Correlation analysis between INR and warfarin / 3’-hydroxywarfarin in the two cohorts of patients investigated.

<p>Correlation analysis between INR and warfarin / 3’-hydroxywarfarin in the two cohorts of patients investigated.</p

Time-frame findings in patients starting OAT (n = 52).

<p>Time-frame findings in patients starting OAT (n = 52).</p

Correlation analyses between: INR, serum warfarin (ng/mL) and 3’-hydroxywarfarin (ng/mL), and the amount of drug (warfarin week) taken by the whole cohort of patients on oral anticoagulant therapy.

<p>Correlation analyses between: INR, serum warfarin (ng/mL) and 3’-hydroxywarfarin (ng/mL), and the amount of drug (warfarin week) taken by the whole cohort of patients on oral anticoagulant therapy.</p

Univariate and multivariate analyses to estimate the contribution of different variables on INR.

<p>Univariate and multivariate analyses to estimate the contribution of different variables on INR.</p

HPLC calibration curves.

<p>Warfarin (1A) and 3’-hydroxywarfarin (1B) calibration curves; R expresses the ratio between the area under the analyte peak (warfarin or 3’-hydroxywarfarin respectively) and the area of the internal standard.</p

Warfarin daily dose for different WRI.

<p>Mean and median warfarin dose increased as WRI increased. WR 0, WRI 1 and WRI 2 classes are as specified in text. Continuous line indicates the median; dashed line indicates the mean, vertical bars indicate the 1^st and 99^th percentile of warfarin day (mg).</p

Genotype distributions in the whole cohort of patients.

<p>Different distributions of <i>CYP2C9</i> haplotypes in the whole cohort of patients stratified by the three <i>VKORC1</i> genotypes according to INR values (A), warfarin and 3’-hydroxywarfarin serum concentration (B, and C respectively), and warfarin week (D).</p

Gene-gene interactions among coding genes of iron-homeostasis proteins and <i>APOE</i>-alleles in cognitive impairment diseases

<div><p>Cognitive impairments of different aetiology share alterations in iron and lipid homeostasis with mutual relationships. Since iron and cholesterol accumulation impact on neurodegenerative disease, the associated gene variants are appealing candidate targets for risk and disease progression assessment. In this light, we explored the role of common single nucleotide polymorphisms (SNPs) in the main iron homeostasis genes and in the main lipoprotein transporter gene (<i>APOE</i>) in a cohort of 765 patients with dementia of different origin: Alzheimer’s disease (AD) n = 276; vascular dementia (VaD), n = 255; mild cognitive impairment (MCI), n = 234; and in normal controls (n = 1086). In details, four genes of iron homeostasis (Hemochromatosis (<i>HFE</i>: C282Y, H63D), Ferroportin (<i>FPN1</i>: -8CG), Hepcidin (<i>HAMP</i>: -582AG), Transferrin (<i>TF</i>: P570S)), and the three major alleles of <i>APOE</i> (<i>APOE</i>2, <i>APOE</i>3, <i>APOE</i>4) were analyzed to explore causative interactions and synergies. In single analysis, <i>HFE</i> 282Y allele yielded a 3-fold risk reduction in the whole cohort of patients (<i>P</i><0.0001), confirmed in AD and VaD, reaching a 5-fold risk reduction in MCI (<i>P =</i> 0.0019). The other iron SNPs slightly associated with risk reduction whereas <i>APOE</i>4 allele resulted in increased risk, reaching more than 7-fold increased risk in AD homozygotes (<i>P</i> = 0.001), confirmed to a lower extent in VaD and MCI (<i>P =</i> 0.038 and <i>P =</i> 0.013 respectively) as well as in the whole group (<i>P</i><0.0001). Comparisons of Mini Mental State Examination (MMSE) among AD showed appreciable lowering in <i>APOE</i>4 carriers (<i>P =</i> 0.038), confirmed in the whole cohort of patients (<i>P =</i> 0.018). In interaction analysis, the <i>HFE</i> 282Y allele completely extinguished the <i>APOE</i>4 allele associated risk. Conversely, the coexistence in patients of a substantial number of iron SNPs accrued the <i>APOE</i>4 detrimental effect on MMSE. Overall, the analysis highlighted how a specific iron-allele burden, defined as different combinations of iron gene variants, might have different effects on cognitive impairment and might modulate the effects of established genetic risk factors such as <i>APOE</i>4. Our results suggest that established genetic risk factors might be affected by specific genetic backgrounds, making patients differently suited to manage iron accumulation adding new genetic insights in neurodegeneration. The recently recognized interconnections between iron and lipids, suggest that these pathways might share more than expected. We therefore extended to additional iron gene variants the newly proposed influencing mechanisms that <i>HFE</i> gene has on cholesterol metabolism. Our results have a strong translational potential promoting new pharmacogenetics studies on therapeutic target identification aimed at optimally tuning brain iron levels.</p></div

Schematic model linking HFE, HAMP and TF to FPN1-APP complex in detoxifying action for balanced iron homeostasis.

<p>The picture highlights the main pathways and molecular mediators involved in iron homeostasis maintenance by FPN1-APP cooperation. HAMP is Hepcidin; TF is Transferrin; TF-R is Transferrin receptor; HFE is Hemochromatosis; FPN is Ferroportin; IRP and IRE are Iron Regulatory Protein and Iron Responsive Element respectively.</p

Multivariate logistic regression analysis.

<p>Multivariate logistic regression analysis.</p