鉴定和描述长链非编码 RNA NFIA-AS2 作为美洲印第安人体重指数的新基因座。
Identification and characterization of the long non-coding RNA NFIA-AS2 as a novel locus for body mass index in American Indians.
机构信息
Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ, 85004, USA.
出版信息
Int J Obes (Lond). 2023 Jun;47(6):434-442. doi: 10.1038/s41366-023-01278-5. Epub 2023 Feb 17.
BACKGROUND
Genome-wide association studies have shown that body mass index (BMI), an estimate of obesity, is highly polygenic. Individual variants typically have small effect sizes, making it challenging to identify unique loci in under-represented ethnic groups which lack statistical power due to their small sample size. Yet obesity is a major health disparity and is particularly prevalent in southwestern American Indians. Here, we identify and characterize a new locus for BMI that was detected by analyzing moderate associations with BMI obtained in a population-based sample of southwestern American Indians together with the well-powered GIANT dataset.
METHODS
Genotypes for 10.5 million variants were tested for association with BMI in 5870 American Indians and 2600 variants that showed an association P < 10 in the American Indian sample were combined in a meta-analysis with the BMI data reported in GIANT (N = 240,608). The newly identified gene, NFIA-AS2 was functionally characterized, and the impact of its lead associated variant rs1777538 was studied both in-silico and in-vitro.
RESULTS
Rs1777538 (T/C; C allele frequency = 0.16 in American Indians and 0.04 in GIANT, meta-analysis P = 5.0 × 10) exhibited a large effect in American Indians (1 kg/m decrease in BMI per copy of C allele). NFIA-AS2 was found to be a nuclear localized long non-coding RNA expressed in tissues pertinent to human obesity. Analysis of this variant in human brown preadipocytes showed that NFIA-AS2 transcripts carrying the C allele had increased RNA degradation compared to the T allele transcripts (half-lives = 9 h, 13 h respectively). During brown adipogenesis, NFIA-AS2 featured a stage-specific regulation of nearby gene expression where rs1777538 demonstrated an allelic difference in regulation in the mature adipocytes (the strongest difference was observed for L1TD1, P = 0.007).
CONCLUSION
Our findings support a role for NFIA-AS2 in regulating pathways that impact BMI.
背景
全基因组关联研究表明，体重指数（BMI）是肥胖的一个高度多基因指标。个体变异通常具有较小的效应大小，因此在代表性不足的少数族裔群体中，由于样本量小，缺乏统计学效力，很难确定独特的基因座。然而，肥胖是一个主要的健康差异，特别是在美国西南部的印第安人中普遍存在。在这里，我们通过分析基于人群的美国西南部印第安人群体的 BMI 与中等关联，并结合具有强大效力的 GIANT 数据集，确定并描述了一个新的 BMI 基因座。
方法
在 5870 名美国印第安人和 2600 名在印第安人群体中显示与 BMI 关联的 P < 10 的变体的组合中，测试了 1050 万个变体与 BMI 的关联。在 GIANT（N = 240608）报告的 BMI 数据中进行荟萃分析。新鉴定的基因 NFIA-AS2 进行了功能特征描述，并研究了其主要相关变体 rs1777538 的体内和体外影响。
结果
rs1777538（T/C；C 等位基因频率=0.16 在美国印第安人和 0.04 在 GIANT 中，荟萃分析 P = 5.0×10）在美国印第安人中表现出较大的影响（每个 C 等位基因的 BMI 降低 1kg/m）。NFIA-AS2 被发现是一种在与人类肥胖相关的组织中表达的核定位长非编码 RNA。对该变体在人类棕色前体脂肪细胞中的分析表明，携带 C 等位基因的 NFIA-AS2 转录本与 T 等位基因转录本相比，RNA 降解增加（半衰期分别为 9h 和 13h）。在棕色脂肪形成过程中，NFIA-AS2 对附近基因表达具有阶段特异性调节，rs1777538 在成熟脂肪细胞中的调节存在等位基因差异（最强的差异观察到 L1TD1，P = 0.007）。
结论
我们的研究结果支持 NFIA-AS2 在调节影响 BMI 的途径中的作用。
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