University of California, San Francisco.
Vanderbilt University Medical Center, Nashville, Tenn.
Am J Med. 2021 Feb;134(2):e98-e100. doi: 10.1016/j.amjmed.2020.06.031. Epub 2020 Aug 28.
Transthyretin (TTR) gene mutations are the most common cause of hereditary amyloidosis. Valine replaced by isoleucine in position 122 (V122I) variant is common, particularly in the black population. Carriers of V122I have increased risk for developing cardiac amyloidosis. Despite a relatively high prevalence, the penetrance of V122I is not firmly established. This study sought to determine the prevalence of clinically apparent cardiac amyloidosis among carriers of the TTR V122I variant.
BioVU, a Vanderbilt University resource linking DNA samples and pre-existing genetic data to de-identified electronic medical records was used to identify TTR V122I mutation carriers. Automated billing code queries (International Classification of Diseases, 9th revision codes), problem list searches, and manual chart reviews were used to identify subjects with clinically diagnosed cardiac amyloidosis.
Among 28,429 subjects with available genotype data, 129 were V122I carriers. Carriers had a median age of 42 years (interquartile range 16-64). Noncarriers had a median age of 62 years, (interquartile range 41-77). The carrier rate was 3.7% in blacks and 0.02% in whites. Overall, the prevalence of clinically apparent cardiac amyloidosis was 0.8% in carriers and 0.04% in noncarriers (P = .05). Above age 60, the prevalence of cardiac amyloidosis was 2.6% in carriers and 0.06% in noncarriers (P = .03).
Carriers of the TTR V122I variant are at a higher risk for development of cardiac amyloidosis, particularly at age>60 years. However, clinically apparent cardiac amyloidosis in this population was uncommon. These results support that the penetrance of TTR V122I is age dependent and suggest it may be significantly lower than previously reported.
转甲状腺素蛋白（TTR）基因突变是遗传性淀粉样变性最常见的原因。第 122 位缬氨酸被异亮氨酸取代（V122I）的变异很常见，尤其是在黑人群体中。携带 V122I 的人患心脏淀粉样变性的风险增加。尽管 V122I 的患病率相对较高，但 V122I 的外显率尚未确定。本研究旨在确定 TTR V122I 变体携带者中临床明显心脏淀粉样变性的患病率。
Vanderbilt 大学的 BioVU 资源将 DNA 样本和预先存在的遗传数据与去识别的电子病历相关联，用于识别 TTR V122I 突变携带者。使用自动计费代码查询（国际疾病分类，第 9 版代码）、问题列表搜索和手动图表审查来识别临床诊断为心脏淀粉样变性的患者。
在 28429 名有可用基因型数据的受试者中，有 129 名是 V122I 携带者。携带者的中位年龄为 42 岁（四分位距 16-64）。非携带者的中位年龄为 62 岁（四分位距 41-77）。黑人的携带者率为 3.7%，白人的携带者率为 0.02%。总体而言，携带者中临床明显心脏淀粉样变性的患病率为 0.8%，非携带者中为 0.04%（P=0.05）。60 岁以上，携带者中心脏淀粉样变性的患病率为 2.6%，非携带者中为 0.06%（P=0.03）。
携带 TTR V122I 变体的个体发生心脏淀粉样变性的风险更高，尤其是年龄>60 岁的个体。然而，在该人群中，临床明显的心脏淀粉样变性并不常见。这些结果支持 TTR V122I 的外显率是年龄依赖性的，并表明其可能明显低于先前的报告。
