Variants in PPARG Associated with Increased Risk of Type 2 Diabetes

About one in every 1,000 individuals carries a variant in PPARG, which is treatable with tailored pharmacotherapy…. 

Peroxisome proliferator-activated receptor gamma, PPARG, is a transcriptional regulator of adipocyte differentiation and glucose metabolism. PPARG promotes postprandial lipid uptake in adipocytes. Antidiabetic drugs such as thiazolidinediones are targeted by PPARG to increase insulin sensitivity. Rarely, loss-of-function (LOF) mutations in PPARG are known; however, whether rare variants in PPARG and defects in adipocyte differentiation increase the risk of type 2 diabetes is unknown.

After sequencing PPARG in 19,752 T2D cases and controls drawn from multiple studies and ethnic groups, the researchers characterized 49 previously unidentified protein-altering mutations; each of the variants was non-synonymous.

With or without computational prediction of functional consequence, these rare variants showed no association with T2D (OR = 1.35; P = 0.17). Nine of the variants showed LOF to novel high-throughput human adipocyte differentiation assay. The researchers found that carriers of any of these nine LOF variants were associated with a significant increased risk of T2D (OR = 7.22; P = 0.005). 

The combination of large-scale DNA sequencing and functional testing in the lab reveals approximately 1 in 1,000 people carries a variant in PPARG that reduces function in a human adipocyte differentiation assay and is associated with a substantial risk of T2D. Genome sequencing of individuals in the population reveals new mutations in almost every protein-coding gene; interpreting the impact of these variants for human health and disease remains challenging.

• Rare variant in PPARG can increase the risk of T2D
• Treatable with tailored pharmacotherapy that targets these variants with LOF mutation
• Genome sequencing of individuals in the population reveals new mutations in almost every protein-coding gene; however, impact of it on human health remained unknown.

Majithia AR." Rare variants in PPARG with decreased activity in adipocyte differentiation are associated with increased risk of type 2 diabetes." Proc Natl Acad Sci USA. July 21, 2014;doi:10.1073/pnas.1410428111.