Villanueva-Martin Gonzalo, Acosta-Herrera Marialbert, Kerick Martin, López-Isac Elena, Simeón Carmen P, Callejas José L, Assassi Shervin, Beretta Lorenzo, SSc Group International, Asig Australian Scleroderma Interest Group, Allanore Yannick, Proudman Susanna M, Nikpour Mandana, Fonseca Carmen, Denton Christopher P, Radstake Timothy R D J, Mayes Maureen D, Jiang Xia, Martin Javier, Bossini-Castillo Lara
Department of Cell Biology and Immunology, Institute of Parasitology and Biomedicine López-Neyra, CSIC, 18016 Granada, Spain.
Systemic Autoimmune Disease Unit, Hospital Clínico San Cecilio, Instituto de Investigación Biosanitaria Ibs. GRANADA, 18016 Granada, Spain.
J Clin Med. 2022 Oct 12;11(20):6014. doi: 10.3390/jcm11206014.
Obesity contributes to a chronic proinflammatory state, which is a known risk factor to develop immune-mediated diseases. However, its role in systemic sclerosis (SSc) remains to be elucidated. Therefore, we conducted a two-sample mendelian randomization (2SMR) study to analyze the effect of three body fat distribution parameters in SSc. As instrumental variables, we used the allele effects described for single nucleotide polymorphisms (SNPs) in different genome-wide association studies (GWAS) for SSc, body mass index (BMI), waist-to-hip ratio (WHR) and WHR adjusted for BMI (WHRadjBMI). We performed local (pHESS) and genome-wide (LDSC) genetic correlation analyses between each of the traits and SSc and we applied several Mendelian randomization (MR) methods (i.e., random effects inverse-variance weight, MR-Egger regression, MR pleiotropy residual sum and outlier method and a multivariable model). Our results show no genetic correlation or causal relationship between any of these traits and SSc. Nevertheless, we observed a negative causal association between WHRadjBMI and SSc, which might be due to the effect of gastrointestinal complications suffered by the majority of SSc patients. In conclusion, reverse causality might be an especially difficult confounding factor to define the effect of obesity in the onset of SSc.
肥胖会导致慢性促炎状态，这是引发免疫介导疾病的一个已知风险因素。然而，其在系统性硬化症（SSc）中的作用仍有待阐明。因此，我们进行了一项两样本孟德尔随机化（2SMR）研究，以分析三个体脂分布参数在SSc中的作用。作为工具变量，我们使用了在不同全基因组关联研究（GWAS）中针对SSc、体重指数（BMI）、腰臀比（WHR）以及经BMI调整的WHR（WHRadjBMI）所描述的单核苷酸多态性（SNP）的等位基因效应。我们对每个性状与SSc之间进行了局部（pHESS）和全基因组（LDSC）遗传相关性分析，并应用了几种孟德尔随机化（MR）方法（即随机效应逆方差权重法、MR-Egger回归法、MR多效性残差和离群值法以及多变量模型）。我们的结果显示，这些性状中的任何一个与SSc之间均无遗传相关性或因果关系。尽管如此，我们观察到WHRadjBMI与SSc之间存在负向因果关联，这可能是由于大多数SSc患者所遭受的胃肠道并发症的影响。总之，反向因果关系可能是确定肥胖在SSc发病中作用的一个特别难以处理的混杂因素。
