Meta-Analysis of Genome-Wide Association Studies for Abdominal Aortic Aneurysm Identifies Four New Disease-Specific Risk Loci

Rationale: Abdominal aortic aneurysm (AAA) is a complex disease with both genetic and environmental risk factors. Together, 6 previously identified risk loci only explain a small proportion of the heritability of AAA. Objective: To identify additional AAA risk loci using data from all available genome-wide association studies (GWAS). Methods and Results: Through a meta-analysis of 6 GWAS datasets and a validation study totalling 10,204 cases and 107,766 controls we identified 4 new AAA risk loci: 1q32.3 (SMYD2), 13q12.11 (LINC00540), 20q13.12 (near PCIF1/MMP9/ZNF335), and 21q22.2 (ERG). In various database searches we observed no new associations between the lead AAA SNPs and coronary artery disease, blood pressure, lipids or diabetes. Network analyses identified ERG, IL6R and LDLR as modifiers of MMP9, with a direct interaction between ERG and MMP9. Conclusions: The 4 new risk loci for AAA appear to be specific for AAA compared with other cardiovascular diseases and related traits suggesting that traditional cardiovascular risk factor management may only have limited value in preventing the progression of aneurysmal disease

Association of rs1466535 LRP1 but not rs3019885 SLC30A8 and rs6674171 TDRD10 gene polymorphisms with abdominal aortic aneurysm in Italian patients

Objective: Recently, a large genome-wide association study in patients with abdominal aortic aneurysm (AAA) and control subjects identified nine loci associated with AAA. Besides the significant association of the rs1466535 single nucleotide polymorphism in the low-density lipoprotein receptor-related protein 1 gene (LRP1), two of eight remaining loci, rs6674171 in the tudor domain containing protein 10 (TDRD10) and rs3019885 in solute carrier family 30 zinc transporter member 8 (SLC30A8) gene, showed a weakly significant association with AAA requiring further attention. Therefore, the aim of our study was to evaluate the role of these three polymorphisms in conferring AAA genetic susceptibility. Methods: We studied these three polymorphisms in 423 patients and 423 sex- and age-comparable control subjects from Italy. All subjects were genotyped with the use of the real-time TaqMan approach. Multiple logistic regression analysis adjusted for traditional cardiovascular risk factor and chronic obstructive pulmonary disease was used to estimated odds ratios and 95% confidence intervals for AAA risk. Results: The prevalence of carriers of the rs3019885 SLC30A8 G allele was higher in control subjects (67.8%) than in patients (60.3%, P =.022), suggesting a protective effect for AAA. The prevalence of carriers of the rs1466535 LRP1 T allele was higher in patients (51.8%) than in control subjects (39.7%, P =.0004), suggesting a risk effect for AAA. rs6674171 polymorphism genotype distribution did not differ between AAA patients and control subjects. In the multiple logistic regression analysis adjusted for traditional AAA risk factors, only the rs1466535 polymorphism remained significantly associated with AAA (odds ratio, 1.85; 95% confidence interval, 1.2-2.84; P =.01). Conclusions: Our findings confirm the role as significant and independent susceptibility factor for AAA of the rs1466535 LRP1 polymorphism (T allele) in an Italian population. Nevertheless, our findings consistently differed from previous published data because in the genome-wide association study, the risk allele was the most frequent rs1466535 C allele. Our findings are consistent with literature data of LRP1 knock-out mice developing atherosclerotic lesions and aortic dilatation and association of the T allele with reduced LRP1 gene expression in humans

Role of rs1466535 low density lipoprotein receptor-related protein 1 (LRP1) gene polymorphism in carotid artery disease

Objective: An association between rs1466535 low density lipoprotein receptor-related protein 1 (LRP1) gene polymorphism and abdominal aortic aneurysm (AAA) was recently demonstrated. It has not yet been defined if this association is specific for AAA or related to atherosclerosis per se. Therefore, we aimed to evaluate the role of the rs1466535 polymorphism in conferring genetic susceptibility for carotid artery stenosis (CAS). Methods: The rs1466535 polymorphism was evaluated in n=814 patients with CAS and n=814 subjects without evidence of carotid atherosclerosis by TaqMan technology. Results: The percentage of T allele rs1466535 carriers was significantly higher in CAS patients (49.3%) than in controls (43.9%, p=0.032). At the multiple logistic regression analysis, the allele T carrier status did not remain a significant determinant of CAS. Conclusions: The rs1466535 LRP1 polymorphism is not a significant and independent risk factor for CAS. Our result suggests this polymorphism in the LRP1 gene is not associated with atherosclerosis in general as it is not associated with CAS (this study), whereas it is strictly associated with AAA (our previous paper

Association of rs1466535 LRP1 but not rs3019885 SLC30A8 and rs6674171 TDRD10 gene polymorphisms with abdominal aortic aneurysm in Italian patients

Objective: Recently, a large genome-wide association study in patients with abdominal aortic aneurysm (AAA) and control subjects identified nine loci associated with AAA. Besides the significant association of the rs1466535 single nucleotide polymorphism in the low-density lipoprotein receptor-related protein 1 gene (LRP1), two of eight remaining loci, rs6674171 in the tudor domain containing protein 10 (TDRD10) and rs3019885 in solute carrier family 30 zinc transporter member 8 (SLC30A8) gene, showed a weakly significant association with AAA requiring further attention. Therefore, the aim of our study was to evaluate the role of these three polymorphisms in conferring AAA genetic susceptibility. Methods: We studied these three polymorphisms in 423 patients and 423 sex- and age-comparable control subjects from Italy. All subjects were genotyped with the use of the real-time TaqMan approach. Multiple logistic regression analysis adjusted for traditional cardiovascular risk factor and chronic obstructive pulmonary disease was used to estimated odds ratios and 95% confidence intervals for AAA risk. Results: The prevalence of carriers of the rs3019885 SLC30A8 G allele was higher in control subjects (67.8%) than in patients (60.3%, P =.022), suggesting a protective effect for AAA. The prevalence of carriers of the rs1466535 LRP1 T allele was higher in patients (51.8%) than in control subjects (39.7%, P =.0004), suggesting a risk effect for AAA. rs6674171 polymorphism genotype distribution did not differ between AAA patients and control subjects. In the multiple logistic regression analysis adjusted for traditional AAA risk factors, only the rs1466535 polymorphism remained significantly associated with AAA (odds ratio, 1.85; 95% confidence interval, 1.2-2.84; P =.01). Conclusions: Our findings confirm the role as significant and independent susceptibility factor for AAA of the rs1466535 LRP1 polymorphism (T allele) in an Italian population. Nevertheless, our findings consistently differed from previous published data because in the genome-wide association study, the risk allele was the most frequent rs1466535 C allele. Our findings are consistent with literature data of LRP1 knock-out mice developing atherosclerotic lesions and aortic dilatation and association of the T allele with reduced LRP1 gene expression in humans

Association Between Motor and Cognitive Performances in Elderly With Atrial Fibrillation: Strat-AF Study

Background/Objective: Growing evidence suggests a close relationship between motor and cognitive abilities, but possible common underlying mechanisms are not well-established. Atrial fibrillation (AF) is associated with reduced physical performance and increased risk of cognitive decline. The study aimed to assess in a cohort of elderly AF patients: (1) the association between motor and cognitive performances, and (2) the influence and potential mediating role of cerebral lesions burden. Design: Strat-AF is a prospective, observational study investigating biological markers for cerebral bleeding risk stratification in AF patients on oral anticoagulants. Baseline cross-sectional data are presented here. Setting: Thrombosis outpatient clinic (Careggi University Hospital). Participants: One-hundred and seventy patients (mean age 77.7 \ub1 6.8; females 35%). Measurements: Baseline protocol included: neuropsychological battery, motor assessment [Short Physical Performance Battery (SPPB), and walking speed], and brain magnetic resonance imaging (MRI) used for the visual assessment of white matter hyperintensities, lacunar and non-lacunar infarcts, cerebral microbleeds, and global cortical and medial temporal atrophies. Results: Mean Montreal Cognitive Assessment (MoCA) total score was 21.9 \ub1 3.9, SPPB total score 9.5 \ub1 2.2, and walking speed 0.9 \ub1 0.2. In univariate analyses, both SPPB and walking speed were significantly associated with MoCA (r = 0.359, r = 0.372, respectively), visual search (r = 0.361, r = 0.322), Stroop (r = 120.272, r = 120.263), short story (r = 0.263, r = 0.310), and semantic fluency (r = 0.311, r = 0.360). In multivariate models adjusted for demographics, heart failure, physical activity, and either stroke history (Model 1) or neuroimaging markers (Model 2), both SPPB and walking speed were confirmed significantly associated with MoCA (Model 1: \u3b2 = 0.256, \u3b2 = 0.236; Model 2: \u3b2 = 0.276, \u3b2 = 0.272, respectively), visual search (Model 1: \u3b2 = 0.350, \u3b2 = 0.313; Model 2: \u3b2 = 0.344, \u3b2 = 0.307), semantic fluency (Model 1: \u3b2 = 0.223, \u3b2 = 0.261), and short story (Model 2: \u3b2 = 0.245, \u3b2 = 0.273). Conclusions: In our cohort of elderly AF patients, a direct association between motor and cognitive functions consistently recurred using different evaluation of the performances, without an evident mediating role of cerebral lesions burden

Role of biological markers for cerebral bleeding risk STRATification in patients with atrial fibrillation on oral anticoagulants for primary or secondary prevention of ischemic stroke (Strat-AF study): Study design and methodology

Background and Objectives: In anticoagulated atrial fibrillation (AF) patients, the validity of models recommended for the stratification of the risk ratio between benefits and hemorrhage risk is limited. Cerebral small vessel disease (SVD) represents the pathologic substrate for primary intracerebral hemorrhage and ischemic stroke. We hypothesize that biological markers-both circulating and imaging-based-and their possible interaction, might improve the prediction of bleeding risk in AF patients under treatment with any type of oral anticoagulant. Materials and Methods: The Strat-AF study is an observational, prospective, single-center hospital-based study enrolling patients with AF, aged 65 years or older, and with no contraindications to magnetic resonance imaging (MRI), referring to Center of Thrombosis outpatient clinic of our University Hospital for the management of oral anticoagulation therapy. Recruited patients are evaluated by means of a comprehensive protocol, with clinical, cerebral MRI, and circulating biomarkers assessment at baseline and after 18 months. The main outcome is SVD progression-particularly microbleeds-as a selective surrogate marker of hemorrhagic complication. Stroke occurrence (ischemic or hemorrhagic) and the progression of functional, cognitive, and motor status will be evaluated as secondary outcomes. Circulating biomarkers may further improve predictive potentials. Results: Starting from September 2017, 194 patients (mean age 78.1 ± 6.7, range 65-97; 61% males) were enrolled. The type of AF was paroxysmal in 93 patients (48%), and persistent or permanent in the remaining patients. Concerning the type of oral anticoagulant, 57 patients (29%) were on vitamin K antagonists, and 137 (71%) were on direct oral anticoagulants. Follow-up clinical evaluation and brain MRI are ongoing. Conclusions: The Strat-AF study may be an essential step towards the exploration of the role of a combined clinical biomarker or multiple biomarker models in predicting stroke risk in AF, and might sustain the incorporation of such new markers in the existing stroke prediction schemes by the demonstration of a greater incremental value in predicting stroke risk and improvement in clinical outcomes in a cost-effective fashion

Meta-Analysis of Genome-Wide Association Studies for Abdominal Aortic Aneurysm Identifies Four New Disease-Specific Risk Loci

Rationale: Abdominal aortic aneurysm (AAA) is a complex disease with both genetic and environmental risk factors. Together, 6 previously identified risk loci only explain a small proportion of the heritability of AAA. Objective: To identify additional AAA risk loci using data from all available genome-wide association studies (GWAS). Methods and Results: Through a meta-analysis of 6 GWAS datasets and a validation study totalling 10,204 cases and 107,766 controls we identified 4 new AAA risk loci: 1q32.3 (SMYD2), 13q12.11 (LINC00540), 20q13.12 (near PCIF1/MMP9/ZNF335), and 21q22.2 (ERG). In various database searches we observed no new associations between the lead AAA SNPs and coronary artery disease, blood pressure, lipids or diabetes. Network analyses identified ERG, IL6R and LDLR as modifiers of MMP9, with a direct interaction between ERG and MMP9. Conclusions: The 4 new risk loci for AAA appear to be specific for AAA compared with other cardiovascular diseases and related traits suggesting that traditional cardiovascular risk factor management may only have limited value in preventing the progression of aneurysmal disease