BACKGROUND: Preferential fat accumulation in the visceral compartment is related to cardiometabolic risk markers and increases the risk for type 2 diabetes and cardiovascular diseases. Changes in local androgen dynamics in adipose tissue have been proposed as a possible mechanism modulating visceral fat accumulation. In this context, 3a hydroxysteroid dehydrogenase type 3 (3a-HSD3), an enzyme encoded by AKR1C2, plays a key role by inactivating 5a-dihydrotestosterone (5a-DHT) in adipose tissue. This reaction decreases the bioavailability of this potent natural androgen, thus facilitating adipogenesis and lipid accumulation. The AKR1C2 promoter possesses a glucocorticoid response element which likely explains the responsiveness of 3a-HSD3 to local glucocorticoid stimulation.
AIM: To identify common genetic variants (i.e. single nucleotides polymorphisms, SNP) regulating AKR1C2 expression in adipose tissue and further link this to body fat distribution in females.
METHODS: We utilized the publicly available GTEx resource (https://gtexportal.org/) providing a rich catalog of densely profiled tissue samples including subcutaneous adipose (SAT) with precomputed association analysis of genotypes vs gene expression (eQTL). We used ~850 SAT samples from the TwinUK/MuTHER study for our analysis of gene expression and phenotypic data. Further, we used reference epigenome data for regulatory element profiling and functional interpretation of genetic data.
RESULTS: We identified an adipose-specific enhancer and open chromatin upstream of AKR1C2 harboring rs28571848 that was strongly associated with the expression level of AKR1C2 (p= 7.8x10-12). The SNP mapped close to the glucocorticoid-receptor (GR) response element within the enhancer identified in GR ChIP-Seq. We further found AKR1C2 expression in SAT to be significantly associated with dual energy x-ray absorptiometry-measured percentage trunk fat after adjustment for BMI (p= 7.8x10-30).
CONCLUSION: We identified a common genetic variant in an enhancer upstream of AKR1C2 that relates to body fat distribution and may be involved in the modulation of visceral fat accumulation in humans.