Abstract
Background: Lymphangioleiomyomatosis (LAM) is a rare disease of women. Decline in lung function is variable making appropriate targeting of therapy difficult. We used unbiased serum proteomics to identify markers associated with outcome in LAM.
Methods: 101 women with LAM and 22 healthy controls were recruited from the National Centre for LAM (Nottingham, UK). 152 DNA and serum samples with linked lung function and outcome data were obtained from patients in the NHLBI LAM Registry (USA). Proteomic analysis was performed on a discovery cohort of 50 LAM and 20 control sera using a SCIEX SWATH mass spectrometric workflow. Protein levels were quantitated by ELISA and SNPs in GC encoding Vitamin D Binding Protein (VTDB) genotyped.
Results: Proteomic analysis showed VTDB was 2.6 fold lower in LAM than controls. Serum VTDB was lower in progressive compared with stable LAM (p=0.001) and correlated with diffusing capacity (p=0.01). Median time to death or lung transplant was reduced by 46 months in those with CC genotypes at rs4588 and 38 months in those with non-A containing haplotypes at rs7041/4588 (p=0.014 and 0.008 respectively).
Conclusions: The VTDB axis is associated with disease severity and outcome, and GC genotype could help predict transplant free survival in LAM.
Footnotes
This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.
Dr. Farmaki has nothing to disclose.
Dr. Boocock has nothing to disclose.
Dr. Coveney has nothing to disclose.
Prof. McCormack reports non-financial support from LAM Therapeutics, Takeda. V.C., Sanofi-Aventis U.S, Promedior and Gilead Sciences. Personal fees from Boehringer Ingelheim International, F. Hoffmann-La Roche, and Novartis outside the submitted work; In addition, Prof. McCormack has a patent: Use of VEGF-D in the diagnosis of lymphangioleiomyomatosis issued and his spouse owns stocks, stock options, and has other ownership interests in Sanofi-Aventis, U.S.
Mrs Johnson has nothing to disclose.
Dr. Gupta has nothing to disclose.
Dr. Miller has nothing to disclose.
Dr. Johnson reports grants from NIHR, grants from LAM Foundation, during the conduct of the study.
Prof. Tobin reports grants from GSK, grants from Pfizer, outside the submitted work.
Prof. Wain reports grants from GlaxoSmithKline, grants from Pfizer, outside the submitted work.
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