Abstract
BackgroundWhile BMPR2 mutation strongly predisposes to pulmonary arterial hypertension (PAH), only 20% of mutation carriers develop clinical disease. This finding suggests that modifier genes contribute to FPAH clinical expression. Since modifiers are likely to be common alleles, this problem is not tractable by traditional genetic approaches. Furthermore, examination of gene expression is complicated by confounding effects attributable to drugs and the disease process itself.MethodsTo resolve these problems, B-cells were isolated, EBV-immortalized, and cultured from familial PAH patients with BMPR2 mutations, mutation positive but disease-free family members, and family members without mutation. This allows examination of differences in gene expression without drug or disease-related effects. These differences were assayed by Affymetrix array, with follow-up by quantitative RT-PCR and additional statistical analyses.ResultsBy gene array, we found consistent alterations in multiple pathways with known relationship to PAH, including actin organization, immune function, calcium balance, growth, and apoptosis. Selected genes were verified by quantitative RT-PCR using a larger sample set. One of these, CYP1B1, had tenfold lower expression than control groups in female but not male PAH patients. Analysis of overrepresented gene ontology groups suggests that risk of disease correlates with alterations in pathways more strongly than with any specific gene within those pathways.ConclusionDisease status in BMPR2 mutation carriers was correlated with alterations in proliferation, GTP signaling, and stress response pathway expression. The estrogen metabolizing gene CYP1B1 is a strong candidate as a modifier gene in female PAH patients.
Highlights
While BMPR2 mutation strongly predisposes to pulmonary arterial hypertension (PAH), only 20% of mutation carriers develop clinical disease
BMPR2 mutation carriers with disease show alteration in multiple PAH-related pathways compared to unaffected carriers RNA derived from lymphoblastoid lines from four affected and three unaffected BMPR2 mutation carriers were used to probe Affymetrix U133 Plus 2.0 gene expression arrays
A comparison of unaffected to affected mutation carriers using moderately strict criteria resulted in a list of 80 genes consistently differentially regulated between groups[18]. These fell into several broad groups with known relevance to PAH, including stress response, actin organization, and proliferation (Figure 1, Additional File 1 – altered genes tabulated by group)
Summary
While BMPR2 mutation strongly predisposes to pulmonary arterial hypertension (PAH), only 20% of mutation carriers develop clinical disease. Understanding modifier genes would both clarify the molecular etiology of the disease, which is obscured by the myriad of BMPR2 functions, and allow the FPAH risk to be refined for asymptomatic individuals that carry BMPR2 mutations The search for these modifiers, which has been ongoing for several years, is complicated by many factors[5,6]. Since the modifier alleles are likely to be common variants, traditional genetic approaches are problematic, since the same allele could be associated with more than one line of inheritance within a family tree[7] This is further complicated by the possibility that predisposition to disease within BMPR2 mutation carriers is caused by a confluence of factors rather than a single modifier gene, even within a single family
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