Role of the leptin receptor overlapping transcript and SOCS3 gene variants in the pathogenesis of nonalcoholic fatty liver disease.

SOOKOIAN S; CASTANO G; FERNANDEZ GIANOTTI T; GEMMA C; ROSELLI MARIA S; PIROLA CARLOS JOSÉ.

San Francisco

Congreso; Annual meetting of the American Association for the Study of Liver Diseases; 2008

AASLD

Leptin, an adipocyte-derived hormone, can modulate energy balance and several metabolic functions. In liver, leptin attenuates some insulin-induced activities causing insulin resistance suggesting a role in the pathogenesis of NAFLD. Leptin acts through the leptin receptor (LEPR), which has several mRNA splice variants with cytoplasmic domains of different length. An additional transcript is generated from the same locus encoding a protein called LEPROT (leptin receptor overlapping transcript) that regulates the cell surface expression of LEPR. LEPR activation induces the expression of the inhibitory suppressor of cytokine signaling 3 (SOCS3) gene, which may impair the insulin action. The aim of this study was to investigate the role of gene variants of the LEPROT and SOCS3 in the susceptibility to NAFLD in a candidate gene association study. Additionally, we tested the hypothesis of a relation between the gene variants and disease severity. Patients & Methods: 167 patients with features of NAFLD (liver biopsy performed in 86), and a group of 63 healthy individuals were included. We selected 3 tagSNPs (minor allele frequency >10 %, r2 >0.8: rs3806318 A/G upstream, rs12145690 A/C intronic, and rs9436738 G/A intronic) in LEPROT. Besides, we selected 2 tags in the SOCS3: rs4969168 (G/A, 3UTR) and rs8064821 (C/A, upstream). Results: Variants either in LEPROT (P values= 0.90, 0.59, and 0.84 for rs380631, rs12145690 and rs9436738, respectively) or in SOCS3 (P values: 0.25 and 0.74 for rs4969168 and rs8064821, respectively) were not associated with NAFLD. We additionally tested the hypothesis of a relation between the variants and the histological spectrum of NAFLD by ordinal multinomial analysis, and a significant association was observed with rs4969168 (P <0.042, independently of age, sex and BMI). In conclusion, our results may support a role for the SOCS3 variants in the severity of NAFLD in our population. As far as to our knowledge, this is the first report about the influence of the genetic polymorphism in the above-mentioned genes on the susceptibility to NAFLD.