以雙樣本全表型 MR 探討基因推估鐵狀況之因果效應

Abstract

人體鐵狀況與健康狀態息息相關，涉及範圍甚廣，不論鐵缺乏或過剩都有某些健康效應，理解缺乏與過盛的健康效應之不同，將有助於理解鐵營養之生物意涵。本研究採用雙樣本全表型孟德爾隨機化（Phenome-wide MR），探討遺傳推估之鐵狀況在台灣人群對各種健康結果之因果影響。 本研究使用一大型東亞族群（n=245,062）的血紅素（Hemoglobin）統合分析找到的23,883個與血紅素相關之單核苷酸多態性指標（Single-nucleotide polymorphism, SNP），透過嚴格的統計標準來確保獨立性以及遺傳工具強度，然後使用鐵蛋白（Ferritin）和eQTL數據驗證其與鐵代謝的生物學相關性，篩選出四個鐵狀況遺傳工具變數組成遺傳估計推估鐵狀況指標；再使用臺灣精準醫療計畫資料檢驗其對1,102個臨床表型的因果效應。 分析結果顯示，遺傳估計鐵過剩與骨關節炎、骨折、顱內出血及情緒障礙的風險增加有因果關聯；對貧血則具有保護作用，並與較低的糖化血色素（HbA1c）相關。這些發現為鐵營養對人體健康的廣泛影響提供生物學證據，顯示鐵質雖為必需元素，應避免其缺乏，但較高的鐵質狀況亦可能涉及多種疾病的病程發展。本研究強調了維持鐵質恆定、鐵營養適中，以及在此領域精準營養應用之重要性。

Systemic iron status is critical for health, with both deficiency and excess leading to a wide range of adverse outcomes, yet its causal effects remain unclear due to limitations in observational studies. This study employed a Two-sample Phenome-wide Mendelian randomization (Phenome-wide MR) to investigate the causal landscape of genetically-proxied iron status across a wide range of health outcomes in Taiwanese population. Using four genetic instruments for iron status, which were filtered from 23,883 candidates based on stringent statistical and biological criteria, from a large East Asian hemoglobin meta-analysis (n=245,062), we tested for causal effects across 1,102 clinical phenotypes with the Taiwan Precision Medicine Initiative statistics. These four instruments were curated from 23,883 candidates by applying stringent statistical filters for independence and strength, and were subsequently validated for biological relevance to iron metabolism using ferritin and eQTL data. Our analysis revealed that a genetic predisposition to higher iron status was causally associated with an increased risk of osteoarthritis, bone fractures, intracranial hemorrhage, and mental disorders. Conversely, it was strongly protective against anemia and associated with lower HbA1c. These findings provide biological evidence for the widespread, pleiotropic effects of iron, demonstrating that while it is essential for maintaining health, excess iron status is a causal risk factor for diverse diseases. This underscores the critical importance of balanced iron homeostasis and cautions against indiscriminate supplementation and highlights the need for precision nutrition strategies to optimize iron status.