Pseudoxanthoma Elasticum-Like in β-Thalassemia Major, a matter of α-Klotho and Parathyroid Hormone?

<p>Pseudoxanthoma elasticum-like (PXL) condition is one of the complications faced by patients with β-thalassemia major (β-TM). Histopathological features include abnormal, mineralized and fragmented elastic fibers in skin, eyes and arterial blood vessels (elastorrhexia). The pathogenesis of PXL lesions in β-TM is not yet completely understood. This study was aimed at analyzing a possible implication of α-Klotho in the clinical manifestation of PXL in patients with β-TM (30 with and 78 without PXL). A significant correlation was observed between Klotho, parathyroid hormone (PTH) and serum calcium (Ca). Our analysis seems to indicate α-Klotho and PTH as factors that can affect the development of PXL.</p

Partial linear correlation coefficients of serum TRAIL levels and metabolic characteristics of study participants.

<p>Partial linear correlation coefficients of serum TRAIL levels and metabolic characteristics of study participants.</p

Metabolic characteristics of study participants.

<p>Metabolic characteristics of study participants.</p

Correlation matrix between metabolic and anthropometric characteristics of study participants.

<p>Correlation matrix between metabolic and anthropometric characteristics of study participants.</p

Multivariable linear regression models predicting serum TRAIL levels according to selected metabolic characteristics of study participants.

<p>Model 1 adjusted for age and gender.</p><p>Model 2 adjusted for age, gender and C-reactive protein.</p><p>Model 3 adjusted for age, gender, C-reactive protein and all variables included in table.</p><p>Model 4 Model 3 with stepwise backward selection of unnecessary variables (p for removal 0.1).</p

Characteristics of study participants according to TRAIL distribution.

<p>Characteristics of study participants according to TRAIL distribution.</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

Peripheral iron levels stratified by SNPs genotypes.

<p>Peripheral iron levels stratified by SNPs genotypes.</p

Multivariate logistic regression analysis.

<p>Multivariate logistic regression analysis.</p