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

Abstract

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 (APOE) 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 (HFE: C282Y, H63D), Ferroportin (FPN1: -8CG), Hepcidin (HAMP: -582AG), Transferrin (TF: P570S)), and the three major alleles of APOE (APOE2, APOE3, APOE4) were analyzed to explore causative interactions and synergies. In single analysis, HFE 282Y allele yielded a 3-fold risk reduction in the whole cohort of patients (P<0.0001), confirmed in AD and VaD, reaching a 5-fold risk reduction in MCI (P = 0.0019). The other iron SNPs slightly associated with risk reduction whereas APOE4 allele resulted in increased risk, reaching more than 7-fold increased risk in AD homozygotes (P = 0.001), confirmed to a lower extent in VaD and MCI (P = 0.038 and P = 0.013 respectively) as well as in the whole group (P<0.0001). Comparisons of Mini Mental State Examination (MMSE) among AD showed appreciable lowering in APOE4 carriers (P = 0.038), confirmed in the whole cohort of patients (P = 0.018). In interaction analysis, the HFE 282Y allele completely extinguished the APOE4 allele associated risk. Conversely, the coexistence in patients of a substantial number of iron SNPs accrued the APOE4 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 APOE4. 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 HFE 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.

Iron Responsive Element (IRE)-mediated responses to iron dyshomeostasis in Alzheimer’s disease

“…The observations of Nixon and colleagues that acidification of the endolysomal pathway is affected both by fAD mutations in PSEN1 [46] and excessive dosage of the APP gene [54], together with our observations from our fAD-like psen1 Q96_K97del /+ mutant zebrafish, support the possibility that fAD brains may suffer a ferrous iron deficiency in a background of ferric iron overload. Intriguingly, the greatest genetic risk factor for late onset AD, the e4 allele of the gene APOE, appears to increase lysosomal pH [55] but e4's increased risk of AD is alleviated in individuals who possess the HFE 282Y allele that predisposes to the iron overload disease hemochromatosis [56]. Given that many other risk loci for sporadic late onset AD also affect endolysosomal pathway function (reviewed in [57]) it is reasonable to suggest that disturbed of iron homeostasis may afflict brains with this disease.…”

“Bridging the Gap” Everything that Could Have Been Avoided If We Had Applied Gender Medicine, Pharmacogenetics and Personalized Medicine in the Gender-Omics and Sex-Omics Era

“…Accordingly, associated gene variants might be appealing candidate for risk and disease progression assessment. In this scenario, our group recently demonstrated that established genetic risk factors, like the different APOE-alleles, might be affected by key genetic backgrounds, making patients differently able to manage local iron accumulation [158] (Figure 5). Studies focused on the link between iron and lipid homeostasis [159][160][161][162] confirmed that the two pathways might share more than expected.…”

“…More efforts to better identify key pathways and molecular mechanisms underlying onset and progression of cognitive decline should be made also in the view of the ongoing ageing process of the worldwide population. The observation that dementia and CVD share common metabolic risk factors including inflammation, oxidative stress and lipids, affecting in turn both brain and myocardium [158,[169][170][171][172], encouraged proteomic studies aimed at recognizing sex differences of the molecular signature of these complex diseases [173][174][175][176]. In conclusion, the comprehension of the molecular bases of the observed sex-differences in neurological disorders would improve by including both female and male animals in preclinical studies focused on brain OMICS change investigations [177].…”

Sex/Gender-Specific Imbalance in CVD: Could Physical Activity Help to Improve Clinical Outcome Targeting CVD Molecular Mechanisms in Women?

“…Of particular relevance is the issue of heart failure, which is expected to double each decade of life and to grow significantly in the whole population due to the dramatic increasing trend of population aging, particularly in the developed countries [3]. Although several novel molecular markers and pharmacogenetic studies have been used to intensively investigate complex polygenic chronic or degenerative diseases [4][5][6][7][8][9][10][11][12][13] leading to the discovery of novel prognostic biomarkers or inherited predispositions [14][15][16][17][18][19], specific dedicated therapies to treat heart failure due to heart wall remodeling do not currently exist, and women experience the worst prognosis [1,20,21]. Epidemiological data highlight that CVD now represents the leading cause of mortality and hospital admission for women, accounting for one in three deaths worldwide and half of all deaths of women over 50 in developing countries [3].…”