An MIF Promoter Polymorphism Is Associated with Susceptibility to Pulmonary Arterial Hypertension in Diffuse Cutaneous Systemic Sclerosis

Objective.Systemic sclerosis (SSc) is a fibrotic immune-mediated disease of unknown etiology. Among its clinical manifestations, pulmonary involvement is the leading cause of mortality in patients with SSc. However, the genetic factors involved in lung complication are not well defined. We aimed to review the association of the MIF gene, which encodes a cytokine implicated in idiopathic pulmonary hypertension among other diseases, with the susceptibility and clinical expression of SSc, in addition to testing the association of this polymorphism with SSc-related pulmonary involvement.Methods.A total of 4392 patients with SSc and 16,591 unaffected controls from 6 cohorts of European origin were genotyped for the MIF promoter variant rs755622. An inverse variance method was used to metaanalyze the data.Results.A statistically significant increase of the MIF rs755622*C allele frequency compared with controls was observed in the subgroups of patients with diffuse cutaneous SSc (dcSSc) and with pulmonary arterial hypertension (PAH) independently (dcSSc: p = 3.20E–2, OR 1.13; PAH: p = 2.19E–02, OR 1.32). However, our data revealed a stronger effect size with the subset of patients with SSc showing both clinical manifestations (dcSSc with PAH: p = 6.91E–3, OR 2.05).Conclusion.We reviewed the association of the MIF rs755622*C allele with SSc and described a phenotype-specific association of this variant with the susceptibility to develop PAH in patients with dcSSc.

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Faculty Opinions recommendation of An MIF Promoter Polymorphism Is Associated with Susceptibility to Pulmonary Arterial Hypertension in Diffuse Cutaneous Systemic Sclerosis.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.727766444.793568479 ◽

2019 ◽

Author(s):

Todd Bull

Keyword(s):

Systemic Sclerosis ◽

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Promoter Polymorphism ◽

Diffuse Cutaneous Systemic Sclerosis ◽

Pulmonary Arterial

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HLA Markers for Poor Prognosis in Systemic Sclerosis Brazilian Patients

Disease Markers ◽

10.1155/2013/301415 ◽

2013 ◽

Vol 35 ◽

pp. 73-78 ◽

Cited By ~ 6

Author(s):

Ana Paula Toledo Del Rio ◽

Zoraida Sachetto ◽

Percival Degrava Sampaio-Barros ◽

João Francisco Marques-Neto ◽

Ana Carolina Santos Londe ◽

...

Keyword(s):

Systemic Sclerosis ◽

Pulmonary Arterial Hypertension ◽

Pulmonary Fibrosis ◽

Arterial Hypertension ◽

Polymerase Chain Reaction Amplification ◽

Clinical Manifestations ◽

Case Series ◽

Delta Method ◽

Hla Typing ◽

Pulmonary Arterial

Objectives. The aim of this study was to evaluate human leukocyte antigen (HLA) involvement in the disease expression and poor prognostic clinical features (pulmonary fibrosis and pulmonary arterial hypertension) in patients diagnosed with systemic sclerosis (SSc) in a multiethnic population.Methods. SSc patients followed up between 2008 and 2011 were included, and clinical data were obtained through records review. Molecular HLA typing was performed (polymerase chain reaction amplification technique using specific primer sequences). The statistical analysis involved Fisher’s exact test and Pearson's corrected chi-square test.P values≤0.05were considered significant. The delta method was used to estimate the variance of the prevalence ratio (PR).Results. A total of 141 patients (120 women and 21 men) with SSc were studied, including 33.3% with diffuse cutaneous SSc (dcSSc), 62.4% with limited cutaneous SSc (lcSSc), and 4.3% with sine scleroderma. Pulmonary fibrosis was present in 61 patients (43.3%), and the HLA-A*30 and DQB1*04 alleles were related to susceptibility. In contrast, the HLA-DRB1*01 and DQB1*05 alleles were protective. Pulmonary arterial hypertension was diagnosed in 19 patients (13.5%) and was associated with HLA-B*35 and C*04; in contrast, C*03 seemed to be protective.Conclusions. Our current study documents the association of some classes I and II HLA alleles with the most severe clinical manifestations in a multiethnic case series. Our findings differed slightly from the previous data in other populations.

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Exhaled Nitric Oxide in Pulmonary Arterial Hypertension Associated with Systemic Sclerosis

Pulmonary Circulation ◽

10.1086/688768 ◽

2016 ◽

Vol 6 (4) ◽

pp. 545-550 ◽

Cited By ~ 4

Author(s):

Zeling Cao ◽

Stephen C. Mathai ◽

Laura K. Hummers ◽

Ami A. Shah ◽

Fredrick M. Wigley ◽

...

Keyword(s):

Nitric Oxide ◽

Systemic Sclerosis ◽

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Pulmonary Involvement ◽

Control Group ◽

Significant Difference ◽

Pulmonary Capillary Blood ◽

Treatment Naïve ◽

Pulmonary Arterial

The fractional exhaled concentration of nitric oxide (FENO) has been shown to be reduced in idiopathic pulmonary arterial hypertension (PAH) but has not been adequately studied in PAH associated with systemic sclerosis (SSc). We measured FENO at an expiratory flow rate of 50 mL/s in 21 treatment-naive patients with SSc-associated PAH (SSc-PAH), 94 subjects with SSc without pulmonary involvement, and 84 healthy volunteers. Measurements of FENO at additional flow rates of 100, 150, and 250 mL/s were obtained to derive the flow-independent nitric oxide exchange parameters of maximal airway flux (J′awNO) and steady-state alveolar concentration (CANO). FENO at 50 mL/s was similar ( P = 0.22) in the SSc-PAH group (19 ± 12 parts per billion [ppb]) compared with the SSc group (17 ± 12 ppb) and healthy control group (21 ± 11 ppb). No change was observed after 4 months of targeted PAH therapy in 14 SSc-PAH group patients ( P = 0.9). J′awNO was modestly reduced in SSc group subjects without lung disease (1.2 ± 0.5 nl/s) compared with healthy controls (1.64 ± 0.9; P < 0.05) but was similar to that in the SSc-PAH group. CANO was elevated in individuals with SSc-PAH (4.8 ± 2.6 ppb) compared with controls with SSc (3.3 ± 1.4 ppb) and healthy subjects (2.6 ± 1.5 ppb; P < 0.001 for both). However, after adjustment for the diffusing capacity of CO, there was no significant difference in CANO between individuals with SSc-PAH and controls with SSc. We conclude that FENO is not useful for the diagnosis of PAH in SSc. Increased alveolar nitric oxide in SSc-PAH likely represents impaired diffusion into pulmonary capillary blood.

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