Serum iron levels and the risk of Parkinson disease: a Mendelian randomization study.
Serum iron levels and the risk of Parkinson disease: a Mendelian randomization study.
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DOI：
10.1371/journal.pmed.1001462
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发表时间：
2013
期刊：
影响因子：
15.8
通讯作者：
Minelli C
中科院分区：
文献类型：
--
作者：
Pichler I;Del Greco M F;Gögele M;Lill CM;Bertram L;Do CB;Eriksson N;Foroud T;Myers RH;PD GWAS Consortium;Nalls M;Keller MF;International Parkinson's Disease Genomics Consortium;Wellcome Trust Case Control Consortium 2;Benyamin B;Whitfield JB;Genetics of Iron Status Consortium;Pramstaller PP;Hicks AA;Thompson JR;Minelli C
在这项研究中，孟德尔随机化被用于研究已知的改变铁水平的基因，并估计铁对帕金森病（PD）风险的影响。根据迄今为止最大样本荟萃分析中对铁和帕金森病遗传效应的估计，研究结果表明，每增加10微克/分升铁含量，血液中铁水平的增加与帕金森病风险降低3%相关。这一分析结果对未来预防帕金森病的研究具有潜在的重要意义。尽管已知帕金森病（PD）患者大脑中的铁含量增加，但关于铁含量对PD风险可能产生影响的流行病学证据尚无定论，报告的影响方向相反。流行病学研究存在混淆和反向因果关系的问题，孟德尔随机化（MR）是提供生物标志物对疾病影响的无混淆估计的另一种方法。我们进行了一项磁共振研究，其中已知的修改铁水平的基因被用作估计铁对PD风险影响的工具，基于迄今为止最大样本荟萃分析中对铁和PD的遗传影响的估计。我们使用影响铁水平的三个遗传变异HFE rs1800562、HFE rs1799945和TMPRSS6 rs855791作为工具变量。它们对血清铁的影响是基于最近对21,567人的全基因组荟萃分析，而它们对PD风险的影响是通过对20,809例PD病例和88,892例对照的全基因组和候选基因研究的荟萃分析得出的。对每种变体获得铁对PD影响的单独MR估计，并通过荟萃分析汇总。我们调查了三种估计的异质性，作为可能的多效性的指示，但没有发现证据。综合磁共振估计显示铁的保护作用具有统计学意义，血清铁每增加10微克/分升，PD的相对风险降低3% （95% CI 1%-6%; p = 0.001）。我们的研究表明，铁含量的增加与患帕金森病的风险降低有因果关系。在提出建议之前，需要进一步的研究来了解血清铁对PD风险作用的病理生理机制。帕金森氏病是一种中枢神经系统的退行性疾病，由中脑黑质（一个区域）中产生多巴胺的细胞死亡引起。最早的症状通常与运动有关，包括震颤、运动缓慢和行走困难，后来可能出现认知和行为问题，痴呆通常发生在疾病的晚期。帕金森氏症影响着全世界约1000万人，发病率随着年龄的增长而增加，男性比女性更容易受到影响。迄今为止，帕金森氏症的病因尚不清楚，尽管遗传和环境因素被认为起着一定的作用。识别可能改变的风险是预防帕金森病的重要一步。先前的研究表明，与对照组相比，帕金森病患者血液中铁含量较低可能存在关联，尽管这些研究的质量使得这一发现难以解释。因此，在这项研究中，研究人员使用孟德尔随机化方法来调查是否有证据表明血铁水平对帕金森病的风险有影响，如果有，则进一步探索任何联系的方向和规模。孟德尔随机化是一种方法，在不适合进行随机对照试验的情况下，使用已知功能基因的测量变异来检查可改变暴露对疾病的因果影响。研究人员利用HFE和TMPRSS6两个基因的三种多态性估计了血铁水平对帕金森病风险的影响。对于每种多态性，他们进行了荟萃分析，结合了研究铁水平遗传影响的研究结果，其中包括来自欧洲和澳大利亚的近22,000人，以及调查帕金森病风险遗传影响的研究的荟萃分析，其中包括来自欧洲和北美的20,809名帕金森病患者和88,892名对照组。然后，他们进行了三次单独的孟德尔随机化分析，以估计铁对帕金森病的三种多态性的影响。通过结合这三个估计，他们获得了统计学上显著的优势比，每增加10微克/分升铁，帕金森病的风险为0.97，对应于每增加10微克/分升铁，帕金森病的风险降低3%。由于基因型对血铁水平的影响通常持续整个成人生活，因此孟德尔随机化综合估计反映了铁在一生中的影响。这些发现表明，血液中铁含量每增加10微克/分升，帕金森病的风险就会降低3%。这一发现很重要，因为它表明血铁水平的增加可能对帕金森病有保护作用，尽管潜在的机制尚不清楚。此外，尽管孟德尔随机化越来越多地被用于解决经典混淆问题，但可能存在孟德尔随机化特有的其他混淆因素，这些因素可能会影响本研究的解释。尽管如此，这一分析结果对未来预防帕金森病的研究具有潜在的重要意义。在提出任何具体治疗建议之前，需要对潜在机制进行进一步研究。请通过本摘要的在线版本http://dx.doi.org/10.1371/journal.pmed.1001462访问这些网站。美国国家神经疾病和中风研究所、MedlinePlus和NHS Choices都有几页关于帕金森病的全面信息，维基百科给出了孟德尔随机化的解释（注意，维基百科是一个免费的在线百科全书，任何人都可以编辑；有几种语言版本）。
In this study, Mendelian randomization was used to study genes known to modify iron levels, and the effect of iron on Parkinson's disease (PD) risk was estimated. Based on estimates of the genetic effects on both iron and PD obtained from the largest sample meta-analyzed to date, the findings suggest that increased iron levels in the blood are associated with a 3% reduction in the risk of Parkinson's disease for every 10 µg/dL increase in iron. The results of this analysis have potentially important implications for future research into the prevention of Parkinson's disease. Please see later in the article for the Editors' Summary Although levels of iron are known to be increased in the brains of patients with Parkinson disease (PD), epidemiological evidence on a possible effect of iron blood levels on PD risk is inconclusive, with effects reported in opposite directions. Epidemiological studies suffer from problems of confounding and reverse causation, and mendelian randomization (MR) represents an alternative approach to provide unconfounded estimates of the effects of biomarkers on disease. We performed a MR study where genes known to modify iron levels were used as instruments to estimate the effect of iron on PD risk, based on estimates of the genetic effects on both iron and PD obtained from the largest sample meta-analyzed to date. We used as instrumental variables three genetic variants influencing iron levels, HFE rs1800562, HFE rs1799945, and TMPRSS6 rs855791. Estimates of their effect on serum iron were based on a recent genome-wide meta-analysis of 21,567 individuals, while estimates of their effect on PD risk were obtained through meta-analysis of genome-wide and candidate gene studies with 20,809 PD cases and 88,892 controls. Separate MR estimates of the effect of iron on PD were obtained for each variant and pooled by meta-analysis. We investigated heterogeneity across the three estimates as an indication of possible pleiotropy and found no evidence of it. The combined MR estimate showed a statistically significant protective effect of iron, with a relative risk reduction for PD of 3% (95% CI 1%–6%; p = 0.001) per 10 µg/dl increase in serum iron. Our study suggests that increased iron levels are causally associated with a decreased risk of developing PD. Further studies are needed to understand the pathophysiological mechanism of action of serum iron on PD risk before recommendations can be made. Please see later in the article for the Editors' Summary Parkinson disease is a degenerative disorder of the central nervous system caused by the death of dopamine-generating cells in the substania nigra, a region of the midbrain. The earliest symptoms are usually movement-related and include tremor, slow movements, and difficulty walking, and later cognitive and behavioral problems may arise, with dementia commonly occurring in the advanced stages of the disease. Parkinson disease affects around ten million people world-wide and incidence increases with age, with men more affected than women. To date, the causes of Parkinson disease remain unknown although a combination of genetic and environmental factors is thought to play a role. Identifying possible modifiable risks is an important step in the possible prevention of Parkinson disease. Previous studies have shown a possible association between lower blood levels of iron in people with Parkinson disease compared with controls, although the quality of these studies makes this finding difficult to interpret. So in this study, the researchers used a mendelian randomization approach to investigate whether there was any evidence of an effect of blood iron levels on the risk of Parkinson disease and if so to further explore the direction and scale of any link. Mendelian randomization is a method of using measured variation in genes of known function to examine the causal effect of a modifiable exposure on disease in situations where it is inappropriate to perform a randomized controlled trial. The researchers estimated the effect of blood iron levels on the risk of Parkinson disease using three polymorphisms in two genes, HFE and TMPRSS6. For each polymorphism, they performed a meta-analysis combining the results of studies investigating the genetic effect on iron levels, which included almost 22,000 people from Europe and Australia, and a meta-analysis of studies investigating the genetic effect on the risk of Parkinson disease, which included a total of 20,809 people with Parkinson disease and 88,892 controls from Europe and North America. They then performed three separate mendelian randomization analyses to estimate the effect of iron on Parkinson disease for the three polymorphisms. By combining the three estimates, they obtained a statistically significant odds ratio of 0.97 for Parkinson disease per 10 µg/dl increase in iron, corresponding to a 3% reduction in the risk of Parkinson disease for every 10 µg/dl increase in blood iron. Since genotype influences on blood iron levels represent differences that generally persist throughout adult life, the combined mendelian randomization estimate reflects an effect of iron over the course of a lifetime. These findings suggest that increased iron levels in the blood are associated with a 3% reduction in the risk of Parkinson disease for every 10 µg/dl increase in iron. This finding is important as it suggests that increased blood iron levels may have a protective effect against Parkinson disease, although the underlying mechanism remains unclear. Furthermore, although mendelian randomization is an increasingly used approach to address the issue of classical confounding, there may be remaining confounding factors specific of mendelian randomization that may influence the interpretation of this study. Nevertheless, the results of this analysis have potentially important implications for future research into the prevention of Parkinson disease. Further studies on the underlying mechanisms are needed before any specific treatment recommendations can be proposed. Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001462. The National Institutes of Neurological Disorder and Stroke, MedlinePlus, and NHS Choices have several pages with comprehensive information on Parkinson disease Wikipedia gives an explanation of mendelian randomization (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
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影响因子：
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