奥尔特加研究中的代谢组学模式、氧化还原相关基因与金属以及骨脆性终点
Metabolomic patterns, redox-related genes and metals, and bone fragility endpoints in the Hortega Study.
作者信息
Galvez-Fernandez Marta, Rodriguez-Hernandez Zulema, Grau-Perez Maria, Chaves F Javier, Garcia-Garcia Ana Barbara, Amigo Nuria, Monleon Daniel, Garcia-Barrera Tamara, Gomez-Ariza Jose L, Briongos-Figuero Laisa S, Perez-Castrillon Jose L, Redon Josep, Tellez-Plaza Maria, Martin-Escudero Juan C
机构信息
Department of Preventive Medicine and Microbiology, School of Medicine, Universidad Autónoma de Madrid, Arzobispo Morcillo, 4, 28029, Madrid, Spain; Department of Preventive Medicine, Hospital Universitario Severo Ochoa, Avenida de Orellana, s/n, 28911, Madrid, Spain; Department of Chronic Diseases Epidemiology, National Center for Epidemiology, Instituto de Salud Carlos III, Monforte de Lemos, 5, 28029, Madrid, Spain.
Department of Chronic Diseases Epidemiology, National Center for Epidemiology, Instituto de Salud Carlos III, Monforte de Lemos, 5, 28029, Madrid, Spain; Department of Biotechnology, Universitat Politècnica de València, Camí de Vera, s/n, 46022, Valencia, Spain.
出版信息
Free Radic Biol Med. 2023 Jan;194:52-61. doi: 10.1016/j.freeradbiomed.2022.11.007. Epub 2022 Nov 9.
BACKGROUND
The potential joint influence of metabolites on bone fragility has been rarely evaluated. We assessed the association of plasma metabolic patterns with bone fragility endpoints (primarily, incident osteoporosis-related bone fractures, and, secondarily, bone mineral density BMD) in the Hortega Study participants. Redox balance plays a key role in bone metabolism. We also assessed differential associations in participant subgroups by redox-related metal exposure levels and candidate genetic variants.
MATERIAL AND METHODS
In 467 participants older than 50 years from the Hortega Study, a representative sample from a region in Spain, we estimated metabolic principal components (mPC) for 54 plasma metabolites from NMR-spectrometry. Metals biomarkers were measured in plasma by AAS and in urine by HPLC-ICPMS. Redox-related SNPs (N = 341) were measured by oligo-ligation assay.
RESULTS
The prospective association with incident bone fractures was inverse for mPC1 (non-essential and essential amino acids, including branched-chain, and bacterial co-metabolites, including isobutyrate, trimethylamines and phenylpropionate, versus fatty acids and VLDL) and mPC4 (HDL), but positive for mPC2 (essential amino acids, including aromatic, and bacterial co-metabolites, including isopropanol and methanol). Findings from BMD models were consistent. Participants with decreased selenium and increased antimony, arsenic and, suggestively, cadmium exposures showed higher mPC2-associated bone fractures risk. Genetic variants annotated to 19 genes, with the strongest evidence for NCF4, NOX4 and XDH, showed differential metabolic-related bone fractures risk.
CONCLUSIONS
Metabolic patterns reflecting amino acids, microbiota co-metabolism and lipid metabolism were associated with bone fragility endpoints. Carriers of redox-related variants may benefit from metabolic interventions to prevent the consequences of bone fragility depending on their antimony, arsenic, selenium, and, possibly, cadmium, exposure levels.
背景
代谢物对骨脆性的潜在联合影响很少被评估。我们在奥尔特加研究参与者中评估了血浆代谢模式与骨脆性终点（主要是骨质疏松症相关的骨折发生率，其次是骨矿物质密度BMD）之间的关联。氧化还原平衡在骨代谢中起关键作用。我们还根据与氧化还原相关的金属暴露水平和候选基因变异评估了参与者亚组中的差异关联。
材料与方法
在来自西班牙一个地区的代表性样本奥尔特加研究中，选取了467名年龄超过50岁的参与者，我们通过核磁共振光谱法估算了54种血浆代谢物的代谢主成分（mPC）。通过原子吸收光谱法测定血浆中的金属生物标志物，通过高效液相色谱 - 电感耦合等离子体质谱法测定尿液中的金属生物标志物。通过寡核苷酸连接测定法测量与氧化还原相关的单核苷酸多态性（N = 341）。
结果
mPC1（非必需和必需氨基酸，包括支链氨基酸，以及细菌共代谢物，包括异丁酸、三甲胺和苯丙酸，与脂肪酸和极低密度脂蛋白相比）和mPC4（高密度脂蛋白）与骨折发生率呈负相关，但mPC2（必需氨基酸，包括芳香族氨基酸，以及细菌共代谢物，包括异丙醇和甲醇）与骨折发生率呈正相关。骨密度模型的结果一致。硒含量降低且锑、砷以及可能的镉暴露增加的参与者显示出与mPC2相关的骨折风险更高。注释到19个基因的基因变异，其中以NCF4、NOX4和XDH的证据最为充分，显示出与代谢相关的骨折风险存在差异。
结论
反映氨基酸、微生物群共代谢和脂质代谢的代谢模式与骨脆性终点相关。根据其锑、砷、硒以及可能的镉暴露水平，与氧化还原相关变异的携带者可能从代谢干预中受益，以预防骨脆性的后果。
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