Common genetic variants in pulmonary arterial hypertension
Authors: Sue Gu, Rahul Kumar, Michael H Lee, Claudia Mickael, Brian B Graham
Journal: The Lancet Respiratory Medicine (2018)

Pulmonary arterial hypertension is currently an incurable disease characterised by increased pulmonary vascular resistance and eventual death due to right ventricular failure. Hereditary pulmonary arterial hypertension has been generally thought to represent a small subset of all pulmonary arterial hypertension cases. The most common mutation identified is loss of function in BMPR2, which encodes a cell surface receptor belonging to the transforming growth factor-β (TGFβ) superfamily.1Deng Z Morse JH Slager SL et al.Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene.Am J Hum Genet. 2000; 67: 737-744Summary Full Text Full Text PDF PubMed Scopus (989) Google Scholar, 2Lane KB Machado RD et al.International PPH ConsortiumHeterozygous germline mutations in BMPR2, encoding a TGF-β receptor, cause familial primary pulmonary hypertension.Nat Genet. 2000; 26: 81-84Crossref PubMed Scopus (1229) Google Scholar Understanding of the pathogenetic role of BMPR2 haploinsufficiency has uncovered new potential therapeutic targets in pulmonary arterial hypertension, with multiple clinical trials focusing on the TGFβ signalling pathway. Despite the documented contribution of common genetic variants as determinants of complex and multifactorial diseases, previous genome-wide association studies (GWAS) in patients with pulmonary arterial hypertension disease have been scarce. In The Lancet Respiratory Medicine, Christopher Rhodes and colleagues3Rhodes CJ Batai K Bleda M et al.Genetic determinants of risk in pulmonary arterial hypertension: international genome-wide association studies and meta-analysis.Lancet Respir Med. 2018; (published online Dec 5.)http://dx.doi.org/10.1016/S2213-2600(18)30409-0Summary Full Text Full Text PDF PubMed Scopus (73) Google Scholar report their findings from the largest genetic analysis to date in patients of European ancestry with pulmonary arterial hypertension. By use of two independent GWAS platforms of whole-genome sequencing and genotyping array (discovery phase), and meta-analysis (validation phase) with multiple internationally collaborative cohorts, the study identified two novel loci associated with risk for the development of pulmonary arterial hypertension: an enhancer region in SOX17, and a locus within HLA-DPA1 and HLA-DPB1. The alleles associated with disease were common, with a relatively modest effect size: for example, 59% of patients with pulmonary arterial hypertension compared with 46% of controls were homozygous for the risk allele at both SOX17 SNPs. The results of the discovery and validation phases converged to substantially decrease the possibility of false-positive results. The authors reported two independent signals in the transcription factor SOX17 locus significantly associated with pulmonary arterial hypertension (rs10103692, odds ratio 1·80 [95% CI 1·55–2·08], p=5·13 × 10–15, and rs13266183, 1·36 [1·25–1·48], p=1·69 × 10–12). These signals identified enhancer regions leading to modified expression of SOX17, which correlated with the diagnosis of pulmonary arterial hypertension. The functional impact of the novel SOX17 locus on pulmonary arterial hypertension susceptibility was confirmed with Hi-C to determine DNA folding patterns and CRISPR-mediated inhibition in human pulmonary artery endothelial cells. This finding corroborates a previous report describing a rare genetic variant in SOX17 associated with heritable pulmonary arterial hypertension.4Gräf S Haimel M Bleda M et al.Identification of rare sequence variation underlying heritable pulmonary arterial hypertension.Nat Commun. 2018; 9: 1416Crossref PubMed Scopus (209) Google Scholar The present study posits that common variation in SOX17 expression is a determinant of pulmonary arterial hypertension and is present more often in patients with pulmonary arterial hypertension than are other rare genetic variants. Conditional deletions of SOX17 in endothelial cells cause abnormal pulmonary vascular morphogenesis5Lange AW Haitchi HM LeCras TD et al.Sox17 is required for normal pulmonary vascular morphogenesis.Dev Biol. 2014; 387: 109-120Crossref PubMed Scopus (43) Google Scholar potentially mediated by Notch pathway signalling to restrict angiogenesis.6Lee S-H Lee S Yang H et al.Notch pathway targets proangiogenic regulator Sox17 to restrict angiogenesis.Circ Res. 2014; 115: 215-226Crossref PubMed Scopus (61) Google Scholar Inactivation of Sox17 in mouse embryos leads to lack of arterial differentiation and vascular remodelling,7Corada M Orsenigo F Morini MF et al.Sox17 is indispensable or acquisition and maintenance of arterial identity.Nat Commun. 2013; 4: 2609Crossref PubMed Scopus (170) Google Scholar and SOX17 has a major role in the development of haemogenic endothelial cells (the precursor of haemopoietic stem cells).8Clarke RL Yzaguirre AD Yashiro-Ohtani Y et al.The expression of Sox17 identifies and regulates haemogenic endothelium.Nat Cell Biol. 2013; 15: 502-510Crossref PubMed Scopus (107) Google Scholar The other key genes identified by this study were HLA-DPA1 and HLA-DPB1 (rs2856830, 1·56 [1·42–1·71], p=7·65 × 10–20), which encode the MHC class II DP α and β chains. The specific variant discovered was located in HLA-DPB1 and, surprisingly, correlated with two seemingly opposite outcomes: increased risk for the development of pulmonary arterial hypertension, but improved survival once having developed pulmonary arterial hypertension. The specific alleles associated with the variants were HLA-DPB1*02:01/02:02/16:01, all of which contain a glutamic acid substituted for a lysine residue at position 69. Of note, variants with the same glutamic acid substitution at position 69 have also been described as increasing the risk for developing chronic beryllium disease (a variant of sarcoidosis) among individuals exposed to beryllium.9Richeldi L Sorrentino R Saltini C HLA-DPB1 glutamate 69: a genetic marker of beryllium disease.Science. 1993; 262: 242-244Crossref PubMed Scopus (421) Google Scholar In studies using crystallography, the negative charge of the glutamine side chain was found to stabilise the Be2+ ion in the MHC II groove, facilitating a neoantigen that triggers a granulomatous lung disease.10Falta MT Pinilla C Mack DG et al.Identification of beryllium-dependent peptides recognized by CD4+ T cells in chronic beryllium disease.J Exp Med. 2013; 210: 1403-1418Crossref PubMed Scopus (53) Google Scholar The finding of the same variants in these patients raises the possibility of an antigenic trigger contributing to the development of pulmonary arterial hypertension. This antigen-triggered disease might have a more benign disease course or improved clinical response to the current clinical armamentarium compared with other forms of pulmonary arterial hypertension, resulting in the improved survival observed. On the basis of the current findings, the next steps include first reproducing and validating these findings with additional and more diverse samples. It will then be important to associate the risk alleles of SOX17 and HLA-DPB1 with clinical characteristics and relevant pathologies in pulmonary arterial hypertension, including inflammatory cytokines, incidence of vasodilator responsiveness, haemodynamics, and right ventricle performance, which will help to contextualise the relevance of the GWAS data to the clinical setting. It remains unanswered whether the significance of these markers generalises to ethnicities, whether these markers drive similar clinical presentations and outcomes in both sexes, whether they can serve as biomarkers to determine predisposition towards and stratification of pulmonary arterial hypertension subtypes, or whether they interact with other genes in a complex disease such as pulmonary arterial hypertension. Transgenic modification of experimental animals with the same mutations will further clarify whether and how these modifications induce disease and provide insights into how they can be pharmacologically targeted. Overall, this study provides hope that the identification of genetic modifiers in pulmonary arterial hypertension will allow more accurate classification of pulmonary arterial hypertension subtypes and more tailored and effective treatments for patients with pulmonary arterial hypertension than are currently available. We declare no competing interests. Salary support for the authors was provided by US National Institutes of Health grants T32HL007085 (SG and MHL), P01HL014985 (BBG), R03HL133306 (BBG), and R01HL135872 (BBG); and American Heart Association grant 17POST33670045 (RK). We declare no competing interests. Genetic determinants of risk in pulmonary arterial hypertension: international genome-wide association studies and meta-analysisThis is the first study to report that common genetic variation at loci in an enhancer near SOX17 and in HLA-DPA1/DPB1 is associated with pulmonary arterial hypertension. Impairment of SOX17 function might be more common in pulmonary arterial hypertension than suggested by rare mutations in SOX17. Further studies are needed to confirm the association between HLA typing or rs2856830 genotyping and survival, and to determine whether HLA typing or rs2856830 genotyping improves risk stratification in clinical practice or trials. Full-Text PDF Open Access