Abstract Purpose Anti-PIT-1 hypophysitis is a rare T cell-mediated autoimmune pituitary disorder presenting as a paraneoplastic syndrome or after immune checkpoint inhibitor (ICI) therapy, and its predominance in Japan suggests an underlying genetic predisposition. The NLR family CARD domain containing 5 ( NLRC5 ) encodes a key transcriptional regulator of major histocompatibility complex (MHC) class I, and its p.Pro191Leu missense variant is associated with ICI-related endocrinopathies and enhanced interferon-γ responses. Therefore, we examined whether NLRC5 p.Pro191Leu is enriched in anti-PIT-1 hypophysitis. Methods We genotyped the NLRC5 p.Pro191Leu variant (c.572 C > T) in seven Japanese individuals with anti-PIT-1 hypophysitis for whom genomic DNA was available. The carrier frequency observed in this cohort was compared with ancestry-matched expectations from the Tohoku Medical Megabank 61KJPN Japanese reference panel using a prespecified one-sided exact binomial test. Sensitivity analyses included Mid- P adjustment, risk differences, and risk ratios. Results Among seven genotyped Japanese individuals with anti-PIT-1 hypophysitis, five (71.4%) were carriers, exceeding the expected ancestry-matched frequency from the Japanese reference panel (expected carrier frequency 37.7%; exact p = 0.076; mid- P = 0.045). The effect sizes were risk difference + 0.337 and risk ratio 1.89. Conclusion This study provides suggestive evidence that the NLRC5 p.Pro191Leu variant may confer genetic susceptibility to anti-PIT-1 hypophysitis in the Japanese population, based on its enrichment relative to ancestry-matched reference panels. These findings, together with NLRC5’s role as the master regulator of MHC class I expression, propose a novel and testable pathogenic model.
Urai et al. (Tue,) studied this question.