Mahdavi Sara, Rosychuk Katie, Jenkins David J A, Percy Andrew J, Borchers Christoph H, El-Sohemy Ahmed
Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, 6 Queens Park Crescent, Toronto, ON M5S 3H2, Canada.
Department of Nutrition, Harvard T.H. Chan School of Public Health, Harvard University, 677 Huntington Ave, Building B, Room 359, Boston, MA 02115, USA.
Nutrients. 2025 Apr 21;17(8):1398. doi: 10.3390/nu17081398.
: Diet is one of the most significant modifiable lifestyle factors influencing human health, contributing to both morbidity and mortality. Genetic variations in the pleiotropic 9p21 risk locus further shape premature aging, disease susceptibility, and have been strongly linked to cardiovascular disease (CVD), metabolic disorders, certain cancers, and neurodegenerative conditions. However, given that this region was discovered based on Genome-Wide Association Studies, the mechanisms by which 9p21 exerts its effects remain poorly understood and its interactions with diet and biomarkers are insufficiently explored. : This study investigated the association between the rs2383206 SNP in 9p21, dietary patterns, and plasma proteomic biomarkers in a multi-ethnic cohort of 1280 young adults from the Toronto Nutrigenomics and Health Study. Participants' dietary intake was assessed using a validated food frequency questionnaire, and dietary patterns were categorized using principal component analysis. Plasma proteomics analyses quantified 54 abundant proteins involved in the cardiometabolic and inflammatory pathways. Genotyping identified individuals who were homozygous for the 9p21 risk allele (GG), known to confer the highest susceptibility risk to premature aging and multiple chronic diseases. : A significant interaction was observed between the 9p21 genotype and adherence to a micronutrient-rich Prudent dietary pattern for eight plasma proteins (α Antichymotrypsin, Complement C4 β chain, Complement C4 γ chain, Complement C9, Fibrinogen α chain, Hemopexin, and Serum amyloid P-component). However, only Complement C4-γ showed a pattern consistent with the risks associated with the 9p21 genotype and adherence to a Prudent diet. Individuals with the high-risk GG genotype had significantly higher concentrations of Complement C4-γ, but only among those with a low adherence to a Prudent diet. : These findings suggest that Prudent dietary patterns rich in micronutrients may counteract genetic-mediated proinflammatory susceptibility by modulating key proteomic biomarkers in young adults, highlighting the potential for tailored dietary interventions to mitigate disease risk. This study also introduces a novel framework for post hoc micronutrient resolution within dietary pattern analysis, offering a new lens to interpret nutrient synergies in gene-diet interaction research.
饮食是影响人类健康的最重要的可改变生活方式因素之一，与发病率和死亡率都有关。多效性9p21风险位点的基因变异进一步影响早衰、疾病易感性，并且与心血管疾病（CVD）、代谢紊乱、某些癌症和神经退行性疾病密切相关。然而，鉴于该区域是基于全基因组关联研究发现的，9p21发挥作用的机制仍知之甚少，其与饮食和生物标志物的相互作用也未得到充分探索。
本研究在多伦多营养基因组学与健康研究的1280名多民族年轻成年人队列中，调查了9p21中rs2383206单核苷酸多态性（SNP）、饮食模式和血浆蛋白质组学生物标志物之间的关联。使用经过验证的食物频率问卷评估参与者的饮食摄入量，并使用主成分分析对饮食模式进行分类。血浆蛋白质组学分析对54种参与心脏代谢和炎症途径的丰富蛋白质进行了定量。基因分型确定了9p21风险等位基因（GG）纯合的个体，已知该等位基因会使早衰和多种慢性疾病的易感性风险最高。
在9p21基因型与对富含微量营养素的谨慎饮食模式的依从性之间，观察到八种血浆蛋白（α抗胰凝乳蛋白酶、补体C4β链、补体C4γ链、补体C9、纤维蛋白原α链、血红素结合蛋白和血清淀粉样P成分）存在显著相互作用。然而，只有补体C4-γ显示出与9p21基因型和遵循谨慎饮食相关的风险一致的模式。高危GG基因型个体的补体C4-γ浓度显著更高，但仅在那些对谨慎饮食依从性低的个体中如此。
这些发现表明，富含微量营养素的谨慎饮食模式可能通过调节年轻成年人的关键蛋白质组学生物标志物来抵消遗传介导的促炎易感性，突出了定制饮食干预以降低疾病风险的潜力。本研究还在饮食模式分析中引入了一种新的事后微量营养素解析框架，为解释基因-饮食相互作用研究中的营养协同作用提供了一个新视角。
