Hindsight: Pro12Ala Missense Mutation of the Peroxisome Proliferator Activated Receptor [gamma] and Diabetes Mellitus

Dr. med. Jens Ringel

Dr. med. Jens Ringel

Since my first publication in 1987, I have authored or co-authored well over 300 peer-reviewed papers, about half of which are on topics related to obesity. This year, I thought I would dedicate my Saturday posts to reviewing some of these papers and sharing the stories behind them. If nothing else, it may point readers to some of the topics that have found my interest me over the years.

The first of my obesity papers to come up in a PubMed search is that of my MD-doctoral student Jens Ringel, published in Biochem Biophys Res Commun (1999), looking at a common genetic variant of the peroxisome proliferator activated receptor-gamma (PPARg), a nuclear receptor, that regulates adipocyte differentiation and possibly lipid metabolism and insulin sensitivity.

In this study, we specifically examined the allelic frequencies of the missense C –> G mutation at codon 12 of this gene, which results in the substitution of proline with alanine (Pro12Ala) in subjects with type 1 (n = 522) and type 2 (n = 503) diabetes compared to that in healthy controls (n = 310) and found no differences between these groups. There was also no significant relationship between dyslipoproteinemia or obesity and the PPARg Pro12Ala genotype.

Thus, these findings did not support the hypothesis that this genetic variant is strongly associated with diabetes, obesity, or dyslipidemia in patients with type 1 or type 2 diabetes mellitus and we concluded that this genetic marker is therefore unlikely to serve as a clinically useful predictor of these disorders in Caucasian patients with diabetes mellitus.

In hindsight such an assumption may appear rather naive, given that today we know that it takes far larger sample sizes (10s of thousands of subjects) and far more sophisticated analyses to stand even a remote chance of identifying genes for complex diseases. But back in 1999, when this paper was published, many of us were churning out papers looking at single nucleotide polymorphisms (SNPs) of candidate genes in a few hundred samples.

According to Google Scholar, this paper has been cited 134 times, so I guess someone did find this study of interest after all.

Edmonton, Alberta

ResearchBlogging.orgRingel J, Engeli S, Distler A, & Sharma AM (1999). Pro12Ala missense mutation of the peroxisome proliferator activated receptor gamma and diabetes mellitus. Biochemical and biophysical research communications, 254 (2), 450-3 PMID: 9918859