Coding mutations in the Transthyretin (TTR) gene cause a hereditary form of amyloidosis characterized by a complex genotype-phenotype correlation with limited information regarding differences among worldwide populations. We compared 676 diverse individuals carrying TTR amyloidogenic mutations (rs138065384, Phe44Leu; rs730881165, Ala81Thr; rs121918074, His90Asn; rs76992529, Val122Ile) to 12,430 non-carriers matched by age, sex, and genetically-inferred ancestry to assess their clinical presentations across 1,693 outcomes derived from electronic health records in UK biobank. In individuals of African descent (AFR), Val122Ile mutation was linked to multiple outcomes related to the circulatory system (fold-enrichment = 2.96, p = 0.002) with the strongest associations being cardiac congenital anomalies (phecode 747.1, p = 0.003), endocarditis (phecode 420.3, p = 0.006), and cardiomyopathy (phecode 425, p = 0.007). In individuals of Central-South Asian descent (CSA), His90Asn mutation was associated with dermatologic outcomes (fold-enrichment = 28, p = 0.001). The same TTR mutation was linked to neoplasms in European-descent individuals (EUR, fold-enrichment = 3.09, p = 0.003). In EUR, Ala81Thr showed multiple associations with respiratory outcomes related (fold-enrichment = 3.61, p = 0.002), but the strongest association was with atrioventricular block (phecode 426.2, p = 2.81 × 10− 4). Additionally, the same mutation in East Asians (EAS) showed associations with endocrine-metabolic traits (fold-enrichment = 4.47, p = 0.003). In the cross-ancestry meta-analysis, Val122Ile mutation was associated with peripheral nerve disorders (phecode 351, p = 0.004) in addition to cardiac congenital anomalies (fold-enrichment = 6.94, p = 0.003). Overall, these findings highlight that TTR amyloidogenic mutations present ancestry-specific and ancestry-convergent associations related to a range of health domains. This supports the need to increase awareness regarding the range of outcomes associated with TTR mutations across worldwide populations to reduce misdiagnosis and delayed diagnosis of TTR-related amyloidosis.

中文翻译：

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不同人群来源中运甲状腺素蛋白淀粉样变性突变的临床谱

甲状腺素运载蛋白 (TTR) 基因的编码突变会导致遗传性淀粉样变性，其特征是复杂的基因型-表型相关性，而有关全球人群差异的信息有限。我们将 676 名携带 TTR 淀粉样变突变（rs138065384、Phe44Leu；rs730881165、Ala81Thr；rs121918074、His90Asn；rs76992529、Val122Ile）的不同个体与 12,430 名年龄、性别和遗传推断血统相匹配的非携带者进行比较，以评估他们的临床表现涵盖 1,693 个结果来自英国生物银行的电子健康记录。在非洲人后裔 (AFR) 个体中，Val122Ile 突变与循环系统相关的多种结果相关（富集倍数 = 2.96，p = 0.002），其中最强的关联是心脏先天性异常（phecode 747.1，p = 0.003）、心内膜炎（phecode 420.3，p = 0.006）和心肌病（phecode 425，p = 0.007）。在中南亚血统 (CSA) 个体中，His90Asn 突变与皮肤病学结果相关（富集倍数 = 28，p = 0.001）。相同的 TTR 突变与欧洲血统个体的肿瘤相关（EUR，富集倍数 = 3.09，p = 0.003）。在 EUR 中，Ala81Thr 显示与呼吸结局相关的多种关联（富集倍数 = 3.61，p = 0.002），但最强的关联是与房室传导阻滞（phecode 426.2，p = 2.81 × 10−4）。此外，东亚人 (EAS) 中的相同突变显示与内分泌代谢特征相关（富集倍数 = 4.47，p = 0.003）。在跨祖先荟萃分析中，Val122Ile 突变除了与先天性心脏异常（富集倍数 = 6.94，p = 0.003）外，还与周围神经疾病（phecode 351，p = 0.004）相关。总体而言，这些发现强调 TTR 淀粉样蛋白生成突变呈现与一系列健康领域相关的祖先特异性和祖先趋同关联。这支持需要提高对全球人群中与 TTR 突变相关的一系列结果的认识，以减少 TTR 相关淀粉样变性的误诊和延迟诊断。