Causal association of micronutrients with osteonecrosis: evidence from a bidirectional Mendelian randomization trial

doi:10.12307/2024.686

Abstract

Abstract: BACKGROUND: Osteonecrosis is a common refractory disease in clinical practice, and observational studies have suggested that micronutrients may have a prognostic role in osteonecrosis. However, the specific causal association between micronutrients and osteonecrosis is not known.
OBJECTIVE: To explore the causal association between micronutrients and osteonecrosis by Mendelian randomization using summary data from a large population-based genome-wide association study (GWAS) for clinical diagnosis and treatment.
METHODS: The required exposure and outcome data (calcium, magnesium, iron, vitamin E, carotenoids, retinol & osteonecrosis) were extracted from the IEU OpenGWAS database, GWAS catalog database, and FinnGen database. Data were analyzed by bidirectional Mendelian randomization with inverse-variance weighted as the primary study method, and weighted median method, simple mode method, weighted mode method, and MR-Egger regression to complement the results. The reliability of the data was then verified through sensitivity analyses.
RESULTS AND CONCLUSION: (1) The results found a positive correlation between serum iron concentration and osteonecrosis, while no correlation was found for other micronutrients. There was no reverse causality in all the data. (2) The results of sensitivity analysis showed a robust causality. (3) By Mendelian randomization method, this study provided evidence of causality between serum iron concentration and osteonecrosis, and understanding the causality of micronutrient elements on osteonecrosis can help in the clinical diagnosis and treatment of osteonecrosis, which is of great clinical significance.

Key words: osteonecrosis, micronutrients, Mendelian randomization, causality, reverse causality, genome-wide association study, ferroptosis, instrumental variable

CLC Number:

Li Wei, Chai Jinlian, Jia Haifeng, Li Hanzheng, Sun Tiefeng, Liang Xuezhen. Causal association of micronutrients with osteonecrosis: evidence from a bidirectional Mendelian randomization trial[J]. Chinese Journal of Tissue Engineering Research, 2024, 28(33): 5308-5314.

Figures/Tables 6

2.1 工具变量首先在探究微量营养素对骨坏死的因果关系时，根据工具变量筛选原则，提取与钙、镁、磷、铁、维生素D、维生素E、胡萝卜素和视黄醇强相关SNP在结局中的信息时分别丢失了3，0，5，0，3，2，0，1个SNP。剔除回文序列后最终得到了34，23，227，19，153，28，28，21个工具变量，其中利用PhenoScanner数据库检索有关的表型，剔除其对应表型与骨坏死具有相关意义的2个SNP(rs1800562，rs116337889)。在探究骨坏死对微量营养素的因果关系时，提取与骨坏死强相关SNP在钙、镁、磷、铁、维生素D、维生素E、胡萝卜素和视黄醇中的信息时分别丢失了9，9，17，9，17，1，1，1个SNP。剔除回文序列后，最终结局为钙、镁、铁、维生素E、胡萝卜素和视黄醇时分别获取了10，10，10，14，14，14个工具变量，磷和维生素D在剔除回文序列后没有足够的SNP进行后续的MR分析。所有SNP均符合工具变量筛选标准。 2.2 微量营养素对骨坏死疾病的影响逆方差加权法分析结果显示，基因预测的钙与骨坏死(OR=0.939，95%CI：0.53-1.664，P=0.828)、镁与骨坏死(OR=1.029，95%CI：0.744-1.422，P=0.864)、磷与骨坏死(OR=0.960，95%CI：0.730-1.263，P=0.772)、维生素D与骨坏死(OR=0.894，95%CI：0.638-1.251，P=0.512)、维生素E与骨坏死(OR=1.005，95%CI：0.575-1.760，P=0.984)、胡萝卜素与骨坏死(OR=1.151，95%CI：0.658-2.011，P=0.622)、视黄醇与骨坏死(OR=0.846，95%CI：0.432-1.656，P=0.626)之间无统计学意义，所以不存在因果关系。而基因预测的铁与骨坏死(OR=1.377，95%CI：1.032-1.837，P=0.030)表明血清铁浓度是骨坏死的危险因素且具有统计学意义，同时应用其他4种分析方法来确认结果的稳健性，其中，该4种方法的分析结果虽无统计学意义，但和逆方差加权法方法分析的方向一致(OR值均> 1)，见图2，3。"

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