Genetic basis of cardiometabolic disease in the Lyon Hypertensive rat

Metabolic Syndrome (MetS) is a collection of diseases including obesity, hypertension, high cholesterol, and other related disorders that affects more quarter of the human population. Susceptibility to MetS is partially genetically determined, but many of the genetic causes are not well understood because these factors are extremely complex. Rat models provide a way to simplify the study of complex diseases like MetS, allowing for easier identification of novel genes than is possible in humans. The Lyon Hypertensive (LH) rat is a genetic model of MetS that was used alongside a closely related, healthy Lyon Normotensive rat to identify many possible candidate genes that contribute to MetS in the LH strain. In the LH rat, genes on chromosome 17 are important for MetS susceptibility and resistance. Using a variety of selective breeding techniques and improved genome sequence, we narrowed down regions of interest from the entire chromosome 17 to just a handful of candidate genes. We produced a novel rat strain that was more obese than the control LHs, despite eating significantly fewer calories. This demonstrates the importance of genetics on body composition, feeding behavior, and overall MetS risk. The best candidate gene, Ercc6l2, codes for a protein involved in DNA damage repair, and has been implicated in several severe human diseases of premature aging but was never previously connected to obesity or MetS. These findings have broad clinical implications for greater understanding of premature aging, as well as other age-related diseases such as MetS, and may lead to new treatments.