Human Genetics and Genomics, Division of Biomedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John's, NL, A1B 3V6, Canada.
Discipline of Medicine, Faculty of Medicine, Memorial University of Newfoundland, St. John's, NL, Canada.
BMC Genomics. 2024 Jan 20;25(1):85. doi: 10.1186/s12864-024-10015-9.
Genomic heterozygosity has been shown to confer a health advantage in humans and play a protective role in complex diseases. Given osteoarthritis (OA) is a highly polygenic disease, we set out to determine if an association exists between OA and genomic heterozygosity.
End-stage knee and hip OA patients and healthy controls were recruited from the Newfoundland and Labrador (NL) population. The Arthritis Research UK Osteoarthritis Genetics (arcOGEN) consortium database was utilized as a replication cohort. DNA was extracted from blood samples and genotyped. Individual rates of observed heterozygosity (HetRate) and heterozygosity excess (HetExcess) relative to the expected were mathematically derived, and standardized to a z-score. Logistic regression modeling was used to examine the association between OA and HetRate or HetExcess. A total of 559 knee and hip OA patients (mean age 66.5 years, body mass index (BMI) 33.7 kg/m, and 55% females) and 118 healthy controls (mean age 56.4 years, BMI 29.5 kg/m, and 59% female) were included in the NL cohort analysis. We found that OA had an inverse relationship with HetRate and HetExcess with odds ratios of 0.64 (95% CI: 0.45-0.91) and 0.65 (95% CI: 0.45-0.93) per standard deviation (SD), respectively. The arcOGEN data included 2,019 end-stage knee and hip OA patients and 2,029 healthy controls, validating our findings with HetRate and HetExcess odds ratios of 0.60 (95% CI: 0.56-0.64) and 0.44 (95% CI: 0.40-0.47) per SD, respectively.
Our results are the first to clearly show evidence, from two separate cohorts, that reduced genomic heterozygosity confers a risk for the future development of OA.
已有研究表明，基因组杂合性赋予了人类健康优势，并在复杂疾病中发挥保护作用。鉴于骨关节炎（OA）是一种高度多基因疾病，我们着手确定 OA 是否与基因组杂合性之间存在关联。
从纽芬兰和拉布拉多（NL）人群中招募了终末期膝和髋关节 OA 患者和健康对照者。利用关节炎研究 UK 骨关节炎遗传学（arcOGEN）联盟数据库作为复制队列。从血液样本中提取 DNA 并进行基因分型。通过数学方法得出个体观察到的杂合率（HetRate）和杂合性过剩（HetExcess）与预期值的比值，并标准化为 z 分数。使用逻辑回归模型检查 OA 与 HetRate 或 HetExcess 之间的关联。NL 队列分析共纳入 559 例膝和髋关节 OA 患者（平均年龄 66.5 岁，体重指数（BMI）33.7kg/m，55%为女性）和 118 例健康对照者（平均年龄 56.4 岁，BMI 29.5kg/m，59%为女性）。我们发现 OA 与 HetRate 和 HetExcess 呈负相关，其优势比分别为 0.64（95%可信区间：0.45-0.91）和 0.65（95%可信区间：0.45-0.93）。arcOGEN 数据包含 2019 例终末期膝和髋关节 OA 患者和 2029 例健康对照者，HetRate 和 HetExcess 的优势比分别为 0.60（95%可信区间：0.56-0.64）和 0.44（95%可信区间：0.40-0.47），这验证了我们的研究结果。
我们的研究结果首次明确表明，从两个独立的队列中获得的证据表明，基因组杂合性降低会增加未来发生 OA 的风险。
