Genetically predicted plasma levels of amino acids and metabolic dysfunction-associated fatty liver disease risk: a Mendelian randomization study.

BACKGROUND: Emerging metabolomics-based studies suggested links between amino acid metabolism and metabolic dysfunction-associated fatty liver disease (MAFLD) risk; however, whether there exists an aetiological role of amino acid metabolism in MAFLD development remains unknown. The aim of the present study was to assess the causal relationship between circulating levels of amino acids and MAFLD risk. METHODS: We conducted a two-sample Mendelian randomization (MR) analysis using summary-level data from genome-wide association studies (GWAS) to evaluate the causal relationship between genetically predicted circulating levels of amino acids and the risk of MAFLD. In the discovery MR analysis, we used data from the largest MAFLD GWAS (8434 cases and 770,180 controls), while in the replication MR analysis, we used data from a GWAS on MAFLD (1483 cases and 17,781 controls) where MAFLD cases were diagnosed using liver biopsy. We used Wald ratios or inverse variance-weighted (IVW) methods in the MR main analysis and weighted median and MR-Egger regression analyses in sensitivity analyses. Furthermore, we performed a conservative MR analysis by restricting genetic instruments to those directly involved in amino acid metabolism pathways. RESULTS: We found that genetically predicted higher alanine (OR = 1.43, 95% CI 1.13-1.81) and lower glutamine (OR = 0.83, 95% CI 0.73-0.96) levels were associated with a higher risk of developing MAFLD based on the results from the MR main and conservative analysis. The results from MR sensitivity analyses and complementary analysis using liver proton density fat fraction as a continuous outcome proxying for MAFLD supported the main findings. CONCLUSIONS: Novel causal metabolites related to MAFLD development were uncovered through MR analysis, suggesting future potential for evaluating these metabolites as targets for MAFLD prevention or treatment.

Global assessment of cadmium concentrations in the skin of free-ranging sperm whales (Physeter macrocephalus).

Cadmium is a non-essential, toxic metal found accumulated in the organs of stranded cetaceans. Currently, there is no baseline cadmium concentration reported in a free-ranging, pelagic cetacean. The aim was to determine cadmium concentrations in the skin of free-ranging sperm whales (n=340) collected from 16 regions around the world during the voyage of the Odyssey (2000-2005) considering region, gender, and age in males. Cadmium was detected in 81% of skin biopsies with a mean of 0.3±0.04µg/g ww (0.02 to 12.4µg/g ww). These concentrations were higher than reported in literature in toothed whale skin (0.002-0.1µg/g ww). Concentrations by region were significantly different (p<0.0001) with the highest mean in Maldives and the Sea of Cortez (0.8 and 0.6µg/g ww, respectively). There was no significant difference in cadmium concentration by gender (p=0.42). Cadmium is known to have a long biological half-life, and cadmium concentrations in males were significantly higher in adults with a mean of 0.3µg/g ww compared to subadults with 0.2µg/g ww (p=0.03). Selenium, an element that binds to cadmium inhibiting its toxicity, had a moderately positive correlation with cadmium (r=0.41). Mercury, a toxic metal that positively correlates with cadmium in cetacean tissue, had a weakly positive relationship (r=0.20). The regional baselines reported in this study may be used to develop residue criteria for prediction of toxicological risk in sperm whale skin. Additionally, this study shows the extent of cadmium exposure in a pelagic cetacean that has global distribution.

Global mercury and selenium concentrations in skin from free-ranging sperm whales (Physeter macrocephalus).

Pollution of the ocean by mercury (Hg) is a global concern. Hg persists, bioaccumulates and is toxic putting high trophic consumers at risk. The sperm whale (Physeter macrocephalus), is a sentinel of ocean health due to its wide distribution, longevity and high trophic level. Our aim was to survey Hg concentrations worldwide in the skin of free-ranging sperm whales considering region, gender and age. Samples were collected from 343 whales in 17 regions during the voyage of the research vessel, Odyssey, between 1999 and 2005. Skin was analyzed for total Hg and detected in all but three samples with a global mean of 2.5±0.1 µg g(-1) ranging from 0.1 to 16.0 µg g(-1). The Mediterranean Sea had the highest regional mean with 6.1 µg g(-1) followed by Australia with 3.5 µg g(-1). Considering gender, females and males did not have significantly different global Hg concentrations. The variation among regions for females was significantly different with highest levels in the Mediterranean and lowest in Sri Lanka; however, males were not significantly different among regions. Considering age in males, adults and subadults did not have significantly different Hg concentrations, and were not significantly different among regions. The toxic effects of these Hg concentrations are uncertain. Selenium (Se), an essential element, antagonizes Hg at equimolar amounts. We measured total Se concentrations and found detectable levels in all samples with a global mean of 33.1±1.1 µg g(-1) ranging from 2.5 to 179 µg g(-1). Se concentrations were found to be several fold higher than Hg concentrations with the average Se:Hg molar ratio being 59:1 and no correlation between the two elements. It is possible Hg is being detoxified in the skin by another mechanism. These data provide the first global analysis of Hg and Se concentrations in a free-ranging cetacean.