Human Genetic Variation at rs10071329 Correlates With Adiposity-Related Traits, Modulates PPARGC1B Expression, and...

Area of Science:

• Genetics
• Metabolism
• Cell Biology

Background:

• Human genetic variation in PPARGC1B is linked to adiposity.
• Specific genetic variants influencing PPARGC1B expression remain experimentally undetermined.

Purpose of the Study:

• To experimentally determine genetic variants affecting PPARGC1B expression.
• To investigate the functional consequences of the candidate causal variant rs10071329.

Main Methods:

• Utilized CRISPR/Cas9 gene editing to modify the rs10071329 genotype in human brown adipocytes.
• Assessed PPARGC1B expression, triglyceride accumulation, mitochondrial gene expression, and cellular respiration.

Main Results:

• Genotype switching from A/A to G/G at rs10071329 enhanced PPARGC1B expression, identifying it as a cis-eQTL.
• The G/G genotype led to increased triglyceride accumulation, higher mitochondrial gene expression, and improved mitochondrial respiration.
• G/G cells showed enhanced norepinephrine-stimulated lipolysis, indicated by increased glycerol release.

Conclusions:

• rs10071329 acts as a cis-eQTL, with the G/G genotype promoting higher PPARGC1B expression.
• Enhanced PPARGC1B expression correlates with improved mitochondrial function and lipolytic response in brown adipocytes.
• This genetic variant offers potential for genotype-based precision medicine in obesity treatment.