FUT2 Nonfunctional Variant: A “Missing Link” Between Genes and Environment in Type 1 Diabetes?

Recent worldwide epidemiological studies demonstrate that the incidence for type 1 diabetes in most regions has been increasing by 2–5% and that type 1 diabetes prevalence in the U.S. is approximately 1 in 300 by the age of 18 (1). In other regions, the rate of increase has been even higher. For example, just 35 years ago type 1 diabetes was a very rare disorder in China, but recent rapid economic development along with changes in lifestyle and, presumably, the living environment have rendered this country with an annual increase of 7.4% for type 1 diabetes prevalence (2). Indeed, the incidence of type 1 diabetes among different geographic/ethnic regions varies up to 500-fold (3). The dramatic increase of type 1 diabetes incidence worldwide in genetically stable populations, the significant international discrepancies for disease incidence, and reports of increased incidence when individuals migrate from low-incidence to high-incidence areas (4,5) cannot be accounted for by the genetic factors alone—thus demonstrating the implication of the complex interactions between susceptibility genes, the environmental/stochastic factors, and the immune system in type 1 diabetes etiology. The famous “hygiene hypothesis” has been frequently used to explain the rapid increase and discrepancy of type 1 diabetes incidence (6). It is believed that our increasingly hygienic environment, resulting from improvements in health care delivery and sanitation, has decreased the frequency of childhood infections, perhaps resulting in concomitant alterations in the gut microbiome, leading to a modulation of the developing immune system in genetically predisposed individuals and favoring the development of autoimmunity. Indeed, recent …