Background/Purpose: Isolated pulmonary arterial hypertension (PAH) secondary to Systemic Sclerosis (SSc) is a severe life-threatening complication. Several pathogenic pathways have been implicated in its development. Bone morphogenic protein receptor 2 (BMPR2) is a protein of the TGF-beta receptor superfamily; mutations in this gene seem to be implicated in the proliferation of pulmonary artery smooth muscle cells, a major component of pulmonary arteriolar remodeling in PAH, and they have been associated to the susceptibility to develop idiopathic and familial PAH; exon 5 has higher frequency of mutations according to previous analyses. The aim of this study was to evaluate if BMPR2 gene exon 5 mutations are associated to isolated PAH in Mexican Mestizo SSc patients.

Methods: DNA samples from 38 Mexican Mestizo SSc patients with isolated PAH (mean resting pulmonary artery pressure (PAP) >25 mmHg, pulmonary wedge pressure < 15 mmHg and pulmonary vascular resistance > 3 Wood units by right side catheterization; or systolic PAP >40 mmHg, tricuspid annular plane systolic excursion <20 mmHg and dilatation and hypertrophy of right ventricle by transthoracic echocardiogram; patients were also required to have no or minimal interstitial lung disease by computed tomography) and 38 Mexican Mestizo SSc patients without PAH, matched by SSc subtype, age (+/- 5 years), gender, time of evolution of the disease and SSc-associated autoantibody were analyzed. High resolution melting analysis (HRMA) of exon 5 of the BMPR2 gene was performed in previously amplified DNA (sense primer: 5ˈTCA TGC TAT TCT GCA TTC ATC.3ˈ, antisense primer: 5ˈCAG GTC TAG TAT CAC AGT AGA.3ˈ). Aberrant curves were considered as positive for mutation in the exon 5 of the BMPR2 gene. Severity of the organ involvement was evaluated using the Medsger severity scale. Statistical analysis was performed using SPSS v.19 and Epi-Info 7.0. Chi square was used to compare mutation frequencies between groups; Student’s t test and Wilcoxon rank test were used to compare numeric variables. Values were considered significant when two-tailed p values were <0.05.

Results: Mean age was 50 years, mean time of SSc evolution was 12.25 years, 80% of patients were female, with no differences between PAH and non-PAH patients. Mean PAP was 57 mmHg in PAH-SSc patients and 25 mmHg in non-PAH-SSc patients (p<0.001); BMPR2 gene exon 5 mutations were detected in 7 (18%) of PAH-SSc patients and in 1 (3%) non-PAH-SSc patient (p=0.001, OR: 31, 95% CI 5.1-1263). From the 7 patients with PAH that had a mutation, 6 were female, 6 had limited cutaneous SSc, 6 had severe vascular involvement (digital ulcers and/or gangrene at any time of the evolution of the disease), 1 had anti-Topoisomerase I and 2 had anti-U1-RNP antibody. Prevalence of BMPR2 gene exon 5 mutation in our sample was 11%.

Conclusion: Prevalence of BMPR2 gene exon 5 mutations in PAH-SSc patients is higher than in non-PAH-SSc patients; prevalence of BMPR2 gene exon 5 mutations in this SSc sample is similar to the prevalence reported in some idiopathic PAH studies; our results suggest that BMPR2 gene exon 5 mutations increase the risk to develop PAH in Mexican Mestizo SSc patients.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/bone-morphogenic-protein-receptor-2-bmpr2-gene-mutations-are-associated-to-the-development-of-isolated-pulmonary-arterial-hypertension-pah-in-systemic-sclerosis-ssc-patients/