The Effect of Body Fat Distribution on Systemic Sclerosis Villanueva Martin, Gonzalo Acosta Herrera, Marialbert Kerick, Martin López Isac, Elena Callejas Rubio, José Luis International SSc Group Australian Scleroderma Interest Group (ASIG) Martín Ibáñez, Javier Bossini Castillo, Lara María Systemic sclerosis Mendelian randomization Obesity 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 genomewide 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. 2022-11-29T09:35:17Z 2022-11-29T09:35:17Z 2022-10-12 journal article Villanueva-Martin, G... [et al.]. The Effect of Body Fat Distribution on Systemic Sclerosis. J. Clin. Med. 2022, 11, 6014. [https://doi.org/10.3390/jcm11206014] https://hdl.handle.net/10481/78168 10.3390/jcm11206014 eng http://creativecommons.org/licenses/by/4.0/ open access Atribución 4.0 Internacional MDPI