前列腺癌（PCa）是非洲男性的重大健康负担，其死亡率是全球平均水平的两倍多。与不良患者预后相关的前列腺特异性 Anoctamin 7 (ANO7) 基因最近被确定为非洲特异性蛋白质截短 PCa 风险等位基因的靶标。我们在一项针对 889 名南部非洲男性的研究中确定了 ANO7 的作用，利用外显子基因分型阵列 PCa 病例对照数据（n = 780，17 个 ANO7 等位基因）和深度测序全基因组数据进行种系和肿瘤 ANO7 询问（n = 109），同时提供临床病理学匹配的欧洲衍生序列数据比较分析（n = 57）。使用计算蛋白质结构分析进一步评估相关预测有害变异 (PDV) 的影响。在欧洲患者中尤其罕见，我们在病例对照分析 (Wilcoxon) 中发现常见的非洲 PDV p.Ile740Leu (rs74804606) 与 PCa 风险相关秩和检验，错误发现率/FDR = 0.03），而测序显示与最近报道的非洲特有的有害风险变异 p.Ser914* (rs60985508) 共现。其他发现包括新型蛋白质截短的非洲特异性移码变体 p.Asp789Leu、与 Ca2 结合位点蛋白质结构改变相关的非洲相关 PDV、与非洲人 PDV 和种系结构变异相关的早发性 PCa（线性回归模型，- 6.42 年，95% CI = -10.68 至 -2.16，P 值 = 0.003）和 ANO7 作为非洲来源肿瘤中染色体间 PCa 相关基因融合伴侣。在这里，我们不仅验证 ANO7 作为非洲相关基因蛋白质改变 PCa 风险位点，但有更多证据证明遗传性和后天性 ANO7 变异在观察到的表型异质性和非洲祖先健康差异中的作用。© 2023。Crown。

Prostate cancer (PCa) is a significant health burden for African men, with mortality rates more than double global averages. The prostate specific Anoctamin 7 (ANO7) gene linked with poor patient outcomes has recently been identified as the target for an African-specific protein-truncating PCa-risk allele.Here we determined the role of ANO7 in a study of 889 men from southern Africa, leveraging exomic genotyping array PCa case-control data (n = 780, 17 ANO7 alleles) and deep sequenced whole genome data for germline and tumour ANO7 interrogation (n = 109), while providing clinicopathologically matched European-derived sequence data comparative analyses (n = 57). Associated predicted deleterious variants (PDVs) were further assessed for impact using computational protein structure analysis.Notably rare in European patients, we found the common African PDV p.Ile740Leu (rs74804606) to be associated with PCa risk in our case-control analysis (Wilcoxon rank-sum test, false discovery rate/FDR = 0.03), while sequencing revealed co-occurrence with the recently reported African-specific deleterious risk variant p.Ser914* (rs60985508). Additional findings included a novel protein-truncating African-specific frameshift variant p.Asp789Leu, African-relevant PDVs associated with altered protein structure at Ca2+ binding sites, early-onset PCa associated with PDVs and germline structural variants in Africans (Linear regression models, -6.42 years, 95% CI = -10.68 to -2.16, P-value = 0.003) and ANO7 as an inter-chromosomal PCa-related gene fusion partner in African derived tumours.Here we provide not only validation for ANO7 as an African-relevant protein-altering PCa-risk locus, but additional evidence for a role of inherited and acquired ANO7 variance in the observed phenotypic heterogeneity and African-ancestral health disparity.© 2023. Crown.