Grant: Operating Grant: Impact Grant : CEEHRC Phase II

One of the most consistent findings in biomedical research is that overwhelming majority of human diseases have inherited risk. Surprisingly, such genetically predisposed individuals do not display any pathology soon after birth, and it takes decades before the first appearance clinical symptoms. For example, the most common age-of-onset for schizophrenia is between 18-25 yrs, 15-30 yrs for bipolar, and 20-29 yrs for Crohn's diseases. We asked how these individuals with genetic risk factors can live 'symptom-free' for many years. To understand the basic principles of delayed age-of-onset, we studied a normal developmental trait of milk lactase non-persistence. Every infant can digest milk at birth and during breastfeeding, however, this ability is lost by adulthood in individuals who carry DNA-variants for milk intolerance. We found that chemical additions (epigenetic factors) on the key gene for milk digestion (lactase) were involved. As lactose digesters and non-digesters aged, the number of epigenetic factors "landing" on the lactase gene were different and this was controlled by DNA variation. Thus, we hypothesized that the age-of-onset of milk intolerance will be earlier with a greater number of accumulating epigenetic factors which depends on DNA variation. However, our findings are limited to two DNA variants. There are several ethnicity-specific DNA variations that may "attract" different numbers of epigenetic factors with age, which may explain the differences in the age-of-onset of milk intolerance across ethnicities. In this project, we will use mice to investigate how different types of DNA interact with epigenetic factors, and how their interactions can explain different latency of inability to digest milk. Our effort to uncover the mechanisms of gradual transition from milk tolerance to intolerance will open very promising avenues in research of a wide variety of diseases, such as schizophrenia, bipolar disorder, and inflammatory bowel disease.