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Purpose <p>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 (<i>NLRC5</i>) 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.</p> Methods <p>We genotyped the NLRC5 p.Pro191Leu variant (c.572&#xa0;C &gt; 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-<i>P</i> adjustment, risk differences, and risk ratios.</p> Results <p>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 <i>p</i> = 0.076; mid-<i>P</i> = 0.045). The effect sizes were risk difference + 0.337 and risk ratio 1.89.</p> Conclusion <p>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.</p>

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NLRC5 p.Pro191Leu as a genetic susceptibility factor in anti-PIT-1 hypophysitis

  • 期刊论文

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  • 发表日期：

    2026年5月26日

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  • Shin Urai,
  • Hironori Bando,
  • Masaaki Yamamoto,
  • Genzo Iguchi,
  • Yutaka Takahashi

摘要

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.