基于孟德尔随机化分析探索砷代谢模式与非酒精性脂肪性肝病的因果关联
Causal association between arsenic metabolism and non-alcoholic fatty liver disease based on Mendelian randomization
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摘要:
背景 动物实验表明砷暴露会导致肝脏脂肪堆积，但流行病学研究结果并不一致。此外，砷代谢模式在其中的作用也并不明确。
目的 探讨砷代谢模式与非酒精性脂肪性肝病（NAFLD）的因果关联。
方法 以东风-同济队列2018年随访中完成尿砷代谢物水平检测和基因分型的1020名居民为研究对象（NAFLD组
n =529，非NAFLD组n =491），通过问卷调查获得流行病学资料，体格检查获得肝脏B超资料，高效液相色谱串联电感耦合等离子体质谱仪检测尿液中的砷代谢物水平，并提取白细胞中的DNA进行全基因组芯片检测。NAFLD的诊断标准为：（1）肝脏B超提示脂肪肝；（2）排除过量饮酒史（男性≥30 g·d−1；女性≥20 g·d−1）和其他原因所导致的脂肪肝。选择既往研究报道与砷代谢相关的单核苷酸多态性位点（SNP）构建遗传风险评分（GRS）和加权遗传风险评分（w-GRS）估计个体的砷代谢模式。采用logistic回归模型分析砷代谢模式与NAFLD的关联，采用线性回归模型分析GRS和w-GRS与砷代谢模式的关联，采用GRS法、逆方差加权法、Egger回归法及加权中位数法进行孟德尔随机化分析。结果 1020名研究对象的年龄为（68.14±7.45）岁，其中64.0%为女性，529名（51.9%）NAFLD病例。尿总砷浓度的
M （P 25，P 75）为18.34（11.93，27.14） μg·L−1，几何均数±标准差为（15.86±1.81）μg·L−1。无机砷、一甲基砷、二甲基砷在总砷中的占比（iAs%、MMA%、DMA%）分别为13.90%±9.90%、9.49%±4.97%、76.60%±11.00%。校正混杂因素后，iAs%和MMA%每增加一个标准差，NAFLD患病风险的OR（95%CI）分别为1.21（1.06~1.38）和0.62（0.51~0.74）。选取77个SNPs构建的GRS每增加一个单位，MMA%增加0.16%，DMA%减少0.19%；w-GRS每增加一个单位，MMA%增加0.17%，DMA%减少0.14%。进一步排除连锁不平衡（r 2>0.3）和多效性位点后，共有25个SNPs纳入孟德尔随机化分析，GRS法显示，MMA%期望值每增加1%，NAFLD患病风险的OR（95%CI）为0.95（0.90~0.99）；逆方差加权法显示，MMA%与NAFLD患病风险关联的OR（95%CI）为0.91（0.84~0.99）。结论 砷代谢模式中MMA%与NAFLD之间存在负向因果关联。
Abstract:Background Animal experimental studies have shown that arsenic exposure contributes to hepatic lipid accumulation, but epidemiological findings are inconsistent. Moreover, the role of arsenic metabolism is still unclear.
Objective To evaluate the potential causal association between arsenic metabolism and non-alcoholic fatty liver disease (NAFLD).
Methods A total of 1020 participants from the Dongfeng-Tongji cohort with urinary arsenic metabolites and genotype data were included in the present study (NAFLD group,
n =529; non- NAFLD group,n =491). Epidemiological information was obtained by questionnaire survey, liver ultrasound was obtained by physical examination, arsenic metabolites in urine were measured by high-performance liquid chromatography-inductively coupled plasma mass spectrometry, and DNA from leukocytes was extracted for genome-wide genotype. NAFLD was diagnosed if the following two criteria were met: (1) positive fatty liver according to abdominal ultrasonography; (2) excluding participants reporting history of excessive alcohol consumption (≥30 g·d−1 for men; ≥20 g·d−1 for women) and/or fatty liver with other known causes. Genetic risk score (GRS) and weighted genetic risk score (w-GRS) were constructed using single nucleotide polymorphisms (SNPs) related to arsenic metabolism reported in previous studies to predict the estimated arsenic metabolism. Logistic regression models were used to analyze the association between arsenic metabolism and NAFLD; linear regression models were used to analyze the association between GRS/w-GRS and arsenic metabolism, and Mendelian randomization analysis was performed using GRS method, inverse variance weighting, Egger regression, and weighted median.Results The mean age of the 1020 participants was (68.14±7.45) years, of which 64% were female, and 529 (51.9%) were NAFLD cases. The median (
P 25,P 75) level of total arsenic in urine was 18.34 (11.93, 27.14) μg·L−1 with a geometric mean and standard deviation of (15.86±1.81) μg·L−1. The proportions of inorganic arsenic (iAs%), monomethylarsenic (MMA%), and dimethylarsenic (DMA%) in the total arsenic were 13.90%±9.90%, 9.49%±4.97%, and 76.60%±11.00%, respectively. After adjustment for potential confounders, the ORs (95%CIs) for NAFLD risk by per standard deviation increase in iAs% and MMA% were 1.21 (1.06, 1.38) and 0.62 (0.51, 0.74) respectively. Each unit increase in GRS constructed from 77 SNPs was associated with a 0.16% increase in MMA% and a 0.19% decrease in DMA%, and each unit increase in w-GRS was associated with a 0.17% increase in MMA% and a 0.14% decrease in DMA%. After further exclusion of SNPs with linkage disequilibrium (r 2>0.3) and pleiotropic effect, a total of 25 SNPs were included in the Mendelian randomization analysis. The GRS method showed that the OR (95%CI) for NAFLD risk by per unit increase in MMA% expectation was 0.95 (0.90, 0.99), and the inverse variance weighting method also showed a significant association between MMA% and NAFLD, with OR (95%CI) of 0.91 (0.84, 0.99).Conclusion There is a negative causal association between MMA% and NAFLD.
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