P7.81 Adult Onset Alopecia Areata is a Complex Polygenic Trait in the C3H/HeJ Mouse

J.P. Sundberg,^{1, 2} Kathleen Silva,¹ Renhua Li,¹ Gregory A. Cox¹ and Lloyd E. King²

¹The Jackson Laboratory, Bar Harbor, ME, USA and ⁴Vanderbilt University, Nashville, TN, USA

Objectives: The C3H/HeJ mouse develops an adult onset alopecia areata-like (AA) disease that appears to be a complex polygenic trait. Our goal was to map genetic intervals linked to susceptibility to AA.

Methods: An intercross was set up between C3H/HeJ females with AA and C57BL/6J males that do not develop AA. We generated 1096 F2 female mice. DNA was extracted from 138 mice with AA and 214 that were normal. A genome wide screen was done using 219 simple sequence length polymorphic markers by PCR. Saturation mapping of areas with purported linkage was done.

Results: Four statistically significant genetic intervals for susceptibility to Alopecia areata were identified: Alaa1 on Chr. 17 (LOD score 10.346), Alaa2 on Chr. 9 (LOD score 2.139), Alaa3 on Chr. 8 (LOD score 2.411), and Alaa4 on Chr. 15 (LOD score 2.791). Each interval contains numerous immunoregulatory genes, especially Alaa1, which contains the major histocompatibility genes.

Conclusions: Within the more significant genetic interval, Alaa1, are H2, the equivalent of purported human susceptibility HLA genes, lymphotoxin alpha (Lta) and beta (Ltb), genes that regulate the purported human alopecia areata susceptibility autoimmune regulator (AIRE) gene, and Notch4, the homologue of the human alopecia areata susceptibility gene NOTCH4. These results confirm that alopecia areata is a complex polygenic disease and the C3H mouse model is a powerful tool to dissect its genetic basis.