血清FGF21濃度之全基因組相關性分析

Abstract

纖維母細胞生長因子(FGF)最早是在從腦下垂體的萃取物中發現的。到目前為止發現FGF家族有22個成員，其中大部分屬於自分泌(autocrine)或旁分泌(paracrine)，然而FGF-19、21和23，其訊息傳遞的方式是透過血液循環到達特定的組織器官與典型的FGFs不同，被歸類為新興的“賀爾蒙”(endocrine hormone)。 FGF-21施打於糖尿病動物可以降低血糖, 減少脂肪肝, 並減輕體重,而過度表現FGF-21於小鼠可以抵抗高脂飲食產生的肥胖,並且增加棕色脂肪組織與能量消耗, 這些證據, 強烈顯示FGF-21為重要的新興代謝荷爾蒙, 可調控糖份與脂質的代謝,為重要之藥物標的。然而調控FGF-21的基因位點迄今尚未知。 本實驗檢體來源為台灣人體生物資料庫5000人之血清檢體，利用ELISA的方法測定FGF-21濃度。與台灣人體生物資料庫所提供的全基因組SNP基因型定型，利用PLINK軟體分析，尋找與FGF-21濃度相關之基因位點。我們除去糖尿病患者(n=607)後,分析4393名非糖尿病受試者, 並校正年齡、性別、BMI。 以P<10-6為閾值找到5個SNP位點與血清FGF-21濃度相關，這些位點都在內含子或兩基因位點之間，無位點在外顯子。這些SNP分別位於或是鄰近於Polyhomeotic Homolog 2(PHC2)、Zinc Finger And SCAN Domain Containing 20(ZSCAN20)、Arginine And Glutamate Rich 1( ARGLU1)、Family With Sequence Similarity 155 Member A(FAM155A)、Regulator Of G Protein Signaling 6(RGS6) 。這些基因參與基因的調節轉錄與細胞訊息傳遞，意味著這些基因可能調節FGF-21血清濃度機轉。

Fibroblast growth factor (FGF) was first found in extracts from the pituitary gland. Up to date, the FGF family has 22 members, most of which act in autocrine or paracrine fashion. However, unlike typical FGFs, FGF-19, 21 and 23, whose message transmission is through the blood circulation to reach specific tissues and organs, are classified as novel endocrine hormone. Administration of FGF-21 lowers blood glucose, reduces fatty liver, and results in weight loss. Forced expression of FGF-21 in mice resists obesity caused by high-fat diet and increases brown adipose tissue and energy expenditure. These evidences strongly suggest that FGF-21 is an important new hormone that regulates the metabolism of glucose and lipids, and is an important drug target. However, the genetic loci regulating serum FGF-21 level is unknown. We recruited 5,000 participants from the Taiwan Biobank and the levels of FGF-21 of these participants were determined using ELISA. Genome-wide SNP genotyping of FGF-21 provided by Taiwan Biobank database was analyzed using pLINK software to locate genetic loci associated with circulating FGF-21 levels. After removing diabetic patients (n=607), 4393 non-diabetic subjects were analyzed and the analyses were further adjusted by age, gender, BMI. Five SNPs loci were associated with serum FGF-21 levels using P<10-6 as threshold. These SNPs are within introns or are between two gene loci and none are found to be located within exons. These associated SNPs are located at or adjacent to the Polyhomeotic Homolog 2(PHC2)、Zinc Finger And SCAN Domain Containing 20(ZSCAN20)、Arginine And Glutamate Rich 1( ARGLU1)、Family With Sequence Similarity 155 Member A(FAM155A)、Regulator Of G Protein Signaling 6(RGS6). These genes are involved in the regulation of gene transcription and cell signal transduction. This means these genes may be involved in the regulation of the serum concentration of FGF-21