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Researchers Link Loci Near Three Genes to Peripheral Artery Disease Risk

NEW YORK (GenomeWeb) – A team of Riken-led researchers has linked loci near three different genes to peripheral artery disease susceptibility.

Through a genome-wide association study drawing on nearly 800 cases and more than 3,000 controls from BioBank Japan as well as further staged analyses, Riken Center for Integrative Medical Sciences' Toshihiro Tanaka and colleagues uncovered loci near IPO5/RAP2A, EDNRA, and HDAC9 that are associated with peripheral artery disease, as they reported today in PLOS One.

"It seems," co-author Kouichi Ozaki from the Laboratory for Cardiovascular Disease at Riken added in a statement, "that people with these three gene polymorphisms are particularly vulnerable to this disease."

Peripheral artery disease is caused by a build up of atherosclerotic plaque in blood vessels, leading to reduced blood flow in the extremities, which causes pain and difficulty walking. It can also lead to cardiovascular and cerebrovascular events, the researchers noted.

To search for loci linked to the disease, Tanaka, Ozaki, and their colleagues performed a genome-wide association study using 785 cases and 3,383 controls that examined almost 432,000 SNPs.

As no SNP reached genome-wide significance at this stage, the researchers focused on the top 500 SNPs linked in their cohort to peripheral artery disease, a number they whittled down to 355 loci after taking linkage disequilibrium into consideration.

They examined these loci in a further 1,229 cases to uncover three linked to peripheral artery disease that were located near the genes IPO5/RAP2A, EDNRA, and HDAC9.

As the top locus they identified was near both IPO5 and RAP2A, the researchers sequenced the region in 48 cases to find 249 SNPs within a 100-kilobase region. They then analyzed 24 tag SNPs in an additional 750 cases and 2,405 controls to find that rs9584669 was the most strongly linked to disease. Six other SNPs in the region were in full linkage disequilibrium with rs9584669.

But none of these SNPs, the researchers said, led to an amino acid change in the resulting protein. Using a reporter gene setup in human aortic smooth muscle cells, they investigated whether any of these SNPs affected the expression of either IPO5 or RAP2A.

Clones containing rs9584669, they reported, had a 1.5-times greater transcription activity in the IPO5 promoter construct, suggesting to the researchers that the rs9584669 SNP locus physically interacts with the IPO5 promoter region, likely in a long-range looping manner. No other IPO5 promoter construct or any of the RAP2A promoter constructs led to any expression changes, they noted.

IPO5, they added, is a member of the importin beta family, and it helps promote the excretion of apolipoprotein A-1, which is a key part of HDL particles. Apolipoprotein A-1 also controls the offloading of cholesterol esters to the liver and to LDL. This, the researchers said, helps HDL reduce the accumulation of plaque within blood vessels — the buildup of which is a key component of peripheral artery disease development.

Meanwhile, another SNP the Riken team uncovered was traced to the 5' flanking region of the endothelian receptor type A gene, EDNRA, which encodes a receptor for endothelin-1.

Endothelin-1, the researchers noted, has a role in vasoconstriction and has pro-inflammatory effects. It also mediates the activation of vascular smooth muscle cells, has increased expression in human atherosclerotic lesions, and induces the release of inflammatory cytokines. This indicated to the researchers that endothelin-1 could contribute to the chronic inflammation associated with atherosclerosis.

At the same time, they said that the signaling of a receptor for endothelin-1, EDNRA, mediates the activation and proliferation of vascular smooth muscle cells. They added that its inhibitors prevent endothelial dysfunction, structural vascular changes in atherosclerosis, and averts cholesterol-induced atherosclerosis.

Together, this suggests that the endothelin-1-EDNRA cascade has a key role in the development and progression of peripheral artery disease, they said.

Finally, the third SNP the researchers uncovered was located near HDAC9, which encodes a histone deacetylase, which modulates transcription events and plays an important role in transcriptional regulation and cell cycle progression.

In particular, HDAC9 is involved in tissue remodeling through the stress-response pathway. An HDAC9 variant, they added, has been linked previously to large vessel ischemic strike, carotid atherosclerosis, and coronary artery disease, suggesting that HDAC9 could also be involved in the pathogenesis and progression of peripheral artery disease.

"What is important," Ozaki added, "is that although this study does help to identify people who might be at risk for PAD, the findings could also be used to elucidate the mechanism through which PAD arises, and hence could help to identify therapeutic targets for future treatments."

He noted that the study was performed in a Japanese population and that other populations might show different patterns.

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