To characterize genetic variation that impacts the severity of blood vessel disease in patients with elastin insufficiency and Williams syndrome, we are using a combination of approaches. First, using a technique called quantitative trait locus analysis, we identified different regions of the mouse genome where differences in genetic background impact the degree of hypertension and vascular narrowingin Eln+/- mice. Subsequent work has identified distinct genetic modifiers from under two of those peaks(Ren1 and Ncf1) with an additional genomic region on chromosome 2 near the Fbn1 and Jag1 genes. With the identification of these modifiers, further study into the mechanism of action and potential therapeutic value can be undertaken. Building on data from previous years we found that NCF1, a component of the NADPH oxidase system, is important for generating reactive oxygen species (ROS) in elastin insufficient vessels. Its production is triggered by the increased shear stress seen in Eln+/- arteries and, once produced, contributes to the high blood pressure and vascular stiffness observed in these patients and animals. Inhibition of ROS production using chemical or genetic modifications, decreases blood pressure and stiffness. Second, we are looking at the association of rare and common genomic variants with disease severity in WS patients. Toward this end, we have collected questionnaire data, medical records and DNA on more than 180 individuals with Williams Beuren syndrome. We performed exome sequencing and began to compare genetic variants between those with no supravalvar aortic stenosis (SVAS, the characteristic vascular lesion associated with this condition) and those with severe SVAS. Because our disease is rare, methods were optimized to the small sample size. Optimizations included extreme cohort analysis and limiting analysis space to only missense and stopgain variants with focus on pathways rather than genes. Ultimately our studies revealed a role for the adaptive immune system, the extracellular matrix and g protein couple receptors in modifying SVAS severity. Subsequent work in animal models has confirmed a role for the adaptive immune system in disease modification. We have now acquired additional WBS simples that will be evaluated by genome sequencing to replicate our initial studies and extend these studies into modifiers outside of the coding sequence. Preliminary work looking comparing WBS exomes to that of a control population is also underway. Finally, in collaboration with Max Muenkes group in NHGRI, we undertook an epidemiological study in 52 mothers of individuals with WBS. In this study, our WBS patients initially served as a control group to his holoprosencephaly (HPE) cohort, identifying environmental influences that predicted HPE manifestations in at risk individuals. We then secondarily analyzed the WBS data looking for differences pre- and perinatal exposures. We again found a signal for the immune system in the form of maternal allergy. At this time, it is unclear whether this represents an effect of an activated maternal immune system or reflects that the child is at higher genetic risk by nature of being born to an affected mother. We are following up several aspects of this initial preliminary finding. Taken together, these three complimentary projects will allow us to identify important pathways that interact with elastin insufficiency to alter disease severity. The identification of modifier pathways may direct us to novel therapies to improve vascular health. Because elastin concentration decreases with age, the lessons learned from these rare disease patients have the potential to provide information regarding genes and pathways that impact blood vessels in aging individuals.
| Kopp, Nathan D; Parrish, Phoebe C R; Lugo, Michael et al. (2018) Exome sequencing of 85 Williams-Beuren syndrome cases rules out coding variation as a major contributor to remaining variance in social behavior. Mol Genet Genomic Med 6:749-765 |
| Duque Lasio, Maria Laura; Kozel, Beth A (2018) Elastin-driven genetic diseases. Matrix Biol : |
| Baldridge, Dustin; Heeley, Jennifer; Vineyard, Marisa et al. (2017) The Exome Clinic and the role of medical genetics expertise in the interpretation of exome sequencing results. Genet Med 19:1040-1048 |
