The School of Biotechnology at Atkins, Atkins Academic and Technology High, Winston-Salem, NC, 27101, USA.
Department of Internal Medicine, Section of Endocrinology and Metabolism, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA.
Int J Obes (Lond). 2024 Mar;48(3):330-338. doi: 10.1038/s41366-023-01417-y. Epub 2023 Nov 22.
Obesity is a common disease with a higher prevalence among African Americans. Obesity alters cellular function in many tissues, including skeletal muscle, and is a risk factor for many life-threatening diseases, including cardiovascular disease and diabetes. The similarities and differences in molecular mechanisms that may explain ethnic disparities in obesity between African and European ancestry individuals have not been studied.
In this study, data from transcriptome-wide analyses on skeletal muscle tissues from well-powered human cohorts were used to compare genes and biological pathways affected by obesity in European and African ancestry populations. Data on obesity-induced differentially expressed transcripts and GWAS-identified SNPs were integrated to prioritize target genes for obesity-associated genetic variants.
Linear regression analysis in the FUSION (European, N = 301) and AAGMEx (African American, N = 256) cohorts identified a total of 2569 body mass index (BMI)-associated transcripts (q < 0.05), of which 970 genes (at p < 0.05) are associated in both cohorts, and the majority showed the same direction of effect on BMI. Biological pathway analyses, including over-representation and gene-set enrichment analyses, identified enrichment of protein synthesis pathways (e.g., ribosomal function) and the ceramide signaling pathway in both cohorts among BMI-associated down- and up-regulated transcripts, respectively. A comparison using the IPA-tool suggested the activation of inflammation pathways only in Europeans with obesity. Interestingly, these analyses suggested repression of the mitochondrial oxidative phosphorylation pathway in Europeans but showed its activation in African Americans. Integration of SNP-to-Gene analyses-predicted target genes for obesity-associated genetic variants (GWAS-identified SNPs) and BMI-associated transcripts suggested that these SNPs might cause obesity by altering the expression of 316 critical target genes (e.g., GRB14) in the muscle.
This study provides a replication of obesity-associated transcripts and biological pathways in skeletal muscle across ethnicities, but also identifies obesity-associated processes unique in either African or European ancestry populations.
肥胖是一种常见疾病，非裔美国人的患病率更高。肥胖会改变许多组织的细胞功能，包括骨骼肌，并且是许多危及生命的疾病的风险因素，包括心血管疾病和糖尿病。尚未研究可能解释非裔和欧洲裔个体之间肥胖的种族差异的分子机制的异同。
在这项研究中，使用来自功能强大的人类队列的骨骼肌组织的转录组全分析数据，比较了肥胖对欧洲和非洲裔人群基因和生物学途径的影响。将肥胖诱导的差异表达转录本数据和 GWAS 鉴定的 SNP 整合在一起，以确定与肥胖相关遗传变异的靶基因。
FUSION（欧洲裔，N=301）和 AAGMEx（非裔美国人，N=256）队列中的线性回归分析总共确定了 2569 个与体重指数（BMI）相关的转录本（q<0.05），其中 970 个基因（p<0.05）在两个队列中均相关，并且大多数基因对 BMI 的影响方向相同。生物途径分析，包括过表达和基因集富集分析，分别在两个队列中鉴定出与 BMI 相关的下调和上调转录本中蛋白合成途径（例如核糖体功能）和神经酰胺信号通路的富集。IPA 工具的比较表明，肥胖的欧洲人只有炎症途径的激活。有趣的是，这些分析表明，肥胖的欧洲人中线粒体氧化磷酸化途径受到抑制，但在非裔美国人中则被激活。SNP 到基因分析的整合-预测了与肥胖相关的遗传变异（GWAS 鉴定的 SNP）和 BMI 相关的转录本的靶基因，表明这些 SNP 可能通过改变肌肉中 316 个关键靶基因（例如 GRB14）的表达来导致肥胖。
本研究提供了跨种族骨骼肌中与肥胖相关的转录本和生物学途径的复制，但也确定了非裔或欧洲裔人群中特有的肥胖相关过程。
