Fig. 6.1
Molecular pathogenesis of hereditary PAH. BMP binds to BMPR2. Upon ligand binding, the type II receptor phosphorylates a type I receptor, including ALK1, ALK2, ALK3 or ALK6. This leads to phosphorylation of Smad1/5/8 and phosphorylation of Smad4 with translocation of the phosphorylated Smads to the nucleus to modulate the expression of target genes. Upon TGFβ ligand binding, the TGFβ type II receptor phosphorylates a type I receptor, ALK5. This leads to phosphorylation of Smad2/3 which phosphorylate Smad4 and translocate to the nucleus. Endoglin is an accessory membrane glycoprotein that interacts with signaling receptor complexes for the BMP and TGF-β superfamily. Caveolin-1 normally dampens BMP signaling by inhibiting receptors or their signaling downstream to prevent vascular proliferation. Lack of caveolin-1 causes activation of STAT3 and ERK1/2 signaling, activation of Ras/p42/44/MAP kinase and upregulation of cyclin D1. Caveolin-1 functions as a tonic inhibitor of eNOS to facilitate NO mediated relaxation. Caveolin-1 modifies TGF beta signaling at the plasma membrane which may provide a mechanistic link between Caveolin–1 and BMPR2 mutations in the pathogenesis of PAH. KCNK3 is a potassium channel protein in pulmonary artery smooth muscle cells. Activation of K+ channel causes K+ efflux, membrane hyper polarization, and vasodilatation [67]. PAH pulmonary arterial hypertension, BMP bone morphogenetic protein, BMPR2 bone morphogenetic protein receptor 2, ALK activin-like kinase, TGFβ transforming growth factor beta, STAT3 signal transducer and activator of transcription 3, ERK extracellularly-regulated kinase, MAP mitogen activated kinase, NO nitric oxide, KCNK3 Potassium channel subfamily K, member 3
In addition to rare mutations as a monogenic cause of HPAH, GWAS performed in a cohort of idiopathic and familial PAH patients identified an association of common variants in CBLN2 with a twofold increased risk of disease expression [43]. CBLN2 is expressed in the lung, with higher expression in explanted lungs from individuals with PAH and in endothelial cells cultured from explanted PAH lungs.
In addition to germ line mutations, somatic changes may also play a role in the pathogenesis of PAH. In normal pulmonary arteries, endothelial cells grow in a monolayer. In the lungs of patients with severe pulmonary hypertension, there is dysregulation of endothelial cell growth, forming intravascular plexiform lesions [121]. Endothelial cells within the plexiform lesions are clonal and arise from a single cell. These cells are genetically unstable and exhibit microsatellite instability and contain mutations in the TGF-β receptor II (TGFBR2) and BCL-2 associated X-protein (BAX) genes. Additionally, protein expression of TGF-BRII (6 of 19 lesions) and BAX (4 of 19 lesions) proteins was reduced in endothelial cells within plexiform lesions [121]. Chromosome abnormalities were identified in five out of nine pulmonary artery endothelial cells and smooth muscle cells analyzed by chromosome microarray from PAH patients [3]. Four of these were whole chromosome losses; the X chromosome was deleted in three female subjects, one patient harbored a germline BMPR2 mutation and somatic loss of chromosome 13, which constitutes a second genetic hit in the same pathway by deleting SMAD8. The fifth abnormality was an interstitial deletion of the short arm of chromosome-8, 8p23.1-p12. These chromosome abnormalities may confer a growth advantage, and, thus, contribute to disease progression [3].
Germline chromosome copy number changes and microdeletion/duplications associated with pulmonary hypertension have not been studied extensively. A germline micro deletion of 17q22q23.2, encompassing T-box transcription factor-2 and 4 (TBX2 and TBX4) was, however, identified in a patient with a syndromic disorder that included pulmonary hypertension [85].
Epigenetic changes do not alter the DNA sequence [17]. Changes in the methylation of superoxide dismutase were found in cells from the pulmonary vasculature in PAH patients [5]. Down regulation of superoxide dismutase 2 (SOD2) and normoxic activation of hypoxia inducible factor (HIF-1α) were found in pulmonary arteries and plexiform lesions in PAH [14, 16]. Decrease in SOD2 results from methylation of CpG islands in SOD2 by lung DNA methyltransferases. The partial silencing of SOD2 alters redox signaling, activates HIF-1α and leads to excessive cell proliferation.
Histone deacetylases (HDACs) catalyze removal of acetyl groups from lysine residues in a variety of proteins. HDACs regulate gene transcription by deacetylating nucleosomal histones. Expression of Class I HDACs is elevated dramatically in pulmonary arteries of PAH patients [122], and recent studies have demonstrated that Class I specific HDAC inhibitors can prevent hypoxia-induced pulmonary arteriole remodeling to preserve right ventricular function [22].
Pediatric PAH
PAH in children is much more heterogeneous than in adults and can be associated with congenital heart disease (CHD), bronchopulmonary dysplasia, vascular disease, pediatric lung disease, hepatic disease, pediatric thromboembolic disease and hematological disorders. The prevalence of IPAH/ HPAH in children was estimated to be ~2.2 cases per million with a lower female/male ratio (1.8:1) compared to adults [95]. The natural history of IPAH in children is poor, with a median untreated survival after diagnosis of 10 months compared to 2.8 years for adults [32]. In children, BMPR2 mutations have been evaluated with variable results. One study identified no BMPR2 mutations in 13 children with IPAH [46] while in a study reported by Harrison and colleagues, 22 % of children with IPAH or pulmonary hypertension associated with CHD had ALK1, ENG or BMPR2 mutations [49]. BMPR2 mutation positive children appeared less likely to respond to acute vasodilators than mutation negative children [95].
Other genes are likely to play an important role in childhood PAH. Two novel missense mutations (c.479 G > A S160N, c.1176 C > A F392L) in BMPR1B were identified in pediatric IPAH [26]. The F392L variant was inherited from unaffected father and S160N was not tested in proband’s parents because their samples were not available. These two variants are located in highly conserved BMPR1B protein regions. Functional studies showed the transcriptional activation of the BMPR1B F392L protein with SMAD8 increased above that of wild-type BMPR1B with SMAD8, and those of BMPR1B S160N and F392L with SMAD8 and SMAD4 were each increased above those of the wild-type BMPR1B with SMAD8 and SMAD4.
Two novel missense mutations (c.2519 G > A p.G840E, c.2698 A > C p.T900P) in NOTCH3 were identified in two PAH patients. Whether these two variants are inherited or de novo is unknown because samples from probands’ parents were not available. These variants are located in highly conserved NOTCH3 protein regions, and functional studies indicated these mutations were involved in cell proliferation and viability [27].
Persistent Pulmonary Hypertension of the Newborn
Persistent pulmonary hypertension of the newborn (PPHN) is characterized by severe hypoxemia shortly after birth, absence of cyanotic congenital heart disease, marked pulmonary hypertension, and vasoreactivity with extrapulmonary right-to-left shunting of blood across the ductus arteriosus and/or foramen ovale. A recent study suggested PPHN is a frequent and life-threatening complication in patients with mutations in TMEM70 which causes a rare nuclear ATP synthase deficiency in pulmonary vascular endothelial cells [21].
Pulmonary Hypertension Secondary to CHD
Pulmonary arterial hypertension is a complication of CHD, most commonly occurring in patients who have systemic-to-pulmonary shunts with increased pulmonary blood flow. With increasing survival of patients with CHD after early surgical repair, PAH associated with CHD is now more common: approximately 5 % of adults with CHD develop PAH. Among adults with PAH, 11.3 % have PAH-CHD, whereas in children, almost half of all PAH cases are linked to CHD [42]. The pathophysiology of PAH with CHD varies according to the underlying structural heart defect, presence and size of intra- or extra-cardiac shunt, and status of the right ventricle. There are cases in which the PAH-CHD cannot be explained fully by the associated cardiac defect alone, and in these cases other mechanisms are likely to be responsible for pulmonary vascular dysfunction. Examples include patients with PAH and small atrial or ventricular septal defects. Interestingly, in one study BMPR2 mutations were identified in 6 % of adults and children with PAH-CHD [92], although this mutation is not known to associate with the pathogenesis of structural heart disease per se. In a different study, one BMPR2 mutation and one Endoglin mutation were identified in 11 children with CHD-PAH [88].
Pulmonary Hypertension Associated with Chronic Obstructive Pulmonary Disease
Chronic obstructive pulmonary disease (COPD) is a group of obstructive lung diseases, primarily emphysema and chronic bronchitis, which can lead to pulmonary hypertension and cor pulmonale. Alpha-1-antitrypsin deficiency, caused by mutations in the serpin peptidase inhibitor, clade A, member 1 (SERPINA1) gene is inherited as an autosomal recessive disorder characterized by increased risk for the development of severe destructive lung disease, such as emphysema, at an early age [99]. Pulmonary hypertension occurs in one-third of these patients.
Co-morbidities Associated with PAH
Several coexisting medical conditions have been associated with pulmonary arterial hypertension including connective tissue disease, infection with the human immunodeficiency virus (HIV), human herpes virus, portal hypertension, thrombocytosis, hemoglobinopathies, and hereditary hemorrhagic telangiectasia [38]. Hepatopulmonary syndrome (HPS) affects 10–30 % of patients with cirrhosis and portal hypertension. One study showed that polymorphisms in eight genes (Caveolin 3, ENG, NADPH Oxidase 4, Estrogen receptor 2, von Willebrand factor, Runt–related transcription factor 1, Tyrosine kinase with immunoglobulin and EGF factor homology domains factor 1) were associated with disease expression, possibly through the regulation of angiogenesis modulating the risk of HPS [93]. Connective tissue disease-associated PAH may be observed in systemic sclerosis (SSc), mixed connective tissue disease and systemic lupus erythematosus, and is most commonly seen in systemic sclerosis (with reported prevalence varying from 4.9 to 26.7 %). Human leukocyte antigen (HLA) DRw52 and DRw6 are associated with significantly increased risks of SSc-PAH [62]. However, sequencing has not identified mutations in TGFβ receptor genes, including BMPR2, ALK1, TGFBR2 and ENG, in SSc-PAH patients [60, 82, 101].
Pulmonary Venous Hypertension
Pulmonary venous hypertension (PVH) is a well-described cause of pulmonary hypertension in patients with left heart disease associated with elevated left heart filling pressure from a number of processes, including left ventricular systolic dysfunction, left-sided valvular disease, constrictive pericardial disease, and restrictive cardiomyopathies. Traditionally, PVH has been defined as a mean pulmonary artery pressure ≥25 mmHg, pulmonary capillary wedge pressure ≥15 mmHg, and transpulmonic gradient <10 mmHg. Risk factors associated with pulmonary venous hypertension are age ≥80 years, left ventricular end diastolic pressure ≥25 mmHg, atrial arrhythmias, chronic obstructive pulmonary disease, and dyspnea on exertion. The spectrum of vascular remodeling seen in PVH varies widely among patients.
Pulmonary Veno-Occlusive Disease
Pulmonary veno-occlusive disease (PVOD) is a rare cause of pulmonary hypertension. Annual incidence of PVOD is approximately 0.1–0.2 cases per million persons in the general population [97]. Unlike IPAH, there does not appear to be a clear gender imbalance among patients with PVOD [73]. Pathologically, PVOD is characterized by the extensive and diffuse obliteration of small pulmonary veins or venules by fibrous tissue. Pulmonary parenchymal abnormalities are common: interstitial edema, pleural effusions and areas of pulmonary hemorrhage are often present [73]. In PVOD, the pressure gradient between the pulmonary capillary wedge and left ventricular compartments at end-diastole is generally increased in affected vascular beds compared to normal lung vascular regions.
The etiology of PVOD remains largely unknown. Infection, toxic exposure, thrombophilia and autoimmune diseases are associated with development of the disease. PVOD presents both sporadically and as familial cases, indicating a genetic cause for at least some forms of PVOD. Mutations in BMPR2 have been reported in patients with PVOD [81]. Recently, mutations in Eukaryotic Translation Initiation Factor 2 Alpha Kinase 4 (EIF2AK4) were identified in multiple independent families with an autosomal recessive form of PVOD [13, 36]. All affected individuals in 13 familial cases carried deleterious homozygous or compound-heterozygous rare variants in EIF2AK4. Additional mutation screening demonstrated EIF2AK4 mutations in 5/20 (25 %) of idiopathic cases of pulmonary capillary hemangiomatosis (PCH) /PVOD [13, 36]. The protein product of EIF2AK4 belongs to a family of kinases that regulates angiogenesis, and the alpha subunit of this protein plays a critical role in the induction of angiogenesis, proliferation, and resistance to apoptosis in stressful environments. Moreover, EIF2AK4 interacts with SMAD4, SMAD1, ALK-1, ENG, and TGFBR2, thereby interacting with the BMPR2-associated signaling network.
When hemoptysis or hemorrhagic pulmonary effusion, interstitial lung infiltrates, or signs of post capillary pulmonary hypertension are present in the setting of pulmonary hypertension, both PCH and pulmonary veno-occlusive disease should be considered [4]. PCH is caused by the proliferation of pulmonary capillaries infiltrating vascular, bronchial, and interstitial pulmonary structures. Most PCH cases are sporadic, but hereditary forms of PCH consistent with autosomal-recessive transmission have been reported. PCH occurs in young adults and is often only diagnosed after death on autopsy. Pathology demonstrates thickened inter alveolar septae infiltrated by numerous thin-walled vessels and infiltration by capillaries into the walls of pulmonary vessels and bronchi. Signs of post capillary pulmonary hypertension (Kerley B lines, transudative pleural effusion, or a high pulmonary artery wedge pressure) are absent in pulmonary hypertension.
The classification of pulmonary hypertension proposed in the new Dana Point Classification was to maintain European Respiratory Society guidelines, which combined PCH and PVOD into a single subcategory within PAH because of specific similarities in their diagnosis, prognosis, and management. Genetic studies have identified compound heterozygous mutations in EIF2AK4 in familial PCH and in 2/10 cases of sporadic PCH. Thus, EIF2AK4 mutations are associated with both PCH and PVOD, which suggests there is a common underlying molecular etiology for PVOD and PCH. [13].
Pulmonary Hypertension due to Luminal Embolism or Chronic Thrombotic Embolic Disease
Pulmonary Embolism
Pulmonary embolism (PE) is common, with an incidence of one to two cases per 1000 person per year [123], which usually occurs in association with deep vein thrombosis. Both inherited and environmental risk factors such as immobility or estrogens predispose to venous thromboemboli (VTE). Approximately 20 % of patients with VTE are believed to have identifiable genetic risk factors, including factor V (F5) Leiden, prothrombin gene mutation G20210A, or deficiencies of protein C, protein S or antithrombin III (AT-III) [12, 29, 45, 89]. The prevalence of factor V Leiden mutations is 9.1 % (272/2977) in patients with isolated PE and 19.4 % (1576/8140) in patients with VTE with or without concomitant PE [34]. The most frequent point mutation in F5 is R506Q. It occurs at one of three cleavage sites for activated protein C and renders factor V relatively resistant to degradation. This mutation is carried by approximately 2–7 % of Caucasians [72] and present in 1–2 % of African Americans [23, 44]. Several other missense mutations and small insertion/deletions have been identified in F5. Heterozygous carriers of Factor V Leiden have a fivefold increased risk of venous thromboembolism, and that risk is increased 10- to 80-fold in homozygotes [61]. According to American College of Medical Genetics, genetic testing should be performed in patients presenting with idiopathic VTE at age <50 or in recurrent VTE irrespective of age. Patients found to have the factor V Leiden mutation may require prolonged oral anticoagulation.
The prothrombin 20210G > A variant in the 3’ untranslated region of the prothrombin gene is present in 2 % of the general population, 6–9 % of individuals with a single VTE, and up to 18 % of individuals with a personal and family history of thrombosis [33, 63, 75, 89]. Carriers of both Factor V Leiden and the Prothrombin 20210G > A variant are found in approximately 0.1 % of the Caucasian population. Mutations in Protein C and Protein S are approximately tenfold less common than Factor V Leiden mutation, with a combined prevalence of 1 % of the population and are found in 1–3 % of individuals with VTE [77]. The 677C > T variant in the Methylenetetrahydrofolate reductase (MTHFR) gene results in a variant thermolabile enzyme with reduced activity for the remethylation of homocysteine. Homozygosity for 677C > T occurs in 10–20 % of the general population and predisposes to mild hyperhomocysteinemia, usually in the setting of suboptimal folate levels [119]. One or more of the genetic variants described above was present in 62.2 % (56/90) of patients with PE [106].
Pulmonary Hypertension due to Chronic Thrombotic Embolic Disease
Patients with recurrent pulmonary emboli are at risk of developing chronic thrombotic embolic pulmonary hypertension (CTEPH), although <1 % of patients with antecedent luminal PE later develop this form of pulmonary vascular disease. Patients with CTEPH have progressive dyspnea, and often present with normal chest radiographs and pulmonary function tests. The diagnosis is suggested when a ventilation perfusion scan shows large perfusion defects with relatively normal ventilation. Pulmonary endarterectomy remains the primary treatment for CTEPH, although recently the soluble guanylyl cyclase stimulator riociguat was demonstrated to significantly improve exercise tolerance and survival in the patient population. Importantly, CTEPH can develop in the setting of chronic PE and is associated with some of the same genetic thromboembolic risk factors reviewed above including factor VIII [55, 59].
Pulmonary Embolism and Pulmonary Hypertension in Sickle Cell Disease, Thalassemia and Other Hemolytic Anemia
Hemolytic anemia includes several genetic diseases such as sickle cell disease, thalassemia, Glucose-6-phosphate dehydrogenase (G6PD) deficiency, pyruvate kinase deficiency, congenital hereditary spherocytosis and paroxysmal nocturnal hemoglobinuria, as well as autoimmune diseases, infection, transfusion and medication induced hemolytic anemia. Patients with hemolytic anemia express a hypercoagulable state [6], and are thus at risk for developing thrombotic complications, including VTE and in situ pulmonary vascular thrombosis.
Sickle cell disease (SCD) is an autosomal recessive genetic disorder due to the E6V mutation in the β-globin gene. Rigidity of erythrocytes leads to hemolysis and veno-occlusion. Heterozygous sickle cell disease increases the risk of PE by approximately fourfold, which is among the most frequent cause of death in this patient population [1]. Indeed, pulmonary hypertension has emerged as a major chronic cardiopulmonary complication of SCD, afflicting 20–30 % of SCD patients. The pathogenesis of PH-SCD is complex and may involve hemolysis that depletes nitric oxide synthesis, prothrombotic state/ thromboembolic disease, iron overload, chronic liver disease, HIV infection, nocturnal hypoxemia, left ventricular diastolic dysfunction, and loss of splenic function [71].
Thalassemia is caused by a partial or complete deficiency of either α or β-globin chain synthesis. Beta-thalassemia is one of the most common autosomal recessive disorders worldwide. Thromboembolic events and pulmonary hypertension are more common in β-thalassemia intermedia [58].
Hemolytic anemia caused by red blood cell (RBC) enzymopathies often occur due to congenital enzyme deficiencies in erythrocyte metabolic pathways. The most common hemolytic anemia is G6PD deficiency caused by X-linked mutations in the G6PD gene that normally provides defense against oxidative damage [80]. Red cell pyruvate kinase (PK) deficiency is the most common cause of hereditary nonspherocytic hemolytic anemia and is caused by recessively inherited mutations in the gene encoding pyruvate kinase [112]. Other hemolytic anemias due to RBC enzymopathies include recessively inherited mutations in adenylate kinase (AK) [79], uridine 5-prime monophosphate hydrolase (NT5C3A) [76], hexokinase (HK) and phosphofructokinase (PFK) [78]. Phosphoglycerate kinase 1 (PGK1) deficiency is an X-linked recessive hemolytic anemia caused by mutations in PGK1 [25].
Pulmonary Vascular Malformation
Pulmonary vascular malformations are congenital anomalies that occur in pulmonary arteries, veins and capillaries. It is a group of diseases that includes pulmonary arterial and venous malformations, hereditary hemorrhagic telangiectasia, alveolar capillary dysplasia, Ehlers-Danlos syndrome and arterial tortuosity syndrome. Although these syndromes are rare, they are associated with the development of clinically significant pulmonary hypertension.
Pulmonary Arterial Venous Malformations
Pulmonary arteriovenous malformations (PAVMs) are low-resistance, high flow-through vascular structures that connect pulmonary arteries to pulmonary veins abnormally, bypassing the normal pulmonary capillary bed and resulting in an intrapulmonary right to left shunt. As a consequence, PAVMs predispose to hypoxemia and paradoxical emboli. PAVMs are rare (incidence of 2–3 per 100,000), affect females preferentially (male-to-female ratio ~1:1.5–1.8), and hereditary, occurring predominately in association with HHT. Hereditary PAVMs tend to increase in size over time, usually expanding and becoming more evident in the second and third decades of life. Sporadic cases can be caused by infections (such as schistosomiasis and actinomycosis), trauma, and Fanconi syndrome, or occur secondary to hepatopulmonary syndrome or bidirectional cavopulmonary shunts [19].
Hereditary Hemorrhagic Telangiectasia
Hereditary hemorrhagic telangiectasia, or Rendu-Osler-Weber syndrome, is a rare autosomal dominantly inherited disease with a prevalence of 1 or 2 per 100,000. The disease is characterized by vascular dysplasia leading to telangiectasias and arteriovenous malformations of the skin, mucosa, and viscera. Between 20 and 23 % of HHT patients have pulmonary arteriovenous malformations (PAVMs), and, thus, are at risk for pulmonary hypertension [90, 114, 107]. Mutations in ENG or ALK1 are the predominant genetic causes of HHT (62.5 %), although a small percentage of cases (1–2 %) express mutations in SMAD4 in association with juvenile polyposis. Overall, however, ALK–1 mutations are the most common genetic cause of HHT-associated PAH [48, 64, 111] and pulmonary arterio-venous malformations [113].
Alveolar Capillary Dysplasia
Alveolar capillary dysplasia with misalignment of the pulmonary veins (ACD/MPV) is a rare childhood disorder that carries a mortality rate approaching 100 %. The pathogenesis of both ACD/MPV and its association with pulmonary hypertension are not well understood. ACD/MPV usually presents with minimal or no parenchymal lung disease and diagnosis is based upon the pathology of immature lobular development, decreased number of pulmonary capillaries located away from the alveolar, epithelium thickened alveolar septae, medial hypertrophy of small pulmonary arteries, muscularization of distal arterioles and malposition of pulmonary vein branches adjacent to pulmonary arteries [20]. Most of ACD/MPV cases are sporadic, but approximately 10 % are familial. Pedigrees suggest both autosomal dominant and recessive patterns of inheritance. Heterozygous point mutations and microdeletions in forkhead box F1 (FOXF1) were identified in 40 % ACD/MPV patients [102, 109].
Ehlers-Danlos Vascular Disease
Ehlers-Danlos syndrome is a group of inherited connective tissue disorders of collagen synthesis. Type IV Ehlers-Danlos syndrome (vascular type) is due to autosomal dominantly inherited defects of type III collagen (COL3A1) synthesis and is characterized by abnormal fragility of blood vessels leading to spontaneous rupture or dissection of blood vessels. Respiratory complications include hemoptysis and hemopneumothorax. In extreme cases the lungs demonstrate diffuse hemorrhage with hemosiderin-laden alveolar macrophages or old/organized thrombi in the small bronchi [51].
Arterial Tortuosity Syndrome
Arterial tortuosity syndrome (ATS) is a rare autosomal recessive disorder characterized by tortuosity, elongation, stenosis and aneurysm formation in the systemic and pulmonary arteries. Disruption of elastic fibers in the medial layer of the arterial wall is observed. ATS is caused by mutations in the solute carrier family 2, member 10 (SLC2A10) gene, encoding the facilitative glucose transporter 10 (GLUT10) [18, 31, 37]. Deficiency of GLUT10 is associated with up regulation of the TGF-beta pathway in the arterial wall, which is responsible for the angiopathy.
Lung Vasculitis
Pulmonary vasculitis occurs with collagen vascular diseases and in granulomatous pulmonary disease. In the collagen vascular group, vasculitis causes diffuse interstitial inflammation and fibrosis. The typical collagen vascular diseases include rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis and dermatomyositis. Granulomatous pulmonary disease typically produces focal inflammation and manifests as nodules and masses. The most common vasculitis granulomatosis is Wegener’s granulomatosis.
Wegener’s Granulomatosis
Wegener’s granulomatosis (WG) is characterized by necrosis, vasculitis and granulomatous inflammation involving the respiratory tract and kidney. In the lung, granulomatous inflammation produces solitary or multiple discrete parenchymal nodules, which may be bronchocentric, angiocentric or interstitial. The vasculitis may or may not be granulomatous in nature, and larger vessels often have only focal involvement. Polymorphisms in PTPN22 (R620W) [56], HLA–DPA1 (rs9277341), HLA–DPB1 (rs9277554), and semaphorin 6A (SEMA6A) (rs26595) [120] are associated with Wegener’s granulomatosis.
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