廣泛性基因探索研究(GWAS)尋找影響排鈉利尿胜肽濃度的區域與舒張性心衰竭的研究

A Genome-Wide Association Study Investigates Quantitative Trait Loci of NT-proBNP and Heart Failure with Preserved Ejection Fraction

吳韋璁(Wei-Tsung Wu)

指導教授 ： 林宗憲

高雄醫學大學/醫學院/醫學研究所碩士班/碩士(2020年)

摘要

背景:
高血壓性心臟病相關的疾病佔國人十大死因的第二名，其中又以心血管疾病相關的高血壓性心臟病為最大宗，高血壓患者約70%死於心臟相關的併發症，如心臟衰竭。利鈉肽(Natriuretic peptide)有利鈉的生理作用，因此被認為對血壓與體液的調節扮演重要的角色。相關研究也都顯示利鈉肽(Natriuretic peptide)相關的生物標記氨基末端腦利鈉尿胜肽前體(NT-proBNP)在心臟衰竭扮演重要角色。本研究在年輕型高血壓病人身上以廣泛性基因研究(Genome-Wide Association Study)找尋與氨基末端腦利鈉尿胜肽前體(NT pro-BNP)濃度相關的基因標記，並探討這些基因標記是否與舒張性心衰竭相關。
方法:
從中央研究院基因研究計畫(Academia Sinica Multi-Centered Young-Onset Hypertension (AS-YOH) Genetic Study)的病人中，其中400 個年輕型高血壓患者用Illumina HumanHap550 SNP Chip核甘酸多型性分析找出與氨基末端腦利鈉尿胜肽前體(NT pro-BNP)濃度相關的基因標記，之後在所有收案的年輕型高血壓病人身上進一步的確認(replication)基因標記與前腦排鈉利尿胜肽濃度的相關性，接著評估氨基末端腦利鈉尿胜肽前體(NT proBNP)濃度與縱向追蹤的心血管監測因子變化的關係，並在另一群族群中針對176位有舒張性心衰竭與176位無舒張性心衰竭的病人做病例對照研究，以探討氨基末端腦利鈉尿胜肽前體(NT pro-BNP)相關的基因標記是否與舒張性心衰竭有關。
結果:
本研究有1023 位年輕型高血壓患者被收案。889位病人最後收錄至本研究。男性有618人(69.5%)，平均年紀為40.87.4歲。氨基末端腦利鈉尿胜肽前體(NT Pro-BNP)濃度的平均濃度為39.860.0 ng/L。與氨基末端腦利鈉尿胜肽前體(NT pro-BNP)濃度2 個最相關的GWAS基因標記，分別為rs12734338 (chromosome 1, p = 2.810-15) 與 rs198388 (chromosome 1, p = 3.510-7)，並在資料齊全的889位年輕型高血壓病人身上進一步的確認 (replication) rs12734338的基因型與氨基末端腦利鈉尿胜肽前體(NT Pro-BNP)濃度相關(p = 2.4910-12)。rs12734338的基因型分布為C/C 1位(0.1%)，C/T 616位(69.3%)，T/T 272位(30.6%)。在高雄醫學大學附設醫院收錄的高血壓患者(N=183)其氨基末端腦利鈉尿胜肽前體(NT Pro-BNP)濃度為35.761.1ng/l，氨基末端腦利鈉尿胜肽前體濃度與第一年的QTc及第三年心電圖的Sokolow-Lyon指標相關(p = 0.014 和 0.020)。病例對照研究顯示rs12734338基因型與舒張性心衰竭無相關(p 分別為0.67與0.38)。
結論:
在台灣年輕型高血壓患者rs12734338基因型與氨基末端腦利鈉尿胜肽前體(NT Pro-BNP)濃度有相關，但rs12734338基因型與舒張性心衰竭無相關。

關鍵字

高血壓 ； 心臟衰竭 ； 廣泛性基因探索研究 ； 排鈉利尿胜肽

並列摘要

Background: Hypertension play an important role in cardiovascular disease and more than 70% of patients with hypertension die from cardiovascular related complications. N-terminal fragment B-type natriuretic peptide (NT-proBNP) is believed to play an important role in the regulation of blood pressure and blood volume. Whether other novel genes influence the variation in NT-proBNP level and the roles of these genetic variants on subsequent presence of heart failure has not been investigated. Therefore, we aimed not only to identify genetic variants modulating plasma NT-proBNP levels but also to investigate whether these variants are associated with heart failure with preserved ejection (HFpEF)
Method: Total 1023 YOH subjects were enrolled. We conducted a genome-wide association study (GWAS) to identify quantitative trait loci (QTL) associated with heart failure levels by genotyping 400 young-onset hypertensive (YOH) subjects with Illumina HumanHap550 SNP chips. The culpable single nucleotide polymorphism (SNP) (rs12734338 and rs198388 ) variants associated with NT-proBNP level were then confirmed in 889 YOH subjects, and the association of these SNP variants with the risk of HFpEF was examined in an independent hospital-based case-control study.

Results: 889 patients were finally enrolled in this analysis. 618 patients (69.5%) were male. Age was 40.87.4 years old. The level of pro-BNP was 39.860.0 ng/L. The genotypes of rs12734338 were C/C 1 patients (0.1%)，C/T 616 patients (69.3%)，and T/T 272 patients (30.6%).We found 2 most significant SNPs rs12734338 (chromosome 1, p = 2.810-15) and rs198388 (chromosome 1, p = 3.510-7) associated with NT-proBNP level in the first stage. We replicated and confirmed the association between rs12734338 and plasma NT-proBNP levels (p = 2.4910-12). Among patients enrolled in the KMUH (N=183), their Pro-BNP levels were 35.761.1ng/l. NT-ProBNP levels were correlated with QTc at baseline and EKG Sokolow-Lyon index at third years (p = 0.014 and 0.020). However, rs12734338 and rs198388 were not associated with the risk of HFpEF (p = 0.67 and 0.38).

Conclusion: We confirm the GWAS findings that there was strongly correlation between rs12734338 genotypes and NT-proBNP level. These findings indicated the role of rs12734338 in modulating NT-proBNP levels but not involving the development of HFpEF.

並列關鍵字

GWAS ； BNP ； heart failure

參考文獻

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