Atherosclerosis narrowing the arteries outside the heart and brain, usually in the legs. This page holds a variant from the first study to find any genetic risk factors for it at all — and the study went as far as showing the risk version of the DNA lowers its nearby gene's activity in the lab.
Peripheral artery disease (PAD) is atherosclerosis — plaque buildup narrowing arteries — outside the heart and brain, most often affecting the legs. It causes pain and cramping on walking that eases with rest (claudication), and in advanced cases can progress to tissue damage and non-healing wounds. It is common, under-diagnosed, and shares the same underlying process as coronary artery disease and stroke.
Despite how common and consequential PAD is, the study behind this page was, at the time it was published, the first to identify genetic risk factors for it at all. Working in a Japanese population — 785 cases and 3,383 controls in the initial stage, expanding to 3,164 cases and 20,134 controls across the full staged analysis — it identified three loci reaching genome-wide significance: near IPO5/RAP2A, near EDNRA, and near HDAC9, a gene already familiar from this site's ischaemic stroke page.
For the strongest of the three, the researchers went further than statistics. They fine-mapped the IPO5/RAP2A region to identify the specific variant most likely to be functionally responsible: rs9584669. They then tested it directly in the laboratory using a luciferase reporter assay — a standard technique in which a DNA sequence of interest is attached to a gene that makes cells glow, so that how strongly the DNA drives activity can be measured directly as light output. The risk version of the DNA reduced expression of IPO5 compared with the non-risk version — a functional anchor for the statistical finding, not only a position correlated with disease.
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 1 more position 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.
Klarin D et al. 2019, Nature medicine rs4722172 (IL6) — PMID:31285632
2026-09-02 · Unraveling causal links between chronic rhinosinusitis and peripheral artery diseases: insights from genetic correlations through genome-wide association studies. Brazilian Journal of Otorhinolaryngology. 2026. DOI:10.1016/j.bjorl.2026.101891
Chronic rhinosinusitis (CRS) and cardiovascular disease are known to co-occur, but whether one actually causes the other -- rather than sharing an unrelated risk factor -- was unclear. This study combined genetic correlation analysis, genomic structural equation modeling, bidirectional Mendelian randomization and cis-eQTL colocalization, then validated the findings in lab-grown human endothelial cells under inflammatory stress. It found CRS genetically correlated with multiple cardiovascular diseases through three distinct pathways (artery disease, myocardial disease, heart failure), with a specific shared local genetic signal at chr6:31.57-33.24 Mb. Mendelian randomization found CRS has a causal effect on peripheral artery disease (OR=1.23, p=0.022) and peripheral atherosclerosis (OR=1.21, p=0.011) -- but not the reverse direction. At the gene level, genetically predicted higher expression of HLA-DRB1, APOM and COL11A2 was protective, while higher HLA-DQA2 expression increased risk. Laboratory validation in endothelial cells under CRS-mimicking inflammatory stress confirmed the direction of each effect: APOM (protective) was downregulated, HLA-DQA2 (risk) and the pro-atherogenic marker VCAM-1 were upregulated, while HLA-DRB1 showed a compensatory increase. This is a genuinely mechanistic chain -- from a shared genetic locus, through specific gene expression changes, to a lab-confirmed cellular effect -- not just a statistical association. This site's peripheral artery disease page currently carries only 1 variant; none of HLA-DRB1, APOM, COL11A2 or HLA-DQA2 are among it, making this a substantial addition to a very thin page.
Diagnosis typically starts with the ankle-brachial index — a simple, painless comparison of blood pressure at the ankle and the arm — and can be confirmed with imaging (ultrasound, CT or MR angiography) when needed. None of this depends on a genotype.
The symptom that gets this looked for. Leg pain, cramping or fatigue that comes on with walking and eases with rest is the classic sign, though many people with PAD have no symptoms at all until it is advanced. The strongest, most established risk factors are smoking, diabetes, high blood pressure and high cholesterol — the same set that drives atherosclerosis throughout the body. Managing those remains the primary prevention strategy, and nothing on this page changes that.
HDAC9, one of the other two loci this study found, also appears on this site's ischaemic stroke page — consistent with the shared atherosclerotic process underlying both diseases.
What a 23andMe/AncestryDNA export or raw VCF can and can't tell you about Peripheral Artery Disease 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 1 of 4 linked studies with a resolved discovery ancestry.
Databases, guidelines and references
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Peripheral Artery Disease. MyGeneLog™. https://www.mygenelog.com/conditions/peripheral-artery-disease
No. This variant does not diagnose the disease. An ankle-brachial index test — a simple comparison of blood pressure at the ankle and arm — is how PAD is actually diagnosed, often prompted by leg pain that comes on with walking.
The researchers fine-mapped the region to identify the specific likely functional variant, then tested it directly in a laboratory assay and showed the risk version of the DNA actually reduces the nearby gene's activity — a demonstrated mechanism, not only a statistical correlation.
PAD genetics had lagged behind coronary artery disease and stroke despite sharing the same underlying atherosclerotic process, and this study filled that specific gap — the authors note these were, to their knowledge, the first genetic risk factors identified for the disease.
Managing smoking, diabetes, blood pressure and cholesterol — the same atherosclerosis risk factors that matter for the heart and brain — remains the established, actionable approach. Nothing on this page changes that advice.
Free to reuse. This page's text is original writing from freely-available research, licensed CC BY 4.0 — reuse it, including commercially, with attribution to MyGeneLog™. It's general research-derived information, not medical advice or a diagnosis — see Terms of Use.