RESUMO
BACKGROUND: Genome wide association studies (GWAS) have allowed for a rapid increase in our understanding of the underlying genetics and biology of many diseases. By capitalizing on common genetic variation between individuals, GWAS can identify DNA variants associated with diseases of interest. A variety of statistical methods can be applied to GWAS results which allows for risk factor identification, stratification, and to identify potential treatments. Peripheral artery disease (PAD) is a common vascular disease that has been shown to have a strong genetic component. This article provides a review of the modern literature and our current understanding of the role of genetics in PAD. METHODS: All available GWAS studies on PAD were reviewed. A literature search involving these studies was conducted and relevant articles applying the available GWAS data were summarized to provide a comprehensive review of our current understanding of the genetic component in PAD. RESULTS: The largest available GWAS on PAD has identified 19 genome wide significant loci, with factor V Leiden and genes responsible for circulating lipoproteins being implicated in the development of PAD. Mendelian randomization (MR) studies have identified risk factors and causal associations with smoking, diabetes, and obesity and many other traits; protein-based MR has also identified circulating lipid and clotting factor levels associated with the incidence of PAD. Polygenic risk scores may allow for improved prediction of disease incidence and allow for early identification of at-risk patients but more work needs to be done to validate this approach. CONCLUSIONS: Genetic epidemiology has allowed for an increased understanding of PAD in the past decade. Genome-wide association studies have led to improved detection of genetic contributions to PAD, and further genetic analyses have validated risk factors and may provide options for improved screening in at-risk populations. Ongoing biobank studies of chronic limb threatening ischemia patients and the increasing ancestral diversity in biobank enrollment will allow for even further exploration into the pathogenesis and progression of PAD.
Assuntos
Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Doença Arterial Periférica , Fenótipo , Humanos , Doença Arterial Periférica/genética , Doença Arterial Periférica/diagnóstico , Doença Arterial Periférica/terapia , Doença Arterial Periférica/epidemiologia , Fatores de Risco , Medição de Risco , Prognóstico , Valor Preditivo dos Testes , Análise da Randomização Mendeliana , Herança Multifatorial , Marcadores GenéticosRESUMO
Patients with peripheral artery disease (PAD) have reduced muscle capillary density. Walking training (WT) is recommended for PAD patients. The goal of the study was to verify whether WT promotes angiogenesis in PAD-affected muscle and to investigate the possible role of miRNA-126 and the vascular endothelium growth factor (VEGF) angiogenic pathways on this adaptation. Thirty-two men with PAD were randomly allocated to two groups: WT (n = 16, 2 sessions/week) and control (CO, n = 16). Maximal treadmill tests and gastrocnemius biopsies were performed at baseline and after 12 weeks. Histological and molecular analyses were performed by blinded researchers. Maximal walking capacity increased by 65% with WT. WT increased the gastrocnemius capillary-fiber ratio (WT = 109 ± 13 vs. 164 ± 21 and CO = 100 ± 8 vs. 106 ± 6%, p < 0.001). Muscular expression of miRNA-126 and VEGF increased with WT (WT = 101 ± 13 vs. 130 ± 5 and CO = 100 ± 14 vs. 77 ± 20%, p < 0.001; WT = 103 ± 28 vs. 153 ± 59 and CO = 100 ± 36 vs. 84 ± 41%, p = 0.001, respectively), while expression of PI3KR2 decreased (WT = 97 ± 23 vs. 75 ± 21 and CO = 100 ± 29 vs. 105 ± 39%, p = 0.021). WT promoted angiogenesis in the muscle affected by PAD, and miRNA-126 may have a role in this adaptation by inhibiting PI3KR2, enabling the progression of the VEGF signaling pathway.
Assuntos
MicroRNAs , Doença Arterial Periférica , Masculino , Humanos , Claudicação Intermitente/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Doença Arterial Periférica/genética , Doença Arterial Periférica/metabolismo , Músculo Esquelético/metabolismo , Caminhada/fisiologia , MicroRNAs/genética , MicroRNAs/metabolismoRESUMO
Resumo O conceito de terapia angiogênica surgiu no início da década de 90, o que pode ser feito com genes que codificam fatores de crescimento para promover a formação de novos vasos e o remodelamento de vasos colaterais. Como o procedimento dessa terapia geralmente consiste em apenas injeções locais de vetores, esse processo é pouco invasivo, rápido e de simples realização. Entretanto, desde as primeiras evidências clínicas do efeito de terapia gênica com o fator de crescimento de endotélio vascular (vascular endothelial growth factor, VEGF) vistos nos pacientes com doença arterial obstrutiva periférica até hoje, apenas dois fármacos de terapia angiogênica foram aprovados, um na Rússia e outro no Japão, o que parece um número muito pequeno diante do grande número de investimentos feitos por meio de estudos pré-clínicos e clínicos. Afinal, podemos considerar que a terapia angiogênica já é uma realidade?
Abstract The concept of angiogenic therapy emerged in the early 1990s. The method employs genes that encode growth factors to promote formation of new vessels and remodeling of collateral vessels. Since the procedure involved in this therapy usually only consists of local injections of vectors, the process is minimally invasive, quick, and simple to perform. However, since the first clinical evidence of the effects of gene therapy with vascular endothelial growth factor (VEGF) was observed in patients with peripheral artery disease, to date only two angiogenic therapy drugs have been approved, one in Russia and another in Japan, which seem a very small number, in view of the large volume of investment made in pre-clinical and clinical studies. After all, can we conclude that angiogenic therapy is a reality?
Assuntos
Humanos , Terapia Genética , Indutores da Angiogênese , Doença Arterial Periférica/terapia , Fator A de Crescimento do Endotélio Vascular/genética , Extremidades , Doença Arterial Periférica/genética , Isquemia Crônica Crítica de Membro/terapiaRESUMO
OBJECTIVE/BACKGROUND: Despite being an important risk factor for venous thromboembolism, the role of the prothrombin G20210A mutation in patients with arterial disease remains unclear. The aim of this review was to evaluate the association of prothrombin G20210A and lower extremity peripheral arterial disease (PAD). METHODS: This was a systematic review and meta-analysis of case-control studies. A systematic review of electronic databases, including MEDLINE and Embase, was conducted to assess the prevalence of prothrombin G20210A in patients with lower extremity PAD. The main outcome was the prevalence of prothrombin G20210A in patients with lower extremity PAD. The random effects model odds ratio (OR) was used as the primary outcome measure. RESULTS: The initial electronic search identified 168 relevant abstracts of which five studies evaluating 1,524 cases of PAD and 1,553 controls were included. Prothrombin G20210A was found in 70 of 1,524 patients with lower extremity PAD and 44 of 1,553 of the controls (random effects OR 1.68, 95% confidence interval [CI] 0.8-3.2). In those with critical limb ischemia (CLI), the prevalence of prothrombin G20210A was 23 of 302 compared with 31 of 1,253 of the controls (OR 3.2, 95% CI 1.6-6.1). CONCLUSION: Despite finding no significant association between lower extremity PAD and prothrombin G20210A, the meta-analysis suggests that the prevalence of prothrombin G20210A is significantly elevated in those with atherosclerotic occlusive disease of the lower extremities presenting with CLI. Well-designed prospective cohort studies evaluating the role of prothrombin G20210A as a predictor of disease progression or adverse vascular events are highly needed.
Assuntos
Isquemia/genética , Extremidade Inferior/irrigação sanguínea , Mutação , Doença Arterial Periférica/genética , Protrombina/genética , Trombofilia/genética , Distribuição de Qui-Quadrado , Estado Terminal , Frequência do Gene , Predisposição Genética para Doença , Humanos , Isquemia/diagnóstico , Razão de Chances , Doença Arterial Periférica/diagnóstico , Fenótipo , Medição de Risco , Fatores de Risco , Trombofilia/sangue , Trombofilia/complicações , Trombofilia/diagnósticoRESUMO
The role of high mobility group box 1 (HMGB1) has been demonstrated in stroke and coronary artery disease but not in peripheral arterial occlusive disease (PAOD). The pathogenesis of HMGB1 in acute and chronic vascular injury is also not well understood. We hypothesized that HMGB1 induces inflammatory markers in diabetic PAOD patients. We studied 36 diabetic patients, including 29 patients with PAOD, who had undergone amputation for diabetic foot and 7 nondiabetic patients who had undergone amputation after traumatic injury. Expression of HMGB1 and inflammatory markers were quantified using immunohistochemical staining. Mitochondrial DNA copy number was quantified using real-time polymerase chain reaction. Compared with that in the traumatic amputation group, HMGB1 expression in vessels was significantly higher in the diabetes and diabetic PAOD groups. In all subjects, arterial stenosis grade was positively correlated with the expression levels of HMGB1, 8-hydroxyguanosine, malondialdehyde, vascular cell adhesion molecule 1, and inflammatory markers CD3, and CD68 in both the intima and the media of vessels. Furthermore, HMGB1 expression level was positively correlated with 8-hydroxyguanosine, vascular cell adhesion molecule 1, nuclear factor-kB, CD3, and CD68 expression. Within the PAOD subgroup, subjects with HMGB1 expression had higher expression of the autophagy marker LC3A/B and higher mitochondrial DNA copy number. HMGB1 may be an inflammatory mediator with roles in oxidative damage and proinflammatory and inflammatory processes in diabetic atherogenesis. Moreover, it may have dual effects by compensating for increased mitochondrial DNA copy number and increased autophagy marker expression.