Diabetes, cigarette smoking and transcription factor 7-like 2 (Tcf7L2) in the UK Biobank cohort

Smokers are 30 to 40 percent more likely to develop type 2 diabetes than non-smokers. A type 2 diabetes gene, Tcf7L2, which had lost activity, caused rats to consume more nicotine. In the present study, we used data from the UK Biobank to examine the relationship of smoking, type 2 diabetes, and Tcf7L2 in human subjects.

The Tcf7L2 gene has two SNPs, rs7903146 and rs4506565, reported to be associated with type 2 diabetes. They have approximately equal power to estimate risk for type 2 diabetes, and the results from one correlate 92% with the other. We examined the genotypes of these SNPs and cigarette consumption.

Genotype TT, linked to type 2 diabetes, smoked the least. But because of the large sample size (approximately 111,000 subjects) the tiny difference in cigarettes smoked daily by each genotype group (effect size), while statistically significant, is probably clinically meaningless. The average subject smoked 19 cigarettes daily, with a difference of 0.12 cigarette between each genotype group.

The fact that Tcf7L2 is involved in nicotine addiction in rats but not in humans, as UKBB data suggest, is hardly surprising. Humans and rodents descended from a common ancestor about 80 million years ago, with rats and mice diverging between 12 and 24 million years ago. Thus, over millions of years Tcf7L2 may have developed vastly different functions in rodents and humans. Genome Wide Association Studies have revealed at least 65 different loci linked to type 2 diabetes. Genes associated with type 2 diabetes include Tcf7L2, PPARG, FTO, KCNJ11, NOTCH2, WFS1, IGF2BP2, SLC30A8, JAZF1, HHEX, DGKB, CDKN2A, CDKN2B, KCNQ1, HNF1A, HNF1B MC4R, GIPR, HNF4A, MTNR1B, PARG6, ZBED3, SLC30A8, CDKAL1, GLIS3, GCK, GCKR, among others. Perhaps one or more of these genes might be the intermediary between type 2 diabetes and cigarette smoking. Further studies are warranted.