Transl Med 8, P46 (2010) doi:10.1186/1479-5876-8-S1-P46
- Pulmonary Arterial Hypertension
- Minor Allele
- Forced Vital Capacity
- Systemic Sclerosis
- Functional Polymorphism