Epistatic interactions between Tgfb1 and genetic loci, Tgfbm2 and Tgfbm3, determine susceptibility to an asthmatic stimulus.

ABSTRACT

TGFß activation and signaling have been extensively studied in experimental models of allergen-induced asthma as potential therapeutic targets during chronic or acute phases of the disease. Outcomes of experimental manipulation of TGFß activity have been variable, in part due to use of different model systems. Using an ovalbumin (OVA)-induced mouse model of asthma, we here show that innate variation within TGFß1 genetic modifier loci, Tgfbm2 and Tgfbm3, alters disease susceptibility. Specifically, Tgfbm2(129) and Tgfbm3(C57) synergize to reverse accentuated airway hyperresponsiveness (AHR) caused by low TGFß1 levels in Tgfb1(+/-) mice of the NIH/OlaHsd strain. Moreover, epistatic interaction between Tgfbm2(129) and Tgfbm3(C57) uncouples the inflammatory response to ovalbumin from those of airway remodeling and airway hyperresponsiveness, illustrating independent genetic control of these responses. We conclude that differential inheritance of genetic variants of Tgfbm genes alters biological responses to reduced TGFß1 signaling in an experimental asthma model. TGFß antagonists for treatment of lung diseases might therefore give diverse outcomes, dependent on genetic variation.