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Published in final edited form as: Curr Diab Rep. 2011 Jun;11(3):218–225. doi: 10.1007/s11892-011-0188-9

Peripheral Arterial Disease in Diabetes: Is There a Role for Genetics?

Arabindra B Katwal 1, Ayotunde O Dokun 2,✉
PMCID: PMC3137910  NIHMSID: NIHMS296686  PMID: 21424681

Abstract

Atherosclerotic occlusion of vessels outside of the heart is commonly referred to as peripheral arterial disease (PAD). The lower extremity is the most common site of PAD and its development is associated with the same risk factors involved in general atherosclerosis. However, there is emerging evidence that other risk factors may play a key role in the development of PAD. Over the past decade polymorphism in a number of genes has been shown to contribute to the risk of developing PAD. These genes can be classified into proartherosclerosis or proatherothrombosis based on the known gene function. Moreover, they can be categorized as “novel” polymorphism when the function of the genes is not known or when the specific gene within an associated genetic locus is not known. It is intriguing that not only are gene polymorphisms associated with PAD being identified, but more recently studies are now finding gene polymorphisms that may be important in development of this syndrome only in the contest of certain environmental factors such as diabetes. Currently how these gene–environment interactions contribute to the pathogenesis of PAD is poorly understood but will likely play a critical role in future understanding of this complex disease.

Keywords: Peripheral arterial disease, Angiogenesis, Genetics, Modifier gene, Gene polymorphism, Single nucleotide polymorphism, Linkage disequilibrium, Haplotype, Gene association studies, Genome-wide association studies, Quantitative trait locus, Hind limb ischemia, Type 1 diabetes, Type 2 diabetes, Diabetes, Artherosclerosis, Gene–environment

Introduction

Peripheral arterial disease (PAD) is characterized by obstruction in arterial beds other than the coronary arteries and is caused by atherosclerosis in the vast majority of patients. The most common site is the lower extremity where occlusive disease leads to impaired perfusion. Although previously under-recognized and under-diagnosed by the medical community and therefore viewed as less important than heart disease, PAD is now recognized to have a prevalence that is similar to that of ischemic heart disease [1, 2] and affects about 3% to 10% of adults in the world [3, 4].

The major established risk factors for the development of PAD are essentially the same as those recognized as important in generalized atherosclerosis and include increasing age after 40 years, cigarette smoking, diabetes mellitus (DM), hyperlipidemia, and hypertension [5, 6]. Elevated levels of C-reactive protein and homocysteine may also be important risk factors [1, 7, 8]. However, smoking and diabetes account for most of the risk of developing PAD [4, 9]. The unique role of diabetes in the pathogenesis of PAD is discussed in more detail later in this article. Nevertheless, there is now evidence that traditional risk factors can only partially account for the risks of developing PAD [10, 11]. Moreover, results of twin studies looking at genetic influences in PAD show high heritability [12]. Taken together this suggests sequence variations in genes in individuals may play a significant role in their risk of developing PAD. This review provides an overview of the result of recent studies looking at the association of genetic polymorphisms with the risk of developing PAD, with an emphasis on gene polymorphisms that influence development of PAD in diabetes.

Epidemiology and Clinical Presentations of PAD

Most patients with PAD lack the classic symptoms of PAD and thus are often considered asymptomatic; some estimates suggest as many as 50% of PAD patients fall into this category [3]. It is currently recommended that patients with multiple risk factors, especially smokers and diabetics, with other risk factors, should undergo noninvasive testing such as ankle-brachial index (ABI). ABI measures the ratio of systolic blood pressure in the ankle to that of the brachial vessels; an ABI less than 0.9 is considered diagnostic for PAD [3, 4, 13]. Once the diagnosis of PAD is made, further testing with duplex ultrasonography, segmental Doppler pressure or volume plethysmography, MRA or angiography may be used depending on the clinical situation.

There are two major clinical manifestations of PAD: intermittent claudication (IC) and critical limb ischemia (CLI). IC manifests as reduced blood flow to the extremities during exercise resulting in pain relieved only by rest, whereas CLI describes pain at rest that may be associated with non-healing leg ulcers or gangrene. Interestingly, although patients with IC have amputation and an annual mortality rate of 1% to 2%, those with CLI have a 6-month amputation risk of 25% to 40% and an annual mortality of 20% [14].

The diagnosis of IC versus CLI is based upon time-tested clinical classification schemes, namely the Rutherford and the Fontaine classifications. In the Rutherford classification, IC encompasses categories 1 to 3 (mild, moderate, and severe claudication, respectively), whereas CLI includes categories 4 to 6 (ischemic rest pain, minor tissue loss, and ulceration or gangrene). The Fontane classification is more commonly used in Europe, with stages IIa and IIb describing IC, whereas stages III to IV are categories of CLI. Although there is evidence of association of some biomarkers with IC and CLI [15–17], there is no biomarker or hemodynamic measure that is pathognomonic for either IC or CLI.

The observation that progressively lower ABIs are associated with worsening symptoms of claudication [18] has made some to assume that IC and CLI are due to a continuum of reduced blood flow. In this line of thought, CLI is simply a worse form of IC. However, the ultimate symptomatic presentation of PAD is heterogeneous with some individuals presenting with claudication while others present de novo with CLI. Moreover, many with IC never progress to CLI and many presenting with CLI do not report antecedent claudication [19–21]; therefore, IC and CLI may actually be distinct.

Diabetes and PAD

As mentioned earlier, diabetes and smoking account for most of the risk of developing PAD [4, 9, 22]. When PAD is present in diabetes there is a higher likelihood of occurrence within the femoral-popliteal and tibia vessels [23], whereas other risk factors such as smoking tend to be associated with more proximal disease (ie, iliofemoral vessels) [9]. In individuals with diabetes, PAD typically presents at an earlier age and is associated with a more rapid progression than in nondiabetics [23]. Moreover, the incidence of PAD increases significantly the longer an individual has been diabetic. For instance, Melton et al. [24] found that the cumulative incidence of PAD was 15% in those with diabetes duration of 10 years, and this increased to 45% in those with an additional 20 years exposure to diabetes. The true prevalence of PAD among individuals with diabetes has been difficult to assess due to a number of factors, including absence of symptoms, poor reporting of symptoms, blunted pain perception due to peripheral neuropathy, and inadequate screening. Nevertheless, using ABI measures some studies have estimated the prevalence of PAD among diabetics to be three times higher than among nondiabetics (7% vs 20.9%) [25]. The prevalence of PAD among individuals with diabetes was found to be as high as 38% in some cohorts [26–28].

Both type 1 and type 2 diabetes are associated with increased risk of PAD [24–26]. However, whether both type of diabetes are associated with similar prevalence of PAD is not clear because conflicting results have been reported. A United Kingdom study showed type 2 DM is associated with a higher prevalence (23.5%) of PAD than type 1 DM (8.7%) [29]. In contrast, an Australian study showed no difference in prevalence of PAD in type 1 and type 2 DM [26]. Nevertheless, because there are differences in the underlying pathology in type 1 and type 2 DM, it is likely that the molecular mechanisms through which they contribute to pathogenesis of PAD differ.

The role of diabetes in the pathogenesis of PAD can be considered in at least two major ways. First, diabetes may accelerate the development of atherosclerotic vessel occlusion; alternatively, it may negatively impact adaptive processes involved in restoring perfusion following vessel occlusion (eg, angiogenesis and arteriogenesis). It is now known that diabetes does accelerate the development of atherosclerosis through different mechanisms [30]. Moreover, there is emerging evidence from our group and others that diabetes may contribute to development of PAD by negatively impacting adaptive processes involved in restoring perfusion following vessel occlusion [31, 32]. Nevertheless, our understanding of the molecular mechanism by which diabetes contributes to the pathogenesis of PAD is quite limited.

Genetic Background as a Risk Factor for PAD

As previously mentioned, the major risk factors for the development of PAD are essentially the same as those recognized as important in generalized atherosclerosis and include increasing age after 40 years, cigarette smoking, DM, hyperlipidemia, hypertension, and elevated levels of C-reactive protein and homocysteine. However, not all patients with these risk factors develop PAD. Even in cohorts in which the prevalence of PAD among diabetics is quite high (38%) about 60% of diabetic individuals do not have PAD. Additionally, in patients with similar risk factors, atherosclerotic burden, and similar peripheral hemodynamics, the clinical presentation of PAD in not necessarily identical. For instance, some patients may present with IC whereas others present with CLI. Taken together these observations suggest that there are factors other than the currently known risk factors for PAD that may influence the development of this clinical syndrome.

Interestingly, there is an emerging body of evidence that suggests the genetic background of an individual may be important in the pathogenesis of PAD. In one study the prevalence of PAD in various ethnic backgrounds was evaluated and their results suggest higher prevalence in African Americans even after adjusting for age and other traditional risk factors for PAD [33]. Because individuals of the same ethnicity are likely to share certain ancestral genes, the higher prevalence of PAD in African Americans suggests that there may be gene polymorphisms contributing to PAD in this group. Further evidence supporting the possible role of genetic risk factors in PAD comes from both association and linkage studies. Estimates of the heritability of PAD using ABI as a surrogate have shown that the contribution of genetic factors to the overall variation in ABI ranges from 21% to 48% [12, 34, 35]. Moreover, in a recent twin study of genetic influences on PAD, Wahlgren et al. [36] showed genetic effects could account for about 58% of the phenotypic variance among twins. Therefore, genetic background may be a major determinant in development of PAD. Nevertheless, our understanding of the role of genetics in the pathogenesis of PAD remains poor [37, 38].

Gene Polymorphisms Contributing to PAD

Sequence variations in a variety of genes have shown statistically significant association with PAD [39•]. These genes can be classified into three different categories: proatherosclerotic, proatherothrombotic, or novel, based on the function of the gene products (Table 1). Below we provide an overview of recently described gene polymorphisms contributing to PAD within each of the three categories stated above and, where known, we will describe gene polymorphisms associated with PAD in the setting of diabetes.

Table 1.

Gene polymorphisms associated with PAD

Gene polymorphisms contributing to atherothrombosis and PAD Gene polymorphisms contributing to atherosclerosis and PAD Novel gene polymorphisms contributing to PAD
Factor II (FII G20210A) Connexin 37a SLC2A10a
P2Y12 (H2 allele) APO E and APO B PAOD1
Fibrinogen (β) IL-6 promoter (−174 G/C)a LSq-1
MTHFR 677Ta E-Selectin Ser128Arg
ICAM-1 (469E/K)		 CHRNA3 (rs1051730)
MCP-1 (−2518 A/G)
MMP-1 and MMP-3
eNOS (−786 C)
ACE D
CDKN2b and CDKN2a rs1333049
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ACE angiotensin-converting enzyme, APO apolipoprotein, eNOS endothelial nitric oxide synthase, ICAM-1 intercellular adhesion molecule-1, IL-6 interleukin-6, MCP-1 monocyte chemoattractant protein-1, MMP matrix metalloproteinase, MTHFR methylenete-trahydrofolate reductase, PAD peripheral arterial disease

a

Gene polymorphisms associated with PAD in individuals with diabetes

Proatherosclerotic Gene Polymorphisms in PAD

PAD is a consequence of atherosclerosis in the lower extremities; therefore, it is not unexpected that polymorphisms of genes contributing to the development of atherosclerosis can be found to be associated with PAD. One of the important events in the initiation and progression of artherogenesis is endothelial dysfunction. Nitric oxide (NO) is a key modulator in this process and it contributes to regulation of vascular tone, leukocyte adhesion to vascular endothelium, inhibition of platelet aggregation, and inhibition of smooth muscle cell migration and proliferation [40]. Endothelial-derived nitric oxide synthase (eNOS) is one of three isoforms of NO synthase responsible for NO synthesis. eNOS gene polymorphisms have been shown to cause decreased NO synthesis, thereby reducing NO availability and causing endothelial dysfunction [41]. Polymorphism of the eNOS gene has been shown to be associated with carotid atherosclerosis and abdominal aortic aneurysm [42, 43]. In a recent study, Sticchi et al. [44] showed that in smokers, but not in nonsmokers, the concomitant presence of the eNOS −786 C/4a haplotype was significantly associated with increased predisposition to PAD. The role of eNOS gene polymorphisms in predisposition to PAD among diabetic individuals is not known.

Angiotensin-converting enzyme (ACE) processes the decapeptide angiotensin I to octapeptide angiotensin II, which is a strong vasoconstrictor. It is thought that ACE may affect the atherosclerotic process through bradykinin degradation and reduction in release of NO [44]. An insertion/deletion (I/D) of a 287-bp fragment in the intron 16 of the ACE gene has been described, and the D allele is associated with increased serum levels of the circulating enzyme [45]. Although prior studies did explore possible association of this allele with PAD they showed only borderline significance [46, 47]. However, a more recent study by Fatini et al. [48] studied association of the ACE I/D polymorphism and the −240 A>T polymorphism in the promoter region of the ACE gene to PAD and showed that the ACE D allele and the ACE D/−240T haplotype significantly and independently influenced the predisposition to PAD. Interestingly, the presence of eNOS −786 C/4a haplotype (previously described above) increased predisposition to PAD in smokers carrying the ACE D allele [44]. These results are consistent with a gene-environment interaction in the modulation of PAD development. Nevertheless, whether polymorphisms in the eNOS or ACE genes play a role in predisposition to PAD in individuals with diabetes is not known.

Inflammation is becoming increasingly recognized as an important factor in the pathogenesis of atherosclerosis, with its development and progression orchestrated by several molecules belonging to different families of inflammatory mediators, such as cytokines, chemokines, adhesion molecules, and proteolytic enzymes [49, 50]. In a study of 157 PAD patients and 206 controls, Flex et al. [50] analyzed gene polymorphisms including interleukin-6 (IL-6;−174 G/C), E-selectin Ser128Arg, intercellular adhesion molecule-1 (ICAM-1; 469 E/K), monocyte chemoattractant protein-1 (MCP-1) −2518 A/G, matrix metalloproteinase (MMP)-1 −1607 1 G/2 G, and MMP-3 −1171 5A/6A. The IL-6, MCP-1, MMP-1, and MMP-3 polymorphisms influence the plasma concentrations of these proteins. They found that IL-6, E-selectin, ICAM-1, MCP-1, MMP-1, and MMP-3 gene polymorphisms were significantly and independently associated with PAD. Interestingly, they also found that polymorphisms of these proinflammatory proteins act synergistically (depending on the number of high-risk genotypes concomitantly present in a given individual) to confer different levels of risk for PAD and CLI. This exemplifies how susceptibility to a disease results from functional interactions between modifier genes [50]. Although 49% of the PAD patients and 29% of the controls were diabetic, the effect of these gene polymorphisms in coffering risk for developing PAD among diabetics is not clear. Of note, a prior study did address the role of one of these gene polymorphisms in promoting the development of PAD among diabetics. The study showed that the GG genotype of the IL-6 (−174 G/C) polymorphism was more common among diabetics with PAD than diabetics without PAD. Moreover, the genotype was associated with higher plasma concentrations of IL-6 [51].

In addition to the above study a recent study also identified proatherosclerotic gene polymorphisms associated with the development of PAD among individuals with diabetes. Connexin 37 is a protein expressed in endothelial cells, monocytes, and macrophages and appears to play a role in atherogenesis [52]. The C to T substitution at nucleotide 1019 in the connexin 37 gene results in a proline to serine substitution. This substitution is thought to contribute to atherosclerosis and its polymorphism has been associated with the development of coronary artery disease. Katakami et al. [53•] investigated association of genetic polymorphisms in the connexin 37 gene with PAD among 2,261 Japanese individuals with PAD. Their data showed a statistically significant higher association of low ABIs among diabetics with the TT genotype than the CC or CT genotypes (7.2% vs 2.0%; P=0.0008). They reported no association of these genotypes to sex, age, body mass index, hemoglobin A1c, duration of diabetes, hypertension, and dyslipidemia.

Guided by previous genome-wide association studies (GWAS) and subsequent replication studies that demonstrated a strong association of a common variant at chromosome 9p21 (tagged by the rs1333049 or rs10757278 single nucleotide polymorphism [SNP]) with myocardial infarction (MI) [54] and coronary artery disease, Cluett et al. [55] hypothesized that this SNP might also be associated with risk of PAD. Using three different study populations (InCHIANTI [Invecchiare in Chianti, aging in the Chianti area); Health, Aging and Body Composition; and Baltimore Longitudinal Study of Aging studies) they analyzed the association of the 9p21 MI SNP (rs1333049) with PAD and found the C allele is associated with an increased prevalence of PAD and lower mean ABI independent of the presence of previous MI and atherosclerotic risk factors. It is intriguing that the nearest genes to this marker are CDKN2b and CDKN2a, which are known cell cycle regulators. These genes may contribute to the development of heart disease (and possibly PAD) via reduced regrowth of arterial intimal cells [56].

Proatherothrombotic Gene Polymorphisms in PAD

It is fairly well established that thrombosis plays an important role in the pathogenesis of atherosclerosis [57]. Thrombin is not only important in fibrin formation and platelet aggregation but thrombin is also important in endothelial activation, platelet and leukocyte recruitment [58]. Consequently, various groups have hypothesized that polymorphisms in genes encoding hemostatic proteins may contribute to development of atherosclerosis and PAD. Studies have shown gene polymorphisms associated with PAD in hemostatic proteins including fibrinogen [59], factor II and V [60].

The importance of platelet aggregation in arterial thrombosis is also well known. The platelet ADP receptor P2Y12 is a seven-transmembrane receptor that upon activation promotes platelet aggregation [61, 62]. Blockade of P2Y12 by thienopyridines has been shown to be beneficial in patients with cardiovascular disease. Polymorphism in the P2Y12 gene has been described and one of the alleles (H2) results in a gain-of-function haplotype on ADP-induced platelet aggregation [63]. Thus, it was hypothesized that this allele may be associated with increased risk of PAD. The H2 allele was found associated with PAD even after adjusting for traditional PAD risk factors [64].

Defects in the folate pathway may contribute to the development of a prothrombotic state [65]. Methylenetetrahydrofolate reductase (MTHFR) is an important folate-metabolizing enzyme involved in metabolism of homocysteine. The MTHFR 677 C/T is a well-described polymorphism of MTHFR enzyme and elevated homocysteine has been described among carriers of the 677 C>T allele [66]. Elevated plasma homocysteine levels may promote vascular disease through endothelial injury predisposing vessels to atherosclerosis [67]. Several studies found a significant positive association between MTHFR 677 C/T polymorphism and PAD [65, 68, 69].

Out of all the genetic polymorphisms described in this section only one has been associated with increased risk of PAD among individuals with diabetes. In a study of PAD among aboriginal Canadians, Pollex et al. [70] showed that individuals with diabetes who also carried the MTHFR 677 T allele had a modest but increased risk of PAD (odds ratio, 3.54; 95% CI, 1.01, 12.4; P=0.049) even after adjusting for traditional risk factors such as age, hypertension, duration of diabetes, current smoking habit, and method of diabetes treatment. Therefore, much less is known about the role of prothrombotic gene polymorphisms and the risk of PAD among individuals with diabetes.

Novel Gene Polymorphisms Involved in PAD

Human studies of the genetics of PAD are quite limited outside of genes contributing to atherosclerosis or thrombosis. Despite an extensive review, we were able to identify only a few studies in which polymorphisms associated with PAD were not of genes contributing to atherosclerosis or thrombosis. One of these was a family-based linkage study that identified a genetic locus conferring susceptibility to PAD. This study of Icelandic families with multiple family members exhibiting PAD identified a locus termed PAOD1, which mapped to human chromosome 1p31 [71]. Interestingly, other risk factors for PAD such as hypertension, hyperlipidemia, and diabetes did not contribute to the positive linkage. Despite these strong and convincing genetic data, the genes responsible for PAOD1 have not been identified. This is not surprising in light of the difficulties involved in studying genetics of a complex disease such as PAD in humans.

More recently, investigators have used GWAS to identify gene polymorphisms associated with susceptibility to PAD. One study found a significant association between nicotine dependence and a SNP (rs1051730) on chromosome 15q2. This SNP is located within the CHRNA3 gene, which is in a linkage disequilibrium block that contains genes encoding nicotinic acetylcholine receptors. Interestingly, this study also demonstrated a significant association of this SNP with PAD and lung cancer, suggesting a gene–environment interaction [72•].

Unlike the above two studies, a recent study by Jiang et al. [73••] directly explored genetic polymorphisms in the SLC2A10 gene and development of PAD among individuals with diabetes [11]. Recent studies have shown that loss-of-function mutation in the gene encoding the facilitative glucose transporter GLUT10 (SLC2A10) causes arterial tortuosity syndrome via upregulation of the transforming growth factor-β (TGF-β). Moreover, TGF-β signaling has been implicated in microangiopathics changes in diabetes; the authors hypothesized that the SLC2A10 gene is a candidate gene for vascular complications in type 2 diabetes [74, 75, 73••]. In a prospective cohort study of 372 diabetic patients, several common SNPs of the SLC2A10 gene were significantly associated with PAD, with the strongest association shown by the T allele at rs2179357. By combining all 11 markers tested they identified a common haplotype termed H4 that conferred a strong risk of PAD among type 2 diabetic individuals at baseline (OR, 14.5; 95% CI, 1.3–160; P=0.03). Furthermore, over an average follow-up period of 5.7 years carriers of the H4 haplotype were more likely to develop PAD than those with other haplotypes (hazard ratio, 6.78; 95% CI, 1.66–27.6; P=0.007) [11]. Of note, the mechanism by which the H4 haplotype and other genetic polymorphisms of the SLC2A10 gene contributes to PAD in diabetes is not known.

Further evidence for novel gene polymorphisms that may be important in PAD comes from preclinical studies of PAD. In a mouse preclinical model of PAD in which the mouse femoral artery is ligated and excised to introduce ischemic stress (hind limb ischemia [HLI]), our group and others observed that recovery is strain-dependent [76•, 77] with C57BL/6 mice showing robust perfusion recovery and rare necrosis compared with the BALB/C or A/J mice after HLI. Because the ischemic stress in this model is independent of atherosclerosis and yet recovery is strain-dependent, this suggests a role for polymorphism in genes other than those contributing to atherosclerosis and is more likely involved in skeletal muscle function and adaptation to ischemic stress.

We took advantage of the strain-determined differences in recovery following HLI described above to identify a single quantitative trait locus (LSq-1) on chromosome 7 spanning approximately 31 Mb and centered at the SNP marker rs13479513 that showed significant linkage to the phenotypes of tissue necrosis and perfusion following HLI (logarithm of the odds score of 7.96 and 3.71, respectively). Moreover, we further refined the locus and identified candidate genes that may prevent the development of necrosis or confer improved perfusion recovery in some mouse strains [76•].

Conclusions

There is sufficient evidence to support a significant role for genetic background in an individual’s risk of developing PAD. Similar to other complex diseases the risk of developing PAD is likely the result of the interaction of several genes that act collectively [39•]. Additionally, the interaction between gene polymorphisms and the environment (eg, diabetes) is likely a key factor in the pathogenesis of PAD. Although a few gene polymorphisms associated with PAD among diabetics have been identified (described earlier in this review), there is much less known about the mechanisms by which this gene–environment interaction contributes to PAD and should be the subject of future studies. Identification of gene polymorphisms important in PAD in the setting of diabetes and other major risk factors such as smoking may result in the creation of personalized screening tests for predicting individual risk of disease and/or development of individualized treatment approaches.

Acknowledgments

This manuscript was supported by the Robert Wood Johnson Foundation, Harold Amos Medical Faculty Development Program Training Grant Award # 65874 to A.O. Dokun.

Footnotes

Disclosure No potential conflicts of interest relevant to this article were reported.

Contributor Information

Arabindra B. Katwal, Division of Cardiovascular Medicine, University of Virginia, Charlottesville, VA, USA

Ayotunde O. Dokun, Email: DOA3Q@hscmail.mcc.virginia.edu, Division of Endocrinology, Department of Medicine, University of Virginia, Charlottesville, VA, USA

References

Papers of particular interest, published recently, have been highlighted as:

• Of importance

•• Of major importance

  • 1.Gerhard M, Baum P, Raby KE. Peripheral arterial-vascular disease in women: prevalence, prognosis, and treatment. Cardiology. 1995;86(4):349–55. doi: 10.1159/000176899. [DOI] [PubMed] [Google Scholar]
  • 2.Kannel WB, McGee DL. Update on some epidemiologic features of intermittent claudication: the Framingham Study. J Am Geriatr Soc. 1985;33(1):13–8. doi: 10.1111/j.1532-5415.1985.tb02853.x. [DOI] [PubMed] [Google Scholar]
  • 3.Hirsch AT, Criqui MH, Treat-Jacobson D, Regensteiner JG, Creager MA, Olin JW, et al. Peripheral arterial disease detection, awareness, and treatment in primary care. JAMA. 2001;286 (11):1317–24. doi: 10.1001/jama.286.11.1317. [DOI] [PubMed] [Google Scholar]
  • 4.Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FG, et al. Inter-society consensus for the management of peripheral arterial disease (TASC II) Eur J Vasc Endovasc Surg. 2007;33 (Suppl 1):S1–S75. doi: 10.1016/j.ejvs.2006.09.024. [DOI] [PubMed] [Google Scholar]
  • 5.Fowkes FG. Peripheral vascular disease: a public health perspective. J Public Health Med. 1990;12(3–4):152–9. doi: 10.1093/oxfordjournals.pubmed.a042540. [DOI] [PubMed] [Google Scholar]
  • 6.Hiatt WR, Hoag S, Hamman RF. Effect of diagnostic criteria on the prevalence of peripheral arterial disease. The San Luis Valley Diabetes Study. Circulation. 1995;91(5):1472–9. doi: 10.1161/01.cir.91.5.1472. [DOI] [PubMed] [Google Scholar]
  • 7.Graham IM, Daly LE, Refsum HM, Robinson K, Brattstrom LE, Ueland PM, et al. Plasma homocysteine as a risk factor for vascular disease. The European Concerted Action Project. JAMA. 1997;277(22):1775–81. doi: 10.1001/jama.1997.03540460039030. [DOI] [PubMed] [Google Scholar]
  • 8.Darius H, Pittrow D, Haberl R, Trampisch HJ, Schuster A, Lange S, et al. Are elevated homocysteine plasma levels related to peripheral arterial disease? Results from a cross-sectional study of 6880 primary care patients. Eur J Clin Invest. 2003;33(9):751–7. doi: 10.1046/j.1365-2362.2003.01196.x. [DOI] [PubMed] [Google Scholar]
  • 9.Association AD. Peripheral arterial disease in people with diabetes. Clin Diabetes. 2004;22(4):181–9. [Google Scholar]
  • 10.Keen H, Clark C, Laakso M. Reducing the burden of diabetes: managing cardiovascular disease†. Diab/Metab Res Rev. 1999;15 (3):186–96. doi: 10.1002/(sici)1520-7560(199905/06)15:3<186::aid-dmrr30>3.0.co;2-5. [DOI] [PubMed] [Google Scholar]
  • 11.Yi-Der J, Yi-Cheng C, Yen-Feng C, Tien-Jyun C, Hung-Yuan L, Wen-Hsing L, et al. SLC2A10 genetic polymorphism predicts development of peripheral arterial disease in patients with type 2 diabetes. SLC2A10 and PADin type 2 diabetes. BMC Med Genet. 11:126–32. doi: 10.1186/1471-2350-11-126. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Carmelli D, Fabsitz RR, Swan GE, Reed T, Miller B, Wolf PA. Contribution of genetic and environmental influences to ankle-brachial blood pressure index in the NHLBI Twin Study. National Heart, Lung, and Blood Institute. Am J Epidemiol. 2000;151 (5):452–8. doi: 10.1093/oxfordjournals.aje.a010230. [DOI] [PubMed] [Google Scholar]
  • 13.Newman AB, Shemanski L, Manolio TA, Cushman M, Mittelmark M, Polak JF, et al. Ankle-arm index as a predictor of cardiovascular disease and mortality in the Cardiovascular Health Study. The Cardiovascular Health Study Group. Arterioscler Thromb Vasc Biol. 1999;19(3):538–45. doi: 10.1161/01.atv.19.3.538. [DOI] [PubMed] [Google Scholar]
  • 14.Ouriel K. Peripheral arterial disease. Lancet. 2001;358(9289):1257–64. doi: 10.1016/S0140-6736(01)06351-6. [DOI] [PubMed] [Google Scholar]
  • 15.Findley CM, Mitchell RG, Duscha BD, Annex BH, Kontos CD. Plasma levels of soluble Tie2 and vascular endothelial growth factor distinguish critical limb ischemia from intermittent claudication in patients with peripheral arterial disease. J Am Coll Cardiol. 2008;52(5):387–93. doi: 10.1016/j.jacc.2008.02.045. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.McDermott MM, Lloyd-Jones DM. The role of biomarkers and genetics in peripheral arterial disease. J Am Coll Cardiol. 2009;54 (14):1228–37. doi: 10.1016/j.jacc.2009.04.081. [DOI] [PubMed] [Google Scholar]
  • 17.Wilson AM, Kimura E, Harada RK, Nair N, Narasimhan B, Meng X-Y, et al. {beta}2-Microglobulin as a biomarker in peripheral arterial disease: proteomic profiling and clinical studies. Circulation. 2007;116(12):1396–403. doi: 10.1161/CIRCULATIONAHA.106.683722. [DOI] [PubMed] [Google Scholar]
  • 18.McDermott MM, Greenland P, Liu K, Guralnik JM, Celic L, Criqui MH, et al. The ankle brachial index is associated with leg function and physical activity: the Walking and Leg Circulation Study. Ann Intern Med. 2002;136(12):873–83. doi: 10.7326/0003-4819-136-12-200206180-00008. [DOI] [PubMed] [Google Scholar]
  • 19.Imparato AM, Kim GE, Davidson T, Crowley JG. Intermittent claudication: its natural course. Surgery. 1975;78(6):795–9. [PubMed] [Google Scholar]
  • 20.Boyd AM. The natural course of arteriosclerosis of the lower extremities. Proc R Soc Med. 1962;55:591–3. [PubMed] [Google Scholar]
  • 21.Cronenwett JL, Warner KG, Zelenock GB, Whitehouse WM, Jr, Graham LM, Lindenauer M, et al. Intermittent claudication. Current results of nonoperative management. Arch Surg. 1984;119 (4):430–6. doi: 10.1001/archsurg.1984.01390160060012. [DOI] [PubMed] [Google Scholar]
  • 22.Sheehan P. Peripheral arterial disease in people with diabetes: consensus statement recommends screening. Clin Diabetes. 2004;22(4):179–80. [Google Scholar]
  • 23.Jude EB, Oyibo SO, Chalmers N, Boulton AJM. Peripheral arterial disease in diabetic and nondiabetic patients. Diab Care. 2001;24(8):1433–7. doi: 10.2337/diacare.24.8.1433. [DOI] [PubMed] [Google Scholar]
  • 24.Melton LJ, 3rd, Mackey KM, Palumbo PJ, Elveback LR. Incidence and prevalence of clinical peripheral vascular disease in a population-based cohort of diabetic patients. Diab Care. 1980;3(6):650–4. doi: 10.2337/diacare.3.6.650. [DOI] [PubMed] [Google Scholar]
  • 25.Beks PJ, Mackaay AJ, de Neeling JN, de Vries H, Bouter LM, Heine RJ. Peripheral arterial disease in relation to glycaemic level in an elderly Caucasian population: the Hoorn study. Diabetologia. 1995;38(1):86–96. doi: 10.1007/BF02369357. [DOI] [PubMed] [Google Scholar]
  • 26.Welborn TA, Kruiman M, McCann V, Stanton K, Constable IJ. Clinical macrovascular disease in Caucasoid diabetic subjects: logistic regression analysis of risk variables. Diabetologia. 1984;27(6):568–73. doi: 10.1007/BF00276969. [DOI] [PubMed] [Google Scholar]
  • 27.Jude EB, Eleftheriadou I, Tentolouris N. Peripheral arterial disease in diabetes—a review. Diab Med. 27(1):4–14. doi: 10.1111/j.1464-5491.2009.02866.x. [DOI] [PubMed] [Google Scholar]
  • 28.Jude EB, Eleftheriadou I, Tentolouris N. Peripheral arterial disease in diabetes—a review. Diabet Med. 2010;27(1):4–14. doi: 10.1111/j.1464-5491.2009.02866.x. [DOI] [PubMed] [Google Scholar]
  • 29.Walters DP, Gatling WA, Mullee MA, Hill RD. The prevalence, detection, and epidemiological correlates of peripheral vascular disease: a comparison of diabetic and non-diabetic subjects in an English community. Diabet Med. 1992;9(8):710–5. doi: 10.1111/j.1464-5491.1992.tb01878.x. [DOI] [PubMed] [Google Scholar]
  • 30.Beckman JA, Creager MA, Libby P. Diabetes and atherosclerosis. JAMA, J Am Med Assoc. 2002;287(19):2570–81. doi: 10.1001/jama.287.19.2570. [DOI] [PubMed] [Google Scholar]
  • 31.Thangarajah H, Yao D, Chang EI, Shi Y, Jazayeri L, Vial IN, et al. The molecular basis for impaired hypoxia-induced VEGF expression in diabetic tissues. Proceedings of the National Academy of Sciences. doi: 10.1073/pnas.0906670106. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Hazarika S, Dokun AO, Li Y, Popel AS, Kontos CD, Annex BH. Impaired angiogenesis after hindlimb ischemia in type 2 diabetes mellitus: differential regulation of vascular endothelial growth factor receptor 1 and soluble vascular endothelial growth factor receptor 1. Circ Res. 2007;101(9):948–56. doi: 10.1161/CIRCRESAHA.107.160630. [DOI] [PubMed] [Google Scholar]
  • 33.Kullo IJ, Bailey KR, Kardia SL, Mosley TH, Jr, Boerwinkle E, Turner ST. Ethnic differences in peripheral arterial disease in the NHLBI Genetic Epidemiology Network of Arteriopathy (GENOA) study. Vasc Med. 2003;8(4):237–42. doi: 10.1191/1358863x03vm511oa. [DOI] [PubMed] [Google Scholar]
  • 34.Kullo IJ, Turner ST, Kardia SL, Mosley TH, Jr, Boerwinkle E, de Andrade M. A genome-wide linkage scan for ankle-brachial index in African American and non-Hispanic white subjects participating in the GENOA study. Atherosclerosis. 2006;187(2):433–8. doi: 10.1016/j.atherosclerosis.2005.10.003. [DOI] [PubMed] [Google Scholar]
  • 35.Murabito JM, Guo CY, Fox CS, D’Agostino RB. Heritability of the ankle-brachial index: the Framingham Offspring study. Am J Epidemiol. 2006;164(10):963–8. doi: 10.1093/aje/kwj295. [DOI] [PubMed] [Google Scholar]
  • 36.Wahlgren CM, Magnusson PKE. Genetic influences on peripheral arterial disease in a twin population. Arterioscler Thromb Vasc Biol. 31(3):678–682. doi: 10.1161/ATVBAHA.110.210385. [DOI] [PubMed] [Google Scholar]
  • 37.Dokun AO, Annex B. Ginsburg HWaG. Genomic and personalized medicine. 1–2. Elsavier; 2008. Genetic polymorphisms in peripheral arterial disease role of genomic methodologies. [Google Scholar]
  • 38.Knowles JW, Assimes TL, Li J, Quertermous T, Cooke JP. Genetic susceptibility to peripheral arterial disease: a dark corner in vascular biology. Arterioscler Thromb Vasc Biol. 2007;27 (10):2068–78. doi: 10.1161/01.ATV.0000282199.66398.8c. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39•.Zintzaras E, Zdoukopoulos N. A Field synopsis and meta-analysis of genetic association studies in peripheral arterial disease: the CUMAGAS-PAD database. Am J Epidemiol. 2009;170(1):1–11. doi: 10.1093/aje/kwp094. This is a recent review that provides a comprehensive overview of gene polymorphisms associated with PAD. [DOI] [PubMed]
  • 40.Kawashima S, Yokoyama M. Dyfunction of endothelial nitric oxide synthase and atherosclerosis. Arterioscler Thromb Vasc Biol. 2004 doi: 10.1161/01.ATV.0000125114.88079.96. 01.ATV.0000125114.0000188079.0000125196. [DOI] [PubMed] [Google Scholar]
  • 41.Hingorani AD. Polymorphisms in endothelial nitric oxide synthase and atherogenesis: John French Lecture 2000. Atherosclerosis. 2001;154(3):521–7. doi: 10.1016/s0021-9150(00)00699-7. [DOI] [PubMed] [Google Scholar]
  • 42.Fatini C, Sofi F, Sticchi E, Bolli P, Sestini I, Falciani M, et al. eNOS G894T polymorphism as a mild predisposing factor for abdominal aortic aneurysm. J Vasc Surg. 2005;42(3):415–9. doi: 10.1016/j.jvs.2005.05.044. [DOI] [PubMed] [Google Scholar]
  • 43.Fatini C, Sofi F, Gensini F, Sticchi E, Lari B, Pratesi G, et al. Influence of eNOS Gene Polymorphisms on Carotid Atherosclerosis. Eur J Vasc Endovasc Surg. 2004;27(5):540–4. doi: 10.1016/j.ejvs.2004.02.008. [DOI] [PubMed] [Google Scholar]
  • 44.Sticchi E, Sofi F, Romagnuolo I, Pratesi G, Pulli R, Pratesi C, et al. eNOS and ACE genes influence peripheral arterial disease predisposition in smokers. J Vasc Surg. 52(1):97–102. e101. doi: 10.1016/j.jvs.2010.02.021. [DOI] [PubMed] [Google Scholar]
  • 45.Rigat B, Hubert C, Alhenc-Gelas F, Cambien F, Corvol P, Soubrier F. An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest. 1990;86(4):1343–6. doi: 10.1172/JCI114844. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Basar Y, Salmayenli N, Aksoy M, Seckin S, Aydin M, Ozkok E. ACE gene polymorphism in peripheral vascular disease. Horm Metab Res. 2007;39(7):534–7. doi: 10.1055/s-2007-982529. [DOI] [PubMed] [Google Scholar]
  • 47.Li R, Nicklas B, Pahor M, Newman A, Sutton-Tyrrell K, Harris T, et al. Polymorphisms of angiotensinogen and angiotensin-converting enzyme associated with lower extremity arterial disease in the Health, Aging and Body Composition study. J Hum Hypertens. 2007;21(8):673–82. doi: 10.1038/sj.jhh.1002198. [DOI] [PubMed] [Google Scholar]
  • 48.Fatini C, Sticchi E, Sofi F, Said AA, Pratesi G, Pulli R, et al. Multilocus analysis in candidate genes ACE, AGT, and AGTR1 and predisposition to peripheral arterial disease: role of ACE D/−240 T haplotype. J Vasc Surg. 2009;50(6):1399–404. doi: 10.1016/j.jvs.2009.07.075. [DOI] [PubMed] [Google Scholar]
  • 49.Cesari M, Penninx BW, Newman AB, Kritchevsky SB, Nicklas BJ, Sutton-Tyrrell K, et al. Inflammatory markers and onset of cardiovascular events: results from the Health ABC study. Circulation. 2003;108(19):2317–22. doi: 10.1161/01.CIR.0000097109.90783.FC. [DOI] [PubMed] [Google Scholar]
  • 50.Flex A, Gaetani E, Angelini F, Sabusco A, Chilla C, Straface G, et al. Pro-inflammatory genetic profiles in subjects with peripheral arterial occlusive disease and critical limb ischemia. J Intern Med. 2007;262(1):124–30. doi: 10.1111/j.1365-2796.2007.01791.x. [DOI] [PubMed] [Google Scholar]
  • 51.Libra M, Signorelli SS, Bevelacqua Y, Navolanic PM, Bevelacqua V, Polesel J, et al. Analysis of G(−174)C IL-6 polymorphism and plasma concentrations of inflammatory markers in patients with type 2 diabetes and peripheral arterial disease. J Clin Pathol. 2006;59(2):211–5. doi: 10.1136/jcp.2004.025452. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52.Gabriels JE, Paul DL. Connexin43 is highly localized to sites of disturbed flow in rat aortic endothelium but connexin37 and connexin40 are more uniformly distributed. Circ Res. 1998;83 (6):636–43. doi: 10.1161/01.res.83.6.636. [DOI] [PubMed] [Google Scholar]
  • 53•.Katakami N, Sakamoto K, Kaneto H, Matsuhisa M, Shimizu I, Ishibashi F, et al. Association between the connexin37 polymorphism and peripheral arterial disease in subjects with type 2 diabetes. Diab Care. 2009;32(5):53–54. doi: 10.2337/dc08-2185. This is a short report, but it is one of only a few recent articles that identified a gene polymorphism associated with PAD among individuals with diabetes. [DOI] [PubMed] [Google Scholar]
  • 54.Helgadottir A, Thorleifsson G, Manolescu A, Gretarsdottir S, Blondal T, Jonasdottir A, et al. A common variant on chromosome 9p21 affects the risk of myocardial infarction. Science. 2007;316 (5830):1491–3. doi: 10.1126/science.1142842. [DOI] [PubMed] [Google Scholar]
  • 55.Cluett C, McDermott MM, Guralnik J, Ferrucci L, Bandinelli S, Miljkovic I, et al. The 9p21 myocardial infarction risk allele increases risk of peripheral artery disease in older people. Circ Cardiovasc Genet. 2009;2(4):347–53. doi: 10.1161/CIRCGENETICS.108.825935. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56.Helgadottir A, Thorleifsson G, Magnusson KP, Gretarsdottir S, Steinthorsdottir V, Manolescu A, et al. The same sequence variant on 9p21 associates with myocardial infarction, abdominal aortic aneurysm and intracranial aneurysm. Nat Genet. 2008;40(2):217–24. doi: 10.1038/ng.72. [DOI] [PubMed] [Google Scholar]
  • 57.Yee KO, Ikari Y, Schwartz SM. An update of the Grutzbalg hypothesis: the role of thrombosis and coagulation in atherosclerotic progression. Thromb Haemost. 2001;85(2):207–17. [PubMed] [Google Scholar]
  • 58.Coughlin SR. Thrombin signalling and protease-activated receptors. Nature. 2000;407(6801):258–64. doi: 10.1038/35025229. [DOI] [PubMed] [Google Scholar]
  • 59.Fowkes FG, Connor JM, Smith FB, Wood J, Donnan PT, Lowe GD. Fibrinogen genotype and risk of peripheral atherosclerosis. Lancet. 1992;339(8795):693–6. doi: 10.1016/0140-6736(92)90596-u. [DOI] [PubMed] [Google Scholar]
  • 60.Reny JL, Alhenc-Gelas M, Fontana P, Bissery A, Julia PL, Fiessinger JN, et al. The factor II G20210A gene polymorphism, but not factor V Arg506Gln, is associated with peripheral arterial disease: results of a case-control study. J Thromb Haemost. 2004;2 (8):1334–40. doi: 10.1111/j.1538-7836.2004.00809.x. [DOI] [PubMed] [Google Scholar]
  • 61.Conley PB, Delaney SM. Scientific and therapeutic insights into the role of the platelet P2Y12 receptor in thrombosis. Curr Opin Hematol. 2003;10(5):333–8. doi: 10.1097/00062752-200309000-00002. [DOI] [PubMed] [Google Scholar]
  • 62.Gachet C. ADP receptors of platelets and their inhibition. Thromb Haemost. 2001;86(1):222–32. [PubMed] [Google Scholar]
  • 63.Fontana P, Dupont A, Gandrille S, Bachelot-Loza C, Reny JL, Aiach M, et al. Adenosine diphosphate-induced platelet aggregation is associated with P2Y12 gene sequence variations in healthy subjects. Circulation. 2003;108(8):989–95. doi: 10.1161/01.CIR.0000085073.69189.88. [DOI] [PubMed] [Google Scholar]
  • 64.Fontana P, Gaussem P, Aiach M, Fiessinger JN, Emmerich J, Reny JL. P2Y12 H2 haplotype is associated with peripheral arterial disease: a case-control study. Circulation. 2003;108(24):2971–3. doi: 10.1161/01.CIR.0000106904.80795.35. [DOI] [PubMed] [Google Scholar]
  • 65.Sofi F, Lari B, Rogolino A, Marcucci R, Pratesi G, Dorigo W, et al. Thrombophilic risk factors for symptomatic peripheral arterial disease. J Vasc Surg. 2005;41(2):255–60. doi: 10.1016/j.jvs.2004.11.015. [DOI] [PubMed] [Google Scholar]
  • 66.Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet. 1995;10(1):111–3. doi: 10.1038/ng0595-111. [DOI] [PubMed] [Google Scholar]
  • 67.Refsum H, Ueland PM, Nygård O, Vollset SE. Homocysteine and cardiovascular disease. Annu Rev Med. 1998;49(1):31–62. doi: 10.1146/annurev.med.49.1.31. [DOI] [PubMed] [Google Scholar]
  • 68.Todesco L, Angst C, Litynski P, Loehrer F, Fowler B, Haefeli WE. Methylenetetrahydrofolate reductase polymorphism, plasma homocysteine and age. Eur J Clin Invest. 1999;29(12):1003–9. doi: 10.1046/j.1365-2362.1999.00578.x. [DOI] [PubMed] [Google Scholar]
  • 69.Sabino A, Fernandes AP, Lima LM, Ribeiro DD, Sousa MO, de Castro Santos ME, et al. Polymorphism in the methylenetetrahydrofolate reductase (C677T) gene and homocysteine levels: a comparison in Brazilian patients with coronary arterial disease, ischemic stroke and peripheral arterial obstructive disease. J Thromb Thrombolysis. 2009;27(1):82–7. doi: 10.1007/s11239-007-0172-z. [DOI] [PubMed] [Google Scholar]
  • 70.Pollex R, Mamakeesick M, Zinman B, Harris S, Hanley A, Hegele R. Methylenetetrahydrofolate reductase polymorphism 677 C>T is associated with peripheral arterial disease in type 2 diabetes. Cardiovasc Diabetol. 2005;4(1):17. doi: 10.1186/1475-2840-4-17. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 71.Gudmundsson G, Matthiasson SE, Arason H, Johannsson H, Runarsson F, Bjarnason H, et al. Localization of a gene for peripheral arterial occlusive disease to chromosome 1p31. Am J Hum Genet. 2002;70(3):586–92. doi: 10.1086/339251. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 72•.Thorgeirsson TE, Geller F, Sulem P, et al. A variant associated with nicotine dependence, lung cancer and peripheral arterial disease. Nature. 2008;452:7187, 638–642. doi: 10.1038/nature06846. This GWAS found an association between nicotine dependence and a SNP (rs1051730) that was also associated with PAD and lung cancer, suggesting a gene–environment interaction. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 73••.Jiang YD, Chang YC, Chiu YF, Chang TJ, Li HY, Lin WH, et al. SLC2A10 genetic polymorphism predicts development of peripheral arterial disease in patients with type 2 diabetes. SLC2A10 and PAD in type 2 diabetes. BMC Med Genet. 11:126. doi: 10.1186/1471-2350-11-126. This recent study used a candidate gene approach to identify novel gene polymorphisms associated with the risk of developing PAD among individuals with diabetes. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 74.Coucke PJ, Willaert A, Wessels MW, Callewaert B, Zoppi N, De Backer J, et al. Mutations in the facilitative glucose transporter GLUT10 alter angiogenesis and cause arterial tortuosity syndrome. Nat Genet. 2006;38(4):452–7. doi: 10.1038/ng1764. [DOI] [PubMed] [Google Scholar]
  • 75.Brownlee M. The pathobiology of diabetic complications: a unifying mechanism. Diabetes. 2005;54(6):1615–25. doi: 10.2337/diabetes.54.6.1615. [DOI] [PubMed] [Google Scholar]
  • 76•.Dokun AO, Keum S, Hazarika S, Li Y, Lamonte GM, Wheeler F, et al. A quantitative trait locus (LSq-1) on mouse chromosome 7 is linked to the absence of tissue loss after surgical hindlimb ischemia. Circulation. 2008;117(9):1207–1215. doi: 10.1161/CIRCULATIONAHA.107.736447. This study exemplifies a novel appraoch to identifying gene polymorphisms that may be important in the pathogenesis of PAD. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 77.Fukino K, Sata M, Seko Y, Hirata Y, Nagai R. Genetic background influences therapeutic effectiveness of VEGF. Biochem Biophys Res Commun. 2003;310(1):143–7. doi: 10.1016/j.bbrc.2003.08.134. [DOI] [PubMed] [Google Scholar]

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