Identification of Novel Genetic Variants and Comorbidities Associated With ICD-10-Based Diagnosis of Hypertrophic Cardiomyopathy Using the UK Biobank Cohort.
Identification of Novel Genetic Variants and Comorbidities Associated With ICD-10-Based Diagnosis of Hypertrophic Cardiomyopathy Using the UK Biobank Cohort.
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DOI：
10.3389/fgene.2022.866042
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发表时间：
2022
影响因子：
3.7
通讯作者：
中科院分区：
文献类型：
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作者：
目的：在英国生物银行队列中确定与ICD-10（国际疾病分类10）诊断肥厚性心肌病相关的先前未被识别的遗传变异和临床变量。背景：肥厚性心肌病（HCM）是最常见的遗传性心血管疾病，在编码肌合成蛋白的8个基因中有一个已知有2000多个突变。然而，在疾病表现上有相当大的差异，表明其他未被认识的因素，遗传和其他因素的作用。人们对使用真实世界的数据（如电子健康记录）来更好地了解疾病机制和发现新的治疗策略非常感兴趣，但基于icd -10的诊断是否可用于研究HCM遗传学尚不清楚。方法：在一项使用UK Biobank的全基因组关联研究（GWAS）中，我们分析了363名基于ICD-10编码诊断为HCM的个体的基因组，并在1:20的病例对照设计中与7260名年龄、血统和性别匹配的对照组进行了比较。采用Plink 's第五逻辑回归分析遗传变异，并评估其与HCM的相关性。我们还检查了363例HCM病例和匹配对照的61个生物标志物和其他诊断。结果：在UK Biobank队列中，基于ICD-10诊断HCM的患病率为1 / 1342，表明基于两个ICD-10代码的疾病分配低估了HCM的患病率。此外，与对照组相比，基于icd -10的HCM病例中常见的心血管合并症更为普遍。我们在KMT2C rs78630626和PARD3B rs188937806中发现了与HCM的ICD-10编码相关的两个新的非肉瘤遗传变异，具有全基因组意义（p < 5 x 10−8）。这些与诊断为HCM的优势比（OR）增加约3.8相关。各变异的次要等位基因频率（Minor等位基因frequency， MAF）均为1%。讨论：严格基于ICD-10编码的疾病分配可能低估HCM的患病率。患有HCM的个体更常被诊断为几种合并症，如高血压、动脉粥样硬化性心脏病、糖尿病和肾衰竭，这表明它们可能有助于疾病的表现。这项基于UK Biobank数据库的GWAS发现了与HCM诊断相关的KMT2C和PARD3B的常见变异，这可能代表了新的修饰基因。我们的研究证明了基于ICD-10诊断在大型人群队列中进行HCM表型和基因型表征的可行性和局限性。
Objectives: To identify previously unrecognized genetic variants and clinical variables associated with the ICD-10 (International Classification of Diseases 10)-based diagnosis of hypertrophic cardiomyopathy in the UK Biobank cohort. Background: Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiovascular disorder with more than 2000 known mutations in one of eight genes encoding sarcomeric proteins. However, there is considerable variation in disease manifestation, suggesting the role of additional unrecognized contributors, genetic and otherwise. There is substantial interest in the use of real-world data, such as electronic health records to better understand disease mechanisms and discover new treatment strategies, but whether ICD-10-based diagnosis can be used to study HCM genetics is unknown. Methods: In a genome-wide association study (GWAS) using the UK Biobank, we analyzed the genomes of 363 individuals diagnosed with HCM based on ICD-10 coding compared to 7,260 age, ancestry, and sex-matched controls in a 1:20 case:control design. Genetic variants were analyzed by Plink’s firth logistic regression and assessed for association with HCM. We also examined 61 biomarkers and other diagnoses in the 363 HCM cases and matched controls. Results: The prevalence of ICD-10-based diagnosis of HCM in the UK Biobank cohort was 1 in 1,342, suggesting disease assignment based on the two ICD-10 codes underestimates HCM prevalence. In addition, common cardiovascular comorbidities were more prevalent in ICD-10-based HCM cases in comparison to controls. We identified two novel, non-sarcomeric genetic variants in KMT2C rs78630626, and PARD3B rs188937806 that were associated with ICD-10 codes for HCM with genome-wide significance (p < 5 x 10−8). These are associated with an increased odds ratio (OR) of ∼3.8 for being diagnosed with HCM. Minor allele frequency (MAF) of each variant was >1%. Discussion: Disease assignment based strictly on ICD-10 codes may underestimate HCM prevalence. Individuals with HCM were more frequently diagnosed with several comorbid conditions, such as hypertension, atherosclerotic heart disease, diabetes, and kidney failure, suggesting they may contribute to disease manifestation. This UK Biobank database-based GWAS identified common variants in KMT2C and PARD3B that are associated with HCM diagnosis, which may represent novel modifier genes. Our study demonstrates the feasibility and limitations of conducting phenotypic and genotypic characterization of HCM based on ICD-10 diagnosis in a large population-based cohort.
影响因子：
1.8
作者：
Nabbaale J;Kibirige D;Ssekasanvu E;Sebatta ES;Kayima J;Lwabi P;Kalyesubula R
通讯作者：
Kalyesubula R