The non-synonymous polymorphism at position 114 of the WRN protein affects cholesterol efflux in vitro and correlates with cholesterol levels in vivo

• Systematic examination of non-synonymous coding SNPs in the human WRN gene
• We provide an association report of WRN SNPs with anthropomorphic measurements.
• The SNP changing a Val for an Iso at position 114 of WRN is associated with high cholesterol.
• The Val-114 WRN variant but not Iso-114 increased cholesterol efflux in WS fibroblasts.

Werner syndrome (WS) is a recessive disorder characterized by the premature onset of a number of age-related diseases. The objective of the present study was to examine the degree of associations between non-synonymous coding Single Nucleotide Polymorphisms (SNPs) in the WRN gene and markers of obesity, diabetes, and hypertension using meta-analyses publically available and to test their effect in WS fibroblasts. The P-value, after genomic control correction, for each non-synonymous coding SNP present in the WRN gene was retrieved from the International Consortium for Blood Pressure Genome-Wide Association Study, the Genome Wide Associations Scans for Total Cholesterol, HDL-cholesterol, LDL-cholesterol and triglycerides, and the Meta-Analyses of Glucose and Insulin-related traits Consortium. For SNPs significantly associated with cholesterol traits, we generated expression vectors containing the amino acid changes and measured cholesterol uptake and efflux in transfected WS fibroblasts. One SNP (rs2230009) changing a valine for an isoleucine at position 114 of the WRN protein was nominally associated with cholesterol and LDL-cholesterol measurements (P-values < 0.05). Interestingly, a WRN cDNA expression vector bearing a valine at position 114 instead of isoleucine significantly affected cholesterol efflux in WS fibroblasts. These results implicate a functional effect of this WRN polymorphism on cholesterol metabolism.