Genetic dissection of serum vaspin highlights its causal role in lipid metabolism

Background and Aim Vaspin (visceral adipose tissue derived serine protease inhibitor) is associated with metabolic traits related to obesity, but its causative role is still elusive. We investigated the role of genetics in the serum vaspin variability to establish its direct causative relationship with metabolically relevant traits.

Material and Methods Meta-analysis of genome-wide association studies (GWAS) for serum vaspin from six independent cohorts (N=7,446) was conducted. Potential functional variants of the vaspin locus were included in Mendelian Randomization (MR) analyses to assess possible causative chains between vaspin and correlated metabolically relevant traits. In vivo studies in dbdb mice were conducted to validate the GWAS findings.

Results In total, 468 single nucleotide polymorphisms (SNPs), all within the vaspin locus, were significantly associated with circulating serum vaspin (all P-values<5x10-8). Five independent SNPs (rs7141073, rs1956709, rs4905216, rs61978267, rs73338689) indicated a considerable locus heterogeneity. Respective credible sets contained 20 variants, none of them showing strong deleteriousness estimates. MR analyses including the five index SNPs revealed causal relationships between serum vaspin concentrations and triglycerides, low-density lipoprotein and total cholesterol. Gene expression correlation analyses based on data retrieved from the GTEx project suggests that genes highly correlating with vaspin expression in the adipose tissue are involved in lipid metabolic processes. Chronic vaspin treatment reduced serum triglyceride levels in genetically obese dbdb mice.

Conclusion Our data show that serum vaspin is strongly determined by genetic variants within vaspin and they further highlight vaspin’s causal role in lipid metabolism.

Publication History

Article published online:
02 May 2023