A rare, progressive disease of high blood pressure in the lung arteries, whose known genetics was almost entirely one gene (BMPR2) until a 2019 GWAS of 11,744 people found the first common-variant risk loci — in SOX17 and in HLA-DPA1/HLA-DPB1.
Pulmonary arterial hypertension (PAH) is high blood pressure specifically in the arteries of the lungs, which forces the right side of the heart to work harder over time. It is rare, and until recently its genetics was understood almost entirely through BMPR2: rare, highly penetrant mutations that cause 70–80% of heritable PAH and 10–20% of idiopathic (no known cause) PAH.
Rhodes et al. 2019 combined two genome-wide association studies and a meta-analysis across four international case-control studies, totaling 11,744 people of European ancestry, including 2,085 cases. This is the study that found common-variant risk for PAH at all, rather than only rare, highly penetrant mutations — and it identified two novel loci, both represented on this page.
rs2856830, near HLA-DPA1 and HLA-DPB1, was the stronger of the two findings: each copy of the risk allele (C) was associated with roughly 1.56 times the odds of PAH (95% CI 1.42–1.71, p=8×10⁻²⁰). The second locus sits in an enhancer region near SOX17, represented here by two variants: rs13266183 (risk allele C, odds ratio 1.36, 95% CI 1.25–1.48, p=2×10⁻¹²) and rs10103692 (risk allele G, odds ratio 1.8, 95% CI 1.55–2.08, p=5×10⁻¹⁵). SOX17 is involved in blood vessel formation and maintenance, a direct, plausible mechanistic link to a disease of the pulmonary vasculature.
Positions joined since this page was written
What this is The text above discusses the variants this page was written around. Since then the catalogue has joined 10 more positions to it, by shared trait or shared paper. They are listed here by the paper each came from; the text does not describe them, and each variant page carries that study's own record.
Loya H et al. 2025, Nature genetics rs448385 (near LINC02793), rs73306876 (ZNF831), rs2627323 (ABHD17C), rs6818198 (ENPEP), rs8102879 (REXO1), rs1923031 (near C20orf181), rs6564889 (CMIP), rs113446918 (AMBRA1) — PMID:39789286
Surendran P et al. 2020, Nature genetics rs139600783 (ARHGAP31) — PMID:33230300
Kim YS et al. 2022, International journal of molecular sciences rs67617923 (EML6) — PMID:36233190
Pulmonary arterial hypertension is diagnosed by right heart catheterization confirming elevated pulmonary artery pressure — not by genotype. None of the 3 variants on this page are used by any guideline to diagnose PAH or decide treatment in an individual. BMPR2 genetic testing, a separate and much stronger signal, is offered in a specialist setting for suspected heritable PAH — this page's variants are common, modest-effect risk factors, not diagnostic mutations.
Prognosis has improved substantially over the past 20 years with targeted therapies — endothelin receptor antagonists, PDE5 inhibitors and prostacyclin pathway drugs, often combined upfront rather than added one at a time. The 3 variants on this page describe population-level susceptibility found in a large international study; they do not change how an individual patient is treated.
What a 23andMe/AncestryDNA export or raw VCF can and can't tell you about Pulmonary Arterial Hypertension comes down to these specific, well-studied positions — not a diagnosis.
The studies behind these variants recruited participants from different ancestries — a result found in one population doesn't always transfer to another. Based on 3 of 13 linked studies with a resolved discovery ancestry.
Databases, guidelines and references
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Pulmonary Arterial Hypertension. MyGeneLog™. https://www.mygenelog.com/conditions/pulmonary-arterial-hypertension
Pulmonary arterial hypertension is high blood pressure specifically in the lung arteries, which forces the right side of the heart to work harder over time. It is rare and, once developed, historically serious, though treatment has improved substantially.
In 11,744 people of European ancestry (2,085 cases), it found the first common-variant risk loci for PAH: one near HLA-DPA1/HLA-DPB1 (odds ratio 1.56 per copy) and one in a SOX17 enhancer region (odds ratios 1.36 and 1.8 at two positions).
No. BMPR2 mutations are rare, highly penetrant, and cause the majority of heritable PAH. The 3 variants on this page are common in the general population and each has a much smaller individual effect — a different, newer kind of finding.
No. Diagnosis requires right heart catheterization. These variants describe population-level risk from a large research study, not an individual diagnostic test.
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