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

Low-density lipoprotein receptor-related protein 5 gene polymorphisms and genetic susceptibility to abdominal aortic aneurysm

Background: Previous data showed decreased low-density lipoprotein receptor-related protein 5 (LRP5) gene expression in peripheral blood cells of abdominal aortic aneurysm (AAA) patients and an association between decreased expression of LRP5 and increased lipoprotein (a) [Lp(a)] levels in AAA. LRP5 gene is involved in bone, lipid, and glucose metabolism, and experimental studies showed that atherosclerotic lesions of ApoE:LRP5 double knockout mice were ∼threefold greater than those in ApoE-knockout mice and were characterized by features of advanced atherosclerosis, with remarkable accumulation of foam cells and destruction of the internal elastic lamina. The aim of this study was to evaluate the role of polymorphisms in LRP5 gene in determining genetic susceptibility to AAA. Methods: A total of 423 AAA patients and 423 controls comparable for sex and age were genotyped for seven polymorphisms within the LRP5 (rs667126, rs3736228, rs4988300, rs3781590, rs312016, rs556442, rs627174) by TaqMan approach. Results: Two polymorphisms were significantly associated with AAA: rs4988300, carriers of the T allele in AAA (74.0% vs 65.3% in controls; P =.007); and rs3781590, carriers of the T allele in AAA (66.5% vs 57.4% in controls; P =.009). At the multiple logistic regression analysis, adjusted for age, sex, dyslipidemia, hypertension, smoking habit, and chronic obstructive pulmonary disease, rs4988300 and rs3781590 polymorphisms remained significant and independent determinants of AAA (OR, 1.62; 95% CI, 1.02-2.56; P =.040, and OR, 1.83; 95% CI, 1.17-2.85; P =.008, respectively). We confirmed that AAA patients had significantly higher Lp(a) levels than control subjects (180.0 mg/L vs 107.6 mg/L; P <.0001). The prevalence of patients with Lp(a) levels ≥300 mg/L was significantly higher in patient carriers of the rs4988300 T allele than in wild-type patients (42.6% vs 30.8%; P =.048). Conclusions: Present data have identified rs4988300 and rs3781590 LPR5 polymorphisms as independent genetic markers of AAA and underlined the need to concentrate our effort in studying the role of these markers in AAA and of LRP5 gene in Lp(a) catabolism and AAA pathophysiology. © 2013 by the Society for Vascular Surgery

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

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)

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