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Genetic association studies in peripheral arterial disease.


Peripheral artery disease (PAD) is a major health concern affecting millions of patients worldwide and is associated with significant morbidity and mortality. (1) PAD is most commonly caused by atherosclerosis, and its prevalence increases sharply with age, from 3% in those under age 60 years to [greater than or equal to] 20% at 75 years and older. (2) A significant proportion of patients have asymptomatic disease; the disease progresses over time, leading to loss of mobility and to cardiovascular-related mortality. (1)

Genome-wide association studies not only appear to be a powerful new tool for identifying genes that influence common diseases but also represent a valuable instrument for examining genomic function and clarifying pathophysiologic mechanisms. (3) Although associated cardiovascular risk factors such as hypertension and diabetes mellitus have been shown to be under genetic control, (4) the contribution of genetic influences to PAD is less well known. The possible existence of an inherited genetic predisposition to PAD has been investigated in various types of familial aggregation studies. (5-9) The following is an overview of genetic associations in PAD focusing on ankle-brachial index (ABI), biological mechanisms of vascular diseases and aortic aneurysm.


ABI is widely used in the clinical evaluation of PAD with excellent sensitivity and specificity. (2) It is a measured index using the highest systolic pressure in either the dorsalis pedis or posterior tibial artery divided by the highest of the brachial systolic pressures. In asymptomatic individuals, an abnormal ABI correlates with other cardiovascular risk factors, such as hypertension, diabetes mellitus, tobacco abuse, impaired glucose metabolism, and dyslipidemia. (2) In the field of PAD, ABI has been investigated in genome-wide association studies. (10)

Abnormal ABI values can be caused by genetic and environmental factors as well as by novel mutations that differ from the genes influencing normal variation. The onset of PAD may also vary widely, and genetic and environmental (eg, tobacco use) factors may play important roles in the manifestation of the disease. Bias in the estimation of genetic effects is commonly present in longitudinal studies of elderly subjects, in which selective mortality and loss to follow-up of high-risk individuals require limitation of the analysis to twin pairs, in which both members participate in the follow-up examination. As an example, smoking and hypertension, previously associated with PAD, were more common among subjects lost to follow-up. (11)

Carmelli et al10 used the ABI as a surrogate measure of PAD while investigating the contributions of genetic and environmental influences to both normative and abnormal values. When ABI was treated as a continuous variable, approximately half of the observed variability in ABI values could be attributed to additive genetic influences, while the remaining half was accounted for by nonshared individual environmental influences. (10) In addition, concordance rates for low ABI values (ie, ABI [less than or equal to] 0.9) regardless of zygosity were statistically significant, which suggests a contribution of shared familial influences. However, the strongest correlates of low ABI in discordant twin pairs, matched for age and genetics, were behavioral risk factors (eg, smoking, physical inactivity). In the unmatched analysis, diabetes and hypertension, in addition to smoking and physical inactivity, were significant correlates of abnormal ABI values. Although this pattern suggests that common genetic factors exist between PAD, hypertension, and diabetes, it also emphasizes the predominant role of individual health behaviors in the early manifestation of disease.

This pattern of results, together with the significant association of persistent smoking and physical inactivity with low ABI in the matched and unmatched analyses, reinforces the relevance of individual health practices in the manifestation of PAD. (10) Additionally, in this study, the prevalence of abnormal ABI values was within the range of estimated prevalence in nontwin males of similar ages. More notable was the association of persistent smoking with abnormal ABI within discordant twin pairs matched for age and genetic make-up. A great amount of data has been accumulated regarding the harmful effects of smoking on the development of arteriosclerosis in the abdominal aorta, major arteries of the lower limbs, coronary arteries, and aortic aneurysm. (12,13)

The power of the matched-paired methodology had previously been demonstrated in a study of carotid arteriosclerosis in identical twins who were discordant for smoking history. (14) In this study, the association of persistent smoking with carotid arteriosclerosis was highly significant after adjusting for age, total plasma cholesterol level, blood pressure, and obesity, which suggests a causal relationship between smoking and the development of arteriosclerosis. Carmelli et al (10) was the first to establish the harmful effect of persistent smoking and the beneficial effect of smoking cessation on PAD in the elderly. In both the matched and unmatched analyses, the relative risk for abnormal ABI values was significant for current smokers but not significant for former smokers. The corollary to this observation is that changes in behavior, such as smoking cessation, have the potential to reduce the risk of premature disease even in subjects who may be initially placed at greater risk due to genetic factors. (10)


PAD is a consequence of systemic disease processes that affect multiple arterial circulations. These pathophysiologic processes are diverse and include preexisting atherosclerosis, inflammation, and in-situ thrombosis and thromboembolism, among others. (17) Although atherosclerosis is the most common cause of PAD worldwide and classic atherosclerotic risk factors are closely associated with the epidemiology and clinical development of PAD,17 activated hemostatic systems and inflammation have also been postulated as contributing factors to the pathophysiology of PAD. (18)

One main approach to disentangling the genetic etiology of complex human traits is the use of association studies. Genetic association studies are central to efforts to identify and characterize genomic variants [eg, single nucleotide polymorphism (SNP)] underlying susceptibility to PAD. Polymorphisms may influence gene activity as messenger RNA conformation, altering the binding ability of a protein to its substrate and thereby changing its subcellular localization. Therefore, polymorphisms are emerging risk factors that may predispose individuals to PAD and correlate with the pathogenesis of the disease. (17)

The following are some of the well-studied polymorphisms and their functional implications in PAD.


Thrombophilia can be mediated through defects in alternative convergent pathways: the coagulation pathway, the folate pathway, the extracellular matrix receptor interaction pathway, and the vitamin K cycle module (Table 1).

The coagulation factor pathway. Factor V, a large plasma glycoprotein that circulates with little or no activity, is encoded by the F5 gene. A nonsynonymous SNP designated 1691 G/A was described as a candidate for increasing the risk of PAD. In the four studies that investigated this potential correlation,18,19 no significant dependence of PAD risk on genotype could be demonstrated.

Factor II (prothrombin) is a coagulation factor that is transformed into thrombin after its activation by the prothrombinase complex at the site of vascular injury. A functional SNP in the F2 gene (20210 G/A) was studied in multiple series. (18,19) A meta-analysis of these studies showed significant heterogeneity for the allele contrast; the association was not significant.

The F7 gene encodes coagulation factor VII, which is a vitamin K-dependent factor essential for hemostasis. Currently, 1289 G/A is the only polymorphism in the F7 gene that has been investigated in association with PAD. (20) However, no evidence exists of an association between F7 1289 G/A polymorphism genotypes and the risk of developing PAD.

The Factor XIIIA subunit is encoded by the F13A1 gene. Only one study has explored the contribution of a functional polymorphism and no association with PAD was observed. (21)

Folate pathway. Methylenetetrahydrofolate reductase is a critical folate-metabolizing enzyme involved in the folate/homocysteine metabolic pathway. MTHFR 677 C/T is a common polymorphism that has been reported for this enzyme. Numerous studies have investigated this polymorphism for susceptibility to PAD, with a positive association being found in three. (19,22,23) The allele contrast showed a positive association in only two studies, (19,22) and the recessive model in only one. (22) The meta-analysis of these studies showed significant heterogeneity among them for the allele contrast; the association was not significant.

Extracellular matrix receptor interaction pathway. A genetic variation in the ITGB3 gene that involves a single amino-acid substitution of proline for leucine at position 33 has been related to increased platelet aggregation. This polymorphism has been evaluated in two studies, and its association with PAD was not significant. (24,25)

Vitamin K cycle module. The VKORC1 gene encodes the enzyme responsible for reducing vitamin K 2,3-epoxide to the enzymatically activated form. No significant association was found between this polymorphism and PAD. (26)


Perturbations in local hemodynamics are implicated in the atherogenetic process and may confer susceptibility to PAD through diverse pathways, such as the calcium signaling pathway, the renin-angiotensin system pathway, and the porphyrin and chlorophyll metabolism pathway (Table 2).

Calcium signaling pathway. The NOS3 gene encodes calcium-regulated endothelial nitric oxide synthase that is capable of producing nitric oxide in blood vessels. (27) This polymorphism did not influence the risk of PAD.

Renin-angiotensin system pathway. Angiotensin-converting enzyme (ACE) processes the decapeptide angiotensin I to the 8-amino-acid peptide angiotensin II, which functions as a potent vasoconstrictor. Studies (28,29) to date have addressed whether a functional insertion/deletion polymorphism in the ACE gene alters the risk of PAD, with borderline significance. The meta-analysis of these studies did not reveal significant heterogeneity among them for the allele contrast, and the association was not significant.

Angiotensinogen is the precursor of angiotensin II, which is involved in the regulation of blood pressure. Three polymorphisms in the AGT gene have been reported with contradictory results. (29)

Porphyrin and chlorophyll metabolism pathway. Heme oxygenase degrades heme into biliverdin, which is subsequently converted to bilirubin and carbon monoxide. A [(GT).sub.n]-length polymorphism in the HMOX1 gene that modulates its transcription has been investigated in relation to PAD, but no significant association was found. (30)


The vascular inflammatory process is pivotal in the pathophysiology of PAD, and it can be initiated through various pathways. The genes that have been investigated in PAD to date can be classified into three distinct pathways: the cytokine-cytokine receptor interaction pathway, the leukocyte transendothelial migration pathway, and the peroxisome proliferator-activated receptor signaling pathway (Table 3).

Cytokine-cytokine receptor interaction pathway. Interleukin-6 is a multifunctional cytokine produced by several cell types, including fibroblasts, monocytes, adipocytes, and endothelial cells. Studies have evaluated the IL6-174 G/C polymorphism for its potential role in PAD, producing contradictory results. (31,32) When study results were analyzed, significant heterogeneity was found among them for the allele contrast, but the association with PAD was not significant.

The CX3CR1 gene encodes the fractalkine receptor, which is a leukocyte chemotactic/adhesion receptor. Gugl et al33 investigated two CX3CR1 polymorphisms (837 G/A and 931 C/T), and the findings provided no evidence that the genes played a role in the development of PAD.

The CCR5 gene encodes a member of the chemokine receptor family. A common 32-base-pair deletion mutation in the CCR5 gene was evaluated in one study with no association observed. (34)

Leukocyte transendothelial migration pathway. The subunit of cytochrome b is encoded by the CYBA gene and is a primary component of nicotinamide adenine dinucleotide phosphate oxidase. The influence of a functional polymorphic variant of the CYBA gene (242 C/T) on the predisposition to develop PAD has been assessed, but no association was found. (35)

Intercellular adhesion molecule 1 (ICAM1) is a member of the cytokine-inducible immunoglobulin gene superfamily and binds leukocyte integrins. A nonsynonymous functional SNP in the ICAM1 gene, designated Lys469Glu, emerged as a potential risk factor for PAD. (36)

E-selectin is expressed by cytokine-stimulated endothelial cells and mediates the adhesion of leukocytes to the vascular lines. Only one polymorphism in the SELE gene has been studied in relation to PAD (561 A/C) with positive associations being demonstrated for the recessive and allele-contrast models. (32)

The enzyme encoded by the matrix metalloproteinase 9 (MMP9) gene degrades type IV and V collagens and has been implicated in the pathogenesis of atherosclerosis. Studies have explored associations between a functional polymorphism in the MMP9 gene (-1562 C/T) and PAD. (32,37) When the two studies were synthesized, no evidence of association was observed.

Matrix metalloproteinase 1 (MMP1) appears to play a significant role in atherosclerotic plaque disruption by contributing to the degradation of interstitial collagens. Flex et al32 investigated a common insertion polymorphism in the MMP1 gene in relation to PAD and showed a positive association for all of the genetic models examined.

Peroxisome proliferator-activated receptor (PPARG) signaling pathway. PPARG was reported as a candidate gene for PAD,38 because a putative functional SNP in the PPARG gene (Pro12Ala) demonstrated significant associations under the allele-contrast and dominant models.


Aortic pathology, including aneurysms and dissections, is the 13th leading cause of death in the United States, with 15,000 deaths per year and >60% mortality when rupture occurs. (39) The two greatest risk factors, both preventable, are cigarette smoking (85% of patients) and hypertension (60% of patients). Other less significant risk factors include chronic obstructive pulmonary disease, family history, and atherosclerosis of other vascular beds. (39) While the risk factors for developing abdominal aortic aneurysms are similar to those for heart disease and peripheral arterial disease (atherosclerosis, hypertension, smoking, advanced age); 19% occur in subjects with a family history of aortic aneurysm, suggesting a genetic predisposition. (39) Several authors have described various genes associated with risk of aortic aneurysm. (30,34,37,39,40) Furthermore, aortic aneurysms may be associated with a number of heritable conditions including a bicuspid aortic valve, Marfan syndrome (MFS), Loeys-Dietz syndrome (LDS), Ehlers-Danlos syndrome (EDS), and familial thoracic aortic aneurysms and dissections (FTAADs) (Table 4). (40)

Marfan syndrome

MFS is an inherited connective tissue disorder characterized by cardiovascular, skeletal, and ocular abnormalities. The primary gene defect lies on chromosome 15q21.1 within the coding sequence for the fibrillin-1 gene (FBN1), a principle component of the 10-12 nm microfibrils that form the scaffold for elastin assembly within the extracellular matrix. The diagnosis of MFS has been based on a defined set of clinical criteria. (40) Approximately 10% of patients classified as having MFS fail to show a defect in the FBN1 gene, suggesting that a second genetic locus is linked to MFS. This syndrome is clinically similar to classic MFS but with no ocular involvement. Subsequent linkage analysis by Collod and colleagues mapped the defect to a locus on chromosome 3p25-24.2 and designated the syndrome Marfan Syndrome Type 2 (MFS2). (41) The MFS phenotype can be caused by mutations in both FBN1 and TGFBR2 (type II transforming growth factor beta receptor). In both cases, the alterations in TGF-8 signaling may contribute to the underlying cause of aneurysm formation. (40) TGF-[beta] is a member of a superfamily of ligands and receptors that include the TGF-[beta]s, bone morphogenetic proteins, and activins/inhibins. These soluble peptide growth factors are produced by multiple cell types and participate in a wide array of cellular responses, including proliferation, angiogenesis, differentiation, apoptosis, inflammation, and wound healing. (40) Although TGF-[beta] is probably best known for its role in matrix deposition/collagen synthesis related to fibrotic disease, it has also been shown to regulate alternate pathways that can lead to matrix degradation. (40)

Loeys-Dietz syndrome

In 2005, Loeys and colleagues described a phenotype characterized by perturbations in cardiovascular, craniofacial, neurocognitive, and skeletal development associated with several heterozygous mutations in the genes encoding either type I or type II TGF-[beta] receptor. (42) This disorder, LDS, was characterized by the enhanced development of aortic aneurysms and dissections that occur at a younger age and smaller aortic diameter. A subset of individuals lack typical craniofacial features other than a bifid uvula and have been designated LDS as type II. Individuals with LDS type I have early cardiovascular mortality compared to LDS type II subjects, although both types are characterized by aggressive arterial aneurysms. (42)

Ehlers-Danlos syndrome

EDS is commonly used to designate a group of inherited connective tissue disorders that are clinically, biochemically, and genetically heterogeneous. (43) EDS type IV, also known as vascular type EDS, is a severe form that primarily affects the skin and large arteries and can lead to medial degenerative disease of the aorta resulting in acute dissection. (40) In a 22-year-old subject with an autosomal dominant inherited form of EDS type IV, the genetic pathology was a 3.3 kb DNA deletion in one allele of the type III procollagen gene (COL3A1), resulting in a truncated procollagen monomer that had decreased thermal stability and could not be proteolytically processed nor efficiently secreted. (43)

Familial thoracic aortic aneurysms and dissections

In addition to the classified aneurysm syndromes that are directly associated with specific gene defects such as MFS, an expanding collection of studies have identified thoracic aortic aneurysm +/- dissections that are not clearly associated with an identifiable syndrome. Of these individuals, approximately 20% display a genetic predisposition that was inherited in an autosomal dominant manner with decreased penetrance and variable expression. These nonsyndromic cases have collectively been referred to as FTAADs. Currently, six causal genetic loci have been identified and linked to FTAAD: 11q23.3-q24, 5q13-q14, 3p24-25, 16p13.13-p13.12, 9q33-q34 and 10q22-q24. (40)


Elucidating the explicit genetic role of polymorphisms in PAD, including aortic aneurysms and dissections, could be considered an essential step toward creating effective screening tests for predicting individual risk of disease, implementing appropriate early therapeutic strategies, and developing gene-targeted treatment approaches.

As with other complex diseases, several genes that act collectively probably determine the development of PAD, and allelic variants in different genes may have either additive or contrasting effects. In addition, several possible interactions between gene polymorphisms and multiple environmental modifiers have been implicated in altering the natural history of PAD. The ABI has been investigated in genome-wide association studies without clear significance. By contrast, individual health behavior such as smoking plays a predominant role in the early manifestation of PAD. Aortic aneurysm and dissection consist of a plethora of genetic-associated pathologies such as MFS, LDS, EDS, and FTAADs, all with genetic linkage. However, the results of genetic association studies investigating the genomic variants and biological pathophysiology of PAD have been inconclusive. Nevertheless, genetic polymorphisms such as those involved in the vascular inflammatory processes appear to be particularly promising and warrant further study.

In conclusion, PAD is a complex disease with multifactorial etiologies. An association of environmental factors and gene polymorphisms likely play a role in its etiology and clinical manifestations.


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Yung-Wei Chi, DO; Olusegun Osinbowale, MD; and Richard Milani, MD

Dr. Chi is currently with the UC Davis Vascular Center in Sacramento, California. Drs. Osinbowale and Milani are with the Ochsner Clinic Health System in Metairie, Louisiana.
Table 1. Thrombophilia.

                  Gene     SNP        Significant
                                      to PAD

Coagulation       F5       1,691      No
factor pathway             G/A

                  F2       20,210     No

                  F7       1,289      No

                  F13A1    204 G/T    No

Folate pathway    MTHFR    MTHFR      No
                           677 C/T

Extracellular     ITGB3    1565 T/C   No
matrix receptor

Vitamin K cycle   VKORC1   1,693      No
module                     G/A

SNP=single nucleotide polymorphism; PAD=peripheral artery

Table 2. Hemodynamics.

               Gene    SNP                     Significant
                                               association to

Calcium        NOS3    Glu298Asp               No

               GBN3    C825T                   No

Renin-         ACE     ACE_1/D                 No

               AGT     Met235Thr               Yes (only
                                               in African

                       Thr174Met               No

                       -6G/A                   No

Porphyrin      HMOX1   [(GT).sub.n] -length    No
and                    polymorphism

SNP=single nucleotide polymorphism; PAD=peripheral artery

Table 3. Inflammation.

                   Gene     SNP           Significant
                                          to PAD

Cytokine-          IL6      IL6-174 G/C   No

                   CX3CR1   837 G/A       No

                            931 C/T       No

                   CCR5     [DELTA] 32    No

Leukocyte          CYBA     242 C/T       No

                   ICAMI    Lys469Glu     Yes

                   SELE     561 A/C       Yes

                   MMP9     -1562 C/T     No

                   MMP1     -16071 G/2G   Yes

Peroxisome         PPARG    Pro12Ala      Yes

SNP=single nucleotide polymorphism; PAD=peripheral artery

Table 4. Aortic aneurysm and dissection: genetic linkage. (50,56)

                       Gene             Locus

Marfan syndrome        Fibrillin-1      15q21.1
                       (FBN 1)

                       Type II          3p24.2-p25

Loeys-Dietz            TGFBR1

Ehlers-Danlos          Type III
syndrome               procollagen

Familial thoracic      Smooth           16p13.13-p13.12
aortic aneurysms and   muscle
dissections            myosin
                       heavy chain

                       [alpha]-smooth   10q22-q24
                       muscle actin
                       ACT A2)

                       TGFBR1           9q33-q34


                       TGFBR2           11q23.3-q24

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Author:Chi, Yung-Wei; Osinbowale, Olusegun; Milani, Richard
Publication:The Journal of the Louisiana State Medical Society
Article Type:Report
Date:Jan 1, 2011
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