AUTHOR=Gong Siqian , Han Xueyao , Li Meng , Cai Xiaoling , Liu Wei , Luo Yingying , Zhang Si-min , Zhou Lingli , Ma Yumin , Huang Xiuting , Li Yufeng , Zhou Xianghai , Zhu Yu , Wang Qiuping , Chen Ling , Ren Qian , Zhang Ping , Ji Linong 

TITLE=Genetics and Clinical Characteristics of PPARγ Variant-Induced Diabetes in a Chinese Han Population

JOURNAL=Frontiers in Endocrinology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2021.677130

DOI=10.3389/fendo.2021.677130

ISSN=1664-2392

ABSTRACT=<sec><title>Objectives</title><p><italic>PPARγ</italic> variants cause lipodystrophy, insulin resistance, and diabetes. This study aimed to determine the relationship between <italic>PPARγ</italic> genotypes and phenotypes and to explore the pathogenesis of diabetes beyond this relationship.</p></sec><sec><title>Methods</title><p><italic>PPARγ2</italic> exons in 1,002 Chinese patients with early-onset type 2 diabetes (diagnosed before 40 years of age) were sequenced. The functions of variants were evaluated by <italic>in vitro</italic> assays. Additionally, a review of the literature was performed to obtain all reported cases with rare <italic>PPARγ2</italic> variants to evaluate the characteristics of variants in different functional domains.</p></sec><sec><title>Results</title><p>Six (0.6%) patients had <italic>PPARγ2</italic> variant-induced diabetes (PPARG-DM) in the early-onset type 2 diabetes group, including three with the p.Tyr95Cys variant in activation function 1 domain (AF1), of which five patients (83%) had diabetic kidney disease (DKD). Functional experiments showed that p.Tyr95Cys suppresses 3T3-L1 preadipocyte differentiation. A total of 64 cases with damaging rare variants were reported previously. Patients with rare <italic>PPARγ2</italic> variants in AF1 of <italic>PPARγ2</italic> had a lower risk of lipodystrophy and a higher rate of obesity than those with variants in other domains, as confirmed in patients identified in this study.</p></sec><sec><title>Conclusion</title><p>The prevalence of PPARG-DM is similar in Caucasian and Chinese populations, and DKD was often observed in these patients. Patients with variants in the AF1 of <italic>PPARγ2</italic> had milder clinical phenotypes and lack typical lipodystrophy features than those with variants in other domains. Our findings emphasize the importance of screening such patients <italic>via</italic> genetic testing and suggest that thiazolidinediones might be a good choice for these patients.</p></sec>