ABSTRACT
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.
Subject(s)
Aortic Aneurysm, Abdominal/genetics , Low Density Lipoprotein Receptor-Related Protein-5/genetics , Polymorphism, Single Nucleotide , Adult , Aged , Aged, 80 and over , Aortic Aneurysm, Abdominal/blood , Biomarkers/blood , Case-Control Studies , Chi-Square Distribution , Female , Gene Frequency , Genetic Predisposition to Disease , Humans , Linear Models , Lipoprotein(a)/blood , Logistic Models , Male , Middle Aged , Multivariate Analysis , Odds Ratio , Phenotype , Risk FactorsABSTRACT
BACKGROUND: NPR3, located on human chromosome 5 (5p14-p13), encodes the natriuretic peptide receptor type C (NPR-C) that is mainly known as the natriuretic peptide clearance receptor. Involvement of NPR3 in susceptibility to cardiovascular diseases, i.e. hypertension, has been previously shown. With regard to stroke predisposition, evidence for a potential role of genetic variation within or nearby NPR3 has been suggested by a previous genome wide association study. METHODS: We investigated the contribution to early-onset ischemic stroke susceptibility of the NPR3 -55 C>A transition by genotyping this variant in an Italian cohort of 368 cases and 335 controls. RESULTS: In a multivariable logistic regression analysis adjusting for age, gender, hypertension, hypercholesterolemia, smoking habit and diabetes, a significant association of the -55 AA genotype with stroke was observed (OR=3.2, 95% CI 1.2-8.3, p=0.016). Remarkably, the polymorphism remained associated with stroke after adjusting for hypertensive status. CONCLUSION: Our observation obtained in an Italian cohort of early onset ischemic strokes suggests that a NPR3 promoter gene variant could have a role on cerebrovascular disease susceptibility.
