Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Department of Epidemiology, School of Public Health, Southeast University, Jiangsu, Nanjing, China.
BMC Med Genomics. 2023 May 23;16(1):112. doi: 10.1186/s12920-023-01545-4.
Fatty acids are involved in a wide range of immunological responses in humans. Supplementation of polyunsaturated fatty acids has been reported to help alleviate symptoms and airway inflammation in asthma patients, whereas the effects of fatty acids on the actual risk of asthma remain controversial. This study comprehensively investigated the causal effects of serum fatty acids on asthma risk using two-sample bidirectional Mendelian Randomization (MR) analysis.
Genetic variants strongly associated with 123 circulating fatty acid metabolites were extracted as instrumental variables, and a large GWAS data of asthma was used to test effects of the metabolites on this outcome. The inverse-variance weighted method was used for primary MR analysis. The weighted median, MR-Egger regression, MR-PRESSO, and leave-one-out analyses were utilized to evaluate heterogeneity and pleiotropy. Potential confounders were adjusted by performing multivariable MR analyses. Reverse MR analysis was also conducted to estimate the causal effect of asthma on candidate fatty acid metabolites. Further, we performed colocalization analysis to examine the pleiotropy of variants within the fatty acid desaturase 1 (FADS1) locus between the significant metabolite traits and the risk of asthma. Cis-eQTL-MR and colocalization analysis were also performed to determine the association between RNA expression of FADS1 and asthma.
Genetically instrumented higher average number of methylene groups was causally associated with a lower risk of asthma in primary MR analysis, while inversely, the higher ratio of bis-allylic groups to double bonds and the higher ratio of bis-allylic groups to total fatty acids, were associated with higher probabilities of asthma. Consistent results were obtained in multivariable MR when adjusted for potential confounders. However, these effects were completely eliminated after SNPs correlated with the FADS1 gene were excluded. The reverse MR also found no causal association. The colocalization analysis suggested that the three candidate metabolite traits and asthma likely share causal variants within the FADS1 locus. In addition, the cis-eQTL-MR and colocalization analyses demonstrated a causal association and shared causal variants between FADS1 expression and asthma.
Our study supports a negative association between several PUFA traits and the risk of asthma. However, this association is largely attributed to the influence of FADS1 polymorphisms. The results of this MR study should be carefully interpreted given the pleiotropy of SNPs associated with FADS1.
脂肪酸在人类的广泛免疫反应中发挥作用。有报道称，补充多不饱和脂肪酸有助于缓解哮喘患者的症状和气道炎症，而脂肪酸对哮喘实际风险的影响仍存在争议。本研究通过两样本双向 Mendelian Randomization（MR）分析，综合研究了血清脂肪酸对哮喘风险的因果影响。
提取与 123 种循环脂肪酸代谢物强烈相关的遗传变异作为工具变量，并利用大型哮喘 GWAS 数据来检验代谢物对该结果的影响。采用逆方差加权法进行主要 MR 分析。采用加权中位数、MR-Egger 回归、MR-PRESSO 和单样本缺失值分析来评估异质性和多效性。通过进行多变量 MR 分析来调整潜在的混杂因素。还进行了反向 MR 分析，以估计哮喘对候选脂肪酸代谢物的因果影响。此外，我们还进行了共定位分析，以检验在显著代谢物特征和哮喘风险之间，脂肪酸去饱和酶 1（FADS1）基因座内变异的多效性。还进行了 cis-eQTL-MR 和共定位分析，以确定 FADS1 的 RNA 表达与哮喘之间的关联。
在主要 MR 分析中，平均甲基数较多的遗传因素与哮喘风险降低有关，而双烯键和总脂肪酸中双烯键的比值较高，以及双烯键和总脂肪酸的比值较高，则与哮喘发生的概率较高有关。在调整了潜在混杂因素后，多变量 MR 分析中得到了一致的结果。然而，当排除与 FADS1 基因相关的 SNP 后，这些影响完全消除。反向 MR 也未发现因果关系。共定位分析表明，三个候选代谢物特征和哮喘可能在 FADS1 基因座内共享因果变异。此外，cis-eQTL-MR 和共定位分析表明，FADS1 表达与哮喘之间存在因果关系和共享因果变异。
本研究支持几种 PUFA 特征与哮喘风险之间存在负相关。然而，这种关联在很大程度上归因于 FADS1 多态性的影响。鉴于与 FADS1 相关的 SNP 存在多效性，因此应谨慎解释本 MR 研究的结果。
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