Hindsight: G-Protein Genetic Variants and Obesity

Prof. Winfried Siffert, Universität Duisburg-Essen, Germany

Continuing in my series of revisiting some of the obesity research I was involved in, here is a paper to which I contributed a fairly significant number of DNA samples from my patients.

The paper, published in the Journal of the American Society of Nephrology in 1999, examined the relationship between obesity and a common genetic variant of the gene encoding the ß3 subunit of G protein, a molecule involved in transmitting chemical signals from outside a cell to the cell inside (though G-protein-coupled receptors).

G proteins regulate metabolic enzymes, ion channels, transporters, and other parts of the cell machinery, controlling transcription, motility, contractility, and secretion, which in turn regulate systemic functions such as embryonic development, learning and memory, and homeostasis.

The lead researcher on this project, Winfried Siffert, had just shown that the 825T allele of the GNB3, associated with the occurrence of a splice variant, termed Gß3-s (which, despite a deletion of 41 amino acids, is functionally active in a reconstituted system), was more common in individuals with high blood pressure.

This study explored the possible association with obesity in young male Germans (samples that I contributed), Chinese, and black South Africans with low, intermediate, and high 825T allele frequencies, respectively.

It turned out that in each of these three distinct cohorts, the 825T allele frequency was significantly higher in overweight and obese individuals compared to those with normal weight.

Thus, the 825T allele frequencies in these three BMI groups were, respectively, 29.5, 39.3, and 47.7% in Germans, 46.8, 53.9, and 58.6% in Chinese, and 83.1, 87.7, and 90.9% in South Africans. In each of these three distinct groups, the 825T allele was significantly associated with obesity with odds ratios between 2 and 3.

The paper also presents the results of genotyping of 5254 individuals from 55 native population samples from Africa, the Americas, Europe, Asia, Australia, and New Guinea showing the highest 825T allele frequencies in black Africans (82%) and intermediate values in east Asians (47%).

This finding prompted us to suggest that “high frequencies of the 825T allele in Africans and Asians may contribute to an obesity and hypertension epidemic if Westernization of lifestyles continues”.

While in hindsight, again, the notion, that a single genetic variant (no matter how common or functionally important) could even begin to explain increased general risk of such a complex multifactorial condition like obesity, may appear naive and it is therefore perhaps no surprise that this genetic variant never turned out to the the definitive “genetic marker” of obesity, at the time, this work did stimulate a lot of interest in the potential role of genetic variants in these important signalling proteins in complex medical conditions like obesity, hypertension and even a few mental health disorders.

According to Google Scholar, this paper has been cited 317 times.

AMS
Edmonton, Alberta

Siffert W, Forster P, Jöckel KH, Mvere DA, Brinkmann B, Naber C, Crookes R, Du P Heyns A, Epplen JT, Fridey J, Freedman BI, Müller N, Stolke D, Sharma AM, Al Moutaery K, Grosse-Wilde H, Buerbaum B, Ehrlich T, Ahmad HR, Horsthemke B, Du Toit ED, Tiilikainen A, Ge J, Wang Y, & Rosskopf D (1999). Worldwide ethnic distribution of the G protein beta3 subunit 825T allele and its association with obesity in Caucasian, Chinese, and Black African individuals. Journal of the American Society of Nephrology : JASN, 10 (9), 1921-30 PMID: 10477144