(LB02-14-25) Polygenic Risk Score and Functional Analysis of CCK Gene Variants in Energy Intake Regulation

Objectives: Evaluate whether a PRS including SNPs related to the regulation of energy intake is associated with body weight and biochemical markers in adults and elderly people in the city of São Paulo.

Investigate the functional impact of CCK gene variants involved in energy regulation, evaluating their potential as regulatory elements in neuronal tissues and adipocytes.

Methods: ISA-Nutrition cohort, 720 unrelated participants from São Paulo. PRS was calculated using 31 SNPs associated with energy intake regulation. A stepwise selection method was used. 

In silico characterizations were conducted using the Epigenome Gateway Website. pGL4.23 was constructed by molecular cloning. HT22 and 3T3 cells were transfected with the recombinant plasmids using Lipofectamine™ 3000 and Lipofectamine™ LTX Plus, respectively. After 48 hours, luciferase activity was quantified.

Results: PRS captured 35% of the weight variation. The integration of sociodemographic factors played a crucial role, enhancing the PRS's effectiveness. The scatter graphs illustrate that PRS positively correlates with body weight, waist circumference, glycemia, and cardiometabolic risk in adults.

In silico analysis, the rs4377469 variant showed low transcriptional activity in neural tissue, while the rs201712624 variant exhibited a potential enhancer region in adipose tissue and promoter regions in certain neural tissues. In vitro analyses, HT22 neuronal lineage revealed that the risk allele of the rs4377469 variant may act as an enhancer. In preadipocyte cells, neither variant exhibited significant activity. 

The discrepancies between these findings underscore the complexity of gene regulation, which can be influenced by specific microenvironmental conditions.

Conclusions: This multifaceted model highlights the interconnected nature of genetic and environmental factors in determining eating behaviors. In addition, we observed a strong link between PRS, energy intake, and the risks of obesity-related chronic diseases. In silico and in vitro analyses provide insights into the functional relevance of CCK gene variants in energy regulation. While in silico data suggested potential regulatory roles for rs4377469 and rs201712624, in vitro experiments revealed cell-type-specific effects.

Funding Sources: FAPESP
ADA