以全外顯子定序分析ALDH2基因和G6PD 基因缺陷間的關係

Abstract

背景 6-磷酸葡萄糖脫氫酶(G6PD)缺乏與乙醛去氫酶(ALDH2)缺乏是兩種常見的代謝酵素缺乏疾病。目前已有許多臨床研究證實這兩個基因的表現會影響癌症的預後。此二者基因的缺陷也會造成包括肥胖、葡萄糖代謝異常、脂肪肝、腎功能受損和心血管病病。若同時帶有此二酵素的缺陷，有可能會加重葡萄糖代謝異常及其他器官的損傷。 6-磷酸葡萄糖脫氫酶(G6PD)缺乏與乙醛去氫酶(ALDH2)缺乏的分佈均具有地域性，目前推測此為拓荒者效應的結果。6-磷酸葡萄糖脫氫酶(G6PD)缺乏已被證實針對瘧疾有保護的作用，乙醛去氫酶(ALDH2)缺乏則被認為可能會減少帶因者酒精的攝取，進而減少肝癌的發生。在台灣6-磷酸葡萄糖脫氫酶(G6PD)缺乏與乙醛去氫酶(ALDH2)缺乏的發生率相較於其他地區均明顯較高，但目前還未有研究調查同時發生6-磷酸葡萄糖脫氫酶與乙醛去氫酶缺乏的比率。因此，我們想要調查在台灣6-磷酸葡萄糖脫氫酶與乙醛去氫酶缺乏的基因型，並嘗試釐清在蠶豆症患者中，乙醛去氫酶缺乏症患者的比率是否較高。 研究目的 分析乙醛去氫酶基因缺損與6-磷酸葡萄糖脫氫酶基因缺損與否的關聯性。同時統計各乙醛去氫酶缺損與6-磷酸葡萄糖脫氫酶缺損之基因型在台灣地區的比率。 研究方法 本研究回朔性收錄於2010年1月至2022年5月這段期間，於台大醫院接受全外顯子定序的個案共594位，使用MViewer分析各患者於G6PD與ALDH2基因中帶有的致病性變異的比率，並嘗試分析各基因型患者可能出現的表現型。 研究結果 在594位個案中，共26位個案帶有致病性的G6PD基因變異（帶因率為4.4%），共284位個案帶有致病性的ALDH2基因變異（帶因率為47.8%）。分析G6PD基因變異的個案，可發現NM_000402.4(G6PD):c.1466G>T (p.Arg489Leu)變異的帶因率為所有G6PD基因中最高，約佔所有G6PD基因變異的50%。在ALDH2基因變異的帶因者中，幾乎所有的帶因者均帶有NM_000690.4(ALDH2):c.1510G>A (p.Glu504Lys)變異。比較帶因率可發現在帶有致病性的G6PD基因變異的個案族群中帶有致病性的ALDH2基因變異的比率較高，但未達統計顯著（65.4% v.s. 47.0%, P=0.067, 檢定力= 0.496）。 結論 我們的回顧性分析顯示台灣人群中 ALDH2 和 G6PD 缺乏症的患病率較世界平均為高。我們也觀察到相較於未帶有G6PD 基因缺陷的族群，在帶有G6PD 基因缺陷的族群，帶有ALDH2 基因缺陷的比例有上升的趨勢。 然而，由於目前缺乏基因型和表現型關聯性的研究，同時帶有此二者基因缺陷對各酵素活性的影響與可能造成臨床疾病均需要更進一步的研究來驗證。

Background Both G6PD and ALDH2 genes encode multimeric metabolic enzymes that play critical roles in mitigating oxidative stress within human cells. The expression of two genes were proved to have a great influence in clinical outcome of hepatocellular carcinoma, renal cell carcinoma, and other kinds of cancer. According to other studies, a lack of these enzymes has been linked to obesity, aberrant glucose metabolites, fatty liver, impaired renal function, and cardiovascular disease. The distribution of G6PD and ALDH2 deficiency was strong geographical correlated. This may be the cause of fundal effect. G6PD deficiency was proved to have protected effect of malaria while ALDH2 deficiency would prevent the carrier from alcohol abused. Though the prevalence of G6PD and ALDH2 deficiency were both high in Taiwan, no prior studies have addressed the potential risk of concurrent G6PD and ALDH2 deficiency. Therefore, the study's objective is to elucidate the genotype distribution of G6PD deficiency and ALDH2 deficiency. Additionally, we also want to investigate whether ALDH2 deficiency is more commonly observed in patients with a G6PD pathogenic variant. Aim Using whole exome sequencing to analyze the genotype of G6PD and ALDH2 deficiency in Taiwan and try to figure out weather G6PD deficiency was a predictive factor of ALDH2 deficiency. Material and Method The study was conducted in National Taiwan University Hospital. We retrospectively reviewed the genomic data of the patient who underwent whole exome sequencing form January, 2010 to May, 2022. 594 patients were recruited in our study. Pathogenic variant classified according to ACMG interpretation criteria or ClinVar clinical significance data base were called with MViewer. The incidence of all kinds of pathogenic variants were calculated. Result Among 594 cases, 26 cases carried a pathogenic variant in G6PD gene (carrier rate 4.4%) and 284 cases carried a pathogenic variant in ALDH2 gene (carrier rate 47.8%). NM_000690.4(ALDH2):c.1510G>A (p.Glu504Lys) was the most common pathogenic variant of G6PD gene in our study population. NM_000690.4(ALDH2):c.1510G>A (p.Glu504Lys) were presented in nearly all of the carriers of pathogenic variant in ALDH2 gene. Compared with those without pathogenic G6PD variant, patient with G6PD pathogenic variant were more likely to suffered from ALDH2 deficiency (65.4% v.s. 47.0%, p = 0.0067). However, our results did not reach statistic significance due to relative small example. Conclusion Our retrospective study revealed that the incidence of G6PD and ALDH2 deficiency were relatively high in Taiwan. We also found that there was a trend of an increasing proportion of ALDH2 deficiency among the G6PD deficient group. Though, due to lack of phenotype study, the precise relationship between mutations in these genes and clinical manifestation remain unclear. Further study is required for exploring these relationships and clarify their implications for health and disease.