探討台灣族群尿酸的遺傳變異及其與健康相關性狀的遺傳重疊性

Abstract

尿酸是嘌呤代謝後的最終產物，也是人體中重要的生化指標之一。高尿酸血症與代謝症候群及心血管疾病有正向關係，同時研究亦指出尿酸的抗氧化特性也可能是認知功能相關疾病的保護因子。尿酸濃度受到遺傳因子與飲食習慣所影響，然而飲食習慣僅造成短期尿酸濃度的小幅度升降，尿酸的遺傳度約為37-63%，遺傳因子決定人體尿酸的代謝平衡。遺傳變異與環境因素導致台灣高尿酸血症與痛風的盛行率高於世界各國，本研究旨在於台灣族群中偵測影響血清尿酸濃度的遺傳變異位點，並且探討尿酸與其他健康相關性狀的遺傳相關性，有助於瞭解調控尿酸代謝相關的基因及生理機制。 我們分析臺灣人體生物資料庫（Taiwan Biobank）11,300人的遺傳資訊，進行全基因組關聯性研究，使用線性回歸模型，校正年齡、性別及調整人口分層（在模型中納入十個主成分因子），檢驗單核甘酸變異（SNP）與尿酸濃度在加成基因模型下（Additive genetic model）的關聯性，更進一步使用條件分析（Conditional analysis）探究達顯著的基因位點與尿酸濃度的關聯性是否獨立。接著運用連鎖不平衡分數迴歸方法（Linkage disequilibrium score regression, LDSC），藉由計算尿酸與其他健康相關性狀的遺傳相關性（Genetic correlation）來探討尿酸與其他性狀的遺傳重疊性。 研究結果發現48個連鎖不平衡區塊（LD block）與尿酸濃度值有顯著關聯（P <5×10^(-8)），48個顯著位點（Index SNP）對應到7個基因：SORCS2、SLC2A9、WDR1、PKD2、ABCG2、SLC22A11與NRXN2。條件分析的結果指出SORCS2、SLC2A9、ABCG2上的位點與尿酸濃度有獨立的關聯性，SLC2A9、ABCG2與尿酸、痛風的關聯已在多個族群的研究中被指出，而SORCS2則是首次被發現與尿酸相關。 尿酸相關性狀與尿酸具有高度且顯著遺傳相關性，例如高尿酸血症 （rG=0.93）、痛風（rG=0.77）、腎結石（rG=-0.47），與肥胖指標、代謝性症候群及肝功能指標亦有顯著的遺傳相關性，包含：身體質量指數 （rG=0.32）, 體重（rG=0.25）、體脂率（rG=0.29）、三酸甘油酯（rG=0.45）以及γ-谷氨醯轉肽酶 （rG=0.40），顯現有相當比例的遺傳因子得以共同解釋這些性狀的變異。 本研究探討影響台灣族群尿酸濃度的基因變異，重現SLC2A9、ABCG2基因與尿酸的關聯，新發現SORCS2基因在台灣族群中與尿酸的顯著相關，亦量化尿酸與其他健康相關性狀的遺傳重疊性，尿酸與其他性狀或正或負的遺傳相關性顯現尿酸在人體中的特殊定位，後續研究可進一步探討其背後的生物途徑與調控機制。

Background Uric acid (UA), the final product of purine metabolism, is one of the most important biomarkers in human bodies, associating with many health conditions positively or negatively. Genetic factor plays a key role in the concentration of uric acid levels in the blood that the heritability of uric acid level is estimated from 37-63%. Taiwan has the comparatively higher prevalence of hyperuricemia and gout around the world, indicating that there might be specific genetic and environmental determinants influencing uric acid levels in Taiwanese population. Understanding the genetic architecture behind UA and other health-related traits may help investigate the evidence of co-regulation or shared physiological pathways, provide useful etiological insights, and enhance the therapeutic strategies. This study aims to identify genetic determinants of uric acid and assess genetic correlations between uric acid and other health-related traits in Taiwanese population. Materials and Methods We conducted a genome-wide association study (GWAS) to identify UA-related genetic variants in the Taiwanese general population with 11,300 subjects from Taiwan Biobank. Linear models were constructed with sex, age and 10 principle components as covariates to test the association between uric acid and single genetic marker. Conditional analyses were performed to confirm the independent effect of markers. LD score regression was applied to compute the genetic correlations between uric acid and health-related traits. Results Forty-eight significantly associated with uric acid levels (P<5×10-8) SNPs were retained after clumping, tagging to seven genes including SORCS2, SLC2A9, WDR1, PKD2, ABCG2, SLC22A11 and NRXN2. There were considerable genetic correlations between UA and UA-related traits including hyperuricemia (rG=0.93), gout (rG=0.77), and kidney stone (rG=-0.47). Besides UA-related traits, we also found significant SNP-based genetic correlation between UA and anthropometric, metabolic and liver-function-related traits including BMI (rG=0.32), weight (rG=0.25), fat rate (rG=0.29) triglyceride (rG=0.45), and GAMMA-GT (rG=0.40). Conclusions We replicated two well-known gene regions SLC2A9 and ABCG2 and identified one genetic variant locating on a novel gene SORCS2 showing associations with uric acid in Taiwanese population. Also, we demonstrated the shared genetic architecture background between uric acid and other phenotypes. Our study emphasizes the special role of uric acid in human bodies under the genetic basis and sheds the light on the investigation strategies for biological etiology of uric acid.