Background: We used a naturally occurring germ-line genetic variant in tyrosine kinase 2 ( TYK2 [P1104A, rs34536443]), which has been shown to cause partial loss of function and protect against autoimmune disease, ¹ to survey the phenotypic consequences of reduced TYK2 function.

Objectives: Survey the phenotypic consequences of a naturally occurring partial loss of TYK2 function, and directly test for an effect of naturally occurring TYK2 partial loss of function on risk of cardiovascular disease, thromboembolism, and lymphoma.

Methods: We performed phenome-wide association studies (PheWAS) in 2 large biobanks (FinnGen and UK Biobank) and across public case-control genetic studies using Open Targets Genetics.

Results: This study found additional support for a protective effect (odds ratio [OR] ≤0.8, P <1x10 ^-4 ) of TYK2 partial loss of function in multiple autoimmune diseases, including rheumatoid arthritis, psoriasis, psoriatic arthritis, systemic lupus erythematosus, sarcoidosis, type 1 diabetes, inflammatory bowel disease, and hypothyroidism. We did not observe any novel phenotypic associations that could highlight safety concerns for TYK2 inhibition. Additionally, we used well-powered and focused analyses to demonstrate that TYK2 partial loss of function is not associated with nonselective Janus kinase inhibitor safety concerns in any of the genetic studies. Our meta-analysis across the included studies showed no association with increased risk of cardiovascular disease (OR=0.97; P =0.02; 258,279 cases / 549,387 controls), venous thromboembolism (OR=0.97; P =0.52; 11,966 cases / 260,704 controls), and lymphoma (OR=1.06; P =0.47; 2687 cases / 220,721 controls).

Conclusion: TYK2 P1104A, a partial loss-of-function polymorphism, enables assessment of TYK2 involvement in immune-mediated disease and other pathologies. Loss of function in TYK2 reduces risk of immune-mediated disease but does not significantly increase risk of cardiovascular disease, thromboembolism, or lymphoma.

REFERENCES:

[1]Dendrou CA et al. Sci Transl Med 2016;8(363):363ra149.

Acknowledgements: This study was sponsored by Bristol Myers Squibb. Editorial assistance was provided by Julianne Hatfield, PhD, of Peloton Advantage, LLC, an OPEN Health company, and was funded by Bristol Myers Squibb.

Disclosure of Interests: Narayanan Raghupathy Shareholder of: employee and shareholder of Bristol Myers Squibb, Employee of: employee and shareholder of Bristol Myers Squibb, Erika Kvikstad Shareholder of: employee and shareholder of Bristol Myers Squibb, Employee of: employee and shareholder of Bristol Myers Squibb, Emily Holzinger Shareholder of: employee and shareholder of Bristol Myers Squibb, Employee of: employee and shareholder of Bristol Myers Squibb, Ian Catlett Shareholder of: employee and shareholder of Bristol Myers Squibb, Employee of: employee and shareholder of Bristol Myers Squibb, Joseph Maranville Shareholder of: employee and shareholder of Bristol Myers Squibb, Employee of: employee and shareholder of Bristol Myers Squibb