The genetic contribution of the X chromosome in age-related hearing loss.

Age-related (AR) hearing loss (HL) is the most common sensory impairment with heritability of 55%. The aim of this study was to identify genetic variants on chromosome X associated with ARHL through the analysis of data obtained from the UK Biobank. We performed association analysis between self-reported measures of HL and genotyped and imputed variants on chromosome X from ∼460,000 white Europeans. We identified three loci associated with ARHL with a genome-wide significance level (p < 5 × 10-8), ZNF185 (rs186256023, p = 4.9 × 10-10) and MAP7D2 (rs4370706, p = 2.3 × 10-8) in combined analysis of males and females, and LOC101928437 (rs138497700, p = 8.9 × 10-9) in the sex-stratified analysis of males. In-silico mRNA expression analysis showed MAP7D2 and ZNF185 are expressed in mice and adult human inner ear tissues, particularly in the inner hair cells. We estimated that only a small amount of variation of ARHL, 0.4%, is explained by variants on the X chromosome. This study suggests that although there are likely a few genes contributing to ARHL on the X chromosome, the role that the X chromosome plays in the etiology of ARHL may be limited.

MAP7D2 reduces CD8+ cytotoxic T lymphocyte infiltration through MYH9-HMGB1 axis in colorectal cancer.

Immune checkpoint inhibitors (ICIs) represent a new paradigm in cancer immunotherapy, but can be largely restricted by the limited presence of CD8+ cytotoxic T lymphocytes (CTLs) in colorectal cancer (CRC) patients with microsatellite stable (MSS) tumors. Here, through next-generation sequencing, we identify microtubule-associated protein 7 domain 2 (MAP7D2) as an exploitable therapeutic maneuver to improve the efficacy of ICIs for MSS CRC therapy. In human CRC tissues, MAP7D2 expression is significantly increased in MSS CRC, and MAP7D2 adversely correlates with the presence of antitumor T lymphocytes. In vitro and in vivo experiments demonstrate that MAP7D2 knockdown significantly increases the infiltration of CD8+ CTLs, thereby inhibiting tumor progression and improving the efficacy of ICIs in MSS CRC murine models. Mechanistically, MAP7D2 interacts with MYH9 and protects it from ubiquitin-mediated degradation, subsequently decreasing the secretion of HMGB1, which suppresses the infiltration of CD8+ CTLs in MSS CRC. These findings highlight the importance of MAP7D2 in determining the infiltration of CD8+ CTLs and indicate that targeting MAP7D2 in MSS CRC may present a novel antitumor immunotherapy.