From Environment to Genome and Back: A Lesson from HFE Mutations

Abstract

The environment and the human genome are closely entangled and many genetic variations that occur in human populations are the result of adaptive selection to ancestral environmental (mainly dietary) conditions. However, the selected mutations may become maladaptive when environmental conditions change, thus becoming candidates for diseases. Hereditary hemochromatosis (HH) is a potentially lethal disease leading to iron accumulation mostly due to mutations in the HFE gene. Indeed, homozygosity for the C282Y HFE mutation is associated with the primary iron overload phenotype. However, both penetrance of the C282Y variant and the clinical manifestation of the disease are extremely variable, suggesting that other genetic, epigenetic and environmental factors play a role in the development of HH, as well as, and in its progression to end-stage liver diseases. Alcohol consumption and dietary habits may impact on the phenotypic expression of HFE-related hemochromatosis. Indeed, dietary components and bioactive molecules can affect iron status both directly by modulating its absorption during digestion and indirectly by the epigenetic modification of genes involved in its uptake, storage and recycling. Thus, the premise of this review is to discuss how environmental pressures led to the selection of HFE mutations and whether nutritional and lifestyle interventions may exert beneficial effects on HH outcomes and comorbidities.

A Haptoglobin Exon Copy Number Variant Associates With HIV-Associated Neurocognitive Impairment in European and African-Descent Populations

“…The disparate effects between AFR and EUR individuals noted in this study is not uncommon. The evolution of the HP alleles have progressed differently in these populations, which have been exposed to very different selection pressures and disease risks, as is described by Boettger et al and others (Gichohi-Wainaina et al, 2016;Rametta et al, 2020). With regard to the HP alleles, divergent HP1-1 associations with cognitive function have been reported to differ between Ashkenazi Jews and non-Ashkenazi Jews with type 2 diabetes (Gichohi-Wainaina et al, 2016).…”

Genetics Is of the Essence to Face NAFLD

“…Concerning the development of fibrosis, the alternative splicing of the Krueppellike factor 6 (KLF6) gene, that is expressed by the HSCs during their transdifferentiation, associates with mild NAFLD and reduced fibrosis [212]. Conversely, variants in HFE and TMPRSS6 genes likely by predisposing to hepatic iron depot formation are correlated with more severe fibrosis in NAFLD patients [213].…”

Genetics, Immunity and Nutrition Boost the Switching from NASH to HCC

“…Later manifestations of iron overload include cirrhosis and cirrhosis-related HCC in patients with hereditary hemochromatosis or chronic hepatic inflammation [ 156 ]. Phlebotomy and chelating agents may dampen the risk of HCC in patients with siderosis.…”