白蛋白尿在台灣族群的全基因組相關分析(GWAS)以及蛋白尿與感染住院的關係

Abstract

介紹：慢性腎臟疾病對全球健康造成巨大負擔，其定義包含腎小球過濾率降低及白蛋白尿。族群特定的相關基因在全基因組相關研究中經常被觀察到。本研究針對台灣非糖尿病人群進行白蛋白尿尿的全基因組相關研究，並且利用大型前瞻性研究探討蛋白尿在感染造成住院率之關係。

方法：本研究從台灣生物資料庫招募了30-70歲、無癌症病史的非糖尿病人群，其中有6,768名受試者進行了尿液檢驗。使用PLINK進行品質控制並使用SHAPEIT和IMPUTE2進行填補，並排除了等位基因頻率低於0.1%的單核苷酸多態性(SNP)，最終共保留了3,638,350個單核苷酸多態性(SNP)，使用線性回歸分析了單核苷酸多態性(SNP)與白蛋白尿/尿肌酐比值之間的關係。此外本研究利用2005年至2008年間參與新北市健康篩檢計畫的慢性腎病1–3期患者，以比例危險回歸模型計算了年輕（<50歲）和老年（≥50歲）慢性腎病患者感染相關住院和死亡的危險比（HR）和95%的信賴區間（CI）以及蛋白尿在兩族群中的影響。

結果：全基因組相關分析(GWAS)顯示在FCRL3（p = 2.56 × 10-6）、TMEM161（p = 4.43 × 10-6）、EFCAB1（p = 2.03 × 10-6）、ELMOD1（p = 2.97 × 10-6）、RYR3（p = 1.34 × 10-6）和PIEZO2（p = 2.19 × 10-7）的附近或內部識別了六個可能位點。FCRL3基因中編碼分泌型IgA受體的遺傳變異與IgA腎病有關，後者可表現為蛋白尿。PIEZO2基因編碼了腎絲球髓質細胞和產腎素細胞中的機械力感應器。還在五個基因中識別到五個p值介於5 × 10-6和5 × 10-5之間的單核苷酸多態性(SNP)，這些基因可能在白蛋白尿的發展中具有生物學作用。 我們並發現蛋白尿與感染引發住院的風險明顯相關, 且獨立於估計腎小球濾過率（eGFR）而這種關係在年長者中更明顯。

結論：在台灣非糖尿病人群中識別了五個新的位點和一個已知的可能位點與白蛋白尿相關，而且蛋白尿與感染造成住院之風險明顯相關，尤其於年長族群。

Introduction: Chronic kidney disease, which is defined by a reduced estimated glomerular filtration rate and albuminuria, imposes a large health burden worldwide, including infection associated complications. Ethnicity-specific associations are frequently observed in genome-wide association studies (GWAS). This study conducts a GWAS of albuminuria and a prospective study of albuminuria associated infection-complication in Taiwanese population.

Methods: Nondiabetic individuals aged 30-70 years without a history of cancer were enrolled from the Taiwan Biobank. A total of 6,768 subjects were subjected to a spot urine examination. After quality control using PLINK and imputation using SHAPEIT and IMPUTE2, a total of 3,638,350 single-nucleotide polymorphisms (SNPs) remained for testing. SNPs with a minor allele frequency of less than 0.1% were excluded. Linear regression was used to determine the relationship between SNPs and log urine albumin-to-creatinine ratio. A proportional hazards regression model was employed to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) for infection-related hospitalization and mortality in 119,871 Taiwanese adults.

Results: GWAS identified six suggestive loci are identified in or near the FCRL3 (p = 2.56 × 10-6), TMEM161 (p = 4.43 × 10-6), EFCAB1 (p = 2.03 × 10-6), ELMOD1 (p = 2.97 × 10-6), RYR3 (p = 1.34 × 10-6), and PIEZO2 (p = 2.19 × 10-7). Genetic variants in the FCRL3 gene that encode a secretory IgA receptor are found to be associated with IgA nephropathy, which can manifest as proteinuria. The PIEZO2 gene encodes a sensor for mechanical forces in mesangial cells and renin-producing cells. Five SNPs with a p-value between 5 × 10-6 and 5 × 10-5 are also identified in five genes that may have a biological role in the development of albuminuria. Proteinuria increases the risk of infection-related hospitalization independently of estimated glomerular filtration rate (eGFR), and this relationship is stronger in elderly individuals.

Conclusion: Five new loci and one known suggestive locus for albuminuria are identified in the nondiabetic Taiwanese population. The risk of infection-related hospitalization is higher in the elderly with proteinuria.