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Article

Blood Levels of the SMOC1 Hepatokine Are Not Causally Linked with Type 2 Diabetes: A Bidirectional Mendelian Randomization Study

1
Centre de Recherche de l’Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, QC G1V 4G5, Canada
2
Department of Medicine, Faculty of Medicine, Université Laval, Québec, QC G1V 0A6, Canada
*
Author to whom correspondence should be addressed.
Academic Editor: Omorogieva Ojo
Nutrients 2021, 13(12), 4208; https://doi.org/10.3390/nu13124208
Received: 25 October 2021 / Revised: 18 November 2021 / Accepted: 20 November 2021 / Published: 24 November 2021
(This article belongs to the Section Nutrition and Diabetes)
Hepatokines are liver-derived proteins that may influence metabolic pathways such as insulin sensitivity. Recently, Sparc-related modular calcium-binding protein 1 (SMOC1) was identified as glucose-responsive hepatokine that is dysregulated in the setting of non-alcoholic fatty liver disease (NAFLD). While SMOC1 may influence glucose-insulin homeostasis in rodents, it is unknown if SMOC1 is influenced by NAFLD in humans. It is also unknown if SMOC1 is causally associated with metabolic and disease traits in humans. Therefore, we aimed to determine the effect of NAFLD on SMOC1 gene expression in the liver and aimed to explore the potential causal associations of SMOC1 levels with NAFLD, T2D, and glycemic traits in humans. Using an RNA sequencing dataset from a cohort of 216 patients with NAFLD, we assessed SMOC1 expression levels across the NAFLD spectrum. We performed a series of bidirectional inverse-variance weighted Mendelian randomization (MR) analyses on blood SMOC1 levels using two sources of genome-wide association studies (GWAS) (Fenland study, n = 10,708 and INTERVAL study, n = 3301). We utilized GWAS summary statistics for NAFLD in 8434 cases and 770,180 controls, as well as publicly available GWAS for type 2 diabetes (T2D), body mass index (BMI), waist-to-hip ratio (WHR), fasting blood insulin (FBI), fasting blood glucose (FBG), homeostatic Model Assessment of Insulin Resistance (HOMA-B and HOMA-IR), and hemoglobin A1c (HbA1C). We found that SMOC1 expression showed no significant differences across NAFLD stages. We also identified that the top single-nucleotide polymorphism associated with blood SMOC1 levels, was associated with SMOC1 gene expression in the liver, but not in other tissues. Using MR, we did not find any evidence that genetically predicted NAFLD, T2D, and glycemic traits influenced SMOC1 levels. We also did not find evidence that blood SMOC1 levels were causally associated with T2D, NAFLD, and glycemic traits. In conclusion, the hepatokine SMOC1 does not appear to be modulated by the presence of NAFLD and may not regulate glucose-insulin homeostasis in humans. Results of this study suggest that blood factors regulating metabolism in rodents may not always translate to human biology. View Full-Text
Keywords: SMOC1; type 2 diabetes; Mendelian randomization; hepatokine SMOC1; type 2 diabetes; Mendelian randomization; hepatokine
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MDPI and ACS Style

Ghodsian, N.; Gagnon, E.; Bourgault, J.; Gobeil, É.; Manikpurage, H.D.; Perrot, N.; Girard, A.; Mitchell, P.L.; Arsenault, B.J. Blood Levels of the SMOC1 Hepatokine Are Not Causally Linked with Type 2 Diabetes: A Bidirectional Mendelian Randomization Study. Nutrients 2021, 13, 4208. https://doi.org/10.3390/nu13124208

AMA Style

Ghodsian N, Gagnon E, Bourgault J, Gobeil É, Manikpurage HD, Perrot N, Girard A, Mitchell PL, Arsenault BJ. Blood Levels of the SMOC1 Hepatokine Are Not Causally Linked with Type 2 Diabetes: A Bidirectional Mendelian Randomization Study. Nutrients. 2021; 13(12):4208. https://doi.org/10.3390/nu13124208

Chicago/Turabian Style

Ghodsian, Nooshin, Eloi Gagnon, Jérôme Bourgault, Émilie Gobeil, Hasanga D. Manikpurage, Nicolas Perrot, Arnaud Girard, Patricia L. Mitchell, and Benoit J. Arsenault. 2021. "Blood Levels of the SMOC1 Hepatokine Are Not Causally Linked with Type 2 Diabetes: A Bidirectional Mendelian Randomization Study" Nutrients 13, no. 12: 4208. https://doi.org/10.3390/nu13124208

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