Background & Aims: The HFE p.C282Y+/+ (homozygous) genotype and central adiposity both increase liver disease and diabetes risks, but combined effects are unclear. We estimated waist-to-hip ratio (WHR) associations with incident clinical outcomes in routine care in p.C282Y+/+ participants in the UK Biobank community cohort. Approach & Results: Baseline WHR in 1,297 male and 1,602 female p.C282Y+/+ with 13.3-year mean follow-up for diagnoses. Spline regressions and Cox proportional hazard models were adjusted for age and genetic principal components. Cumulative incidence was from age 40 to 80 years. In p.C282Y+/+ males, there were positive linear WHR relationships for hospital inpatient diagnosed liver fibrosis/cirrhosis (p=2.4*10−5), liver cancer (p=0.007), non-alcoholic fatty liver disease (NAFLD) (p=7.7*10−11), and type 2 diabetes (T2D) (p=5.1*10−16). The Hazard Ratio (HR) for high WHR in p.C282Y+/+ males (≥0.96; 33.9%) was HR=4.13 for liver fibrosis/cirrhosis (95%CI: 2.04-8.39, p=8.4*10−5 vs. normal WHR); cumulative age 80 incidence 15.0% (95%CI: 9.8%-22.6%) versus 3.9% (95%CI: 1.9%-7.6%); for liver cancer, cumulative incidence was 9.2% (95%CI: 5.7%-14.6%) versus 3.6% (95%CI: 1.9%-6.6%). Hemochromatosis was diagnosed in 23 (96%) of the 24 high WHR p.C282Y+/+ males with incident fibrosis/cirrhosis. High WHR (≥0.85; 30.0%) p.C282Y+/+ females had raised hazards for liver fibrosis/cirrhosis (HR=9.17, 95%CI: 2.51-33.50, p=3.8*10−7) and NAFLD (HR=5.17, 95%CI: 2.48-10.78, p=1.2*10−5). Fibrosis/cirrhosis associations were similar in the subset with additional primary care diagnoses. Conclusion: In p.C282Y+/+ males and females, increasing WHR is associated with substantially higher risks of liver complications. Interventions to reduce central adiposity to improve these outcomes should be tested.

中文翻译：

---

与血色素沉着病相关的 HFE p.C282Y 纯合性肝脏并发症的发生率：中心性肥胖的作用


背景和目的：HFE p.C282Y+/+（纯合）基因型和中心性肥胖都会增加肝病和糖尿病的风险，但综合影响尚不清楚。我们估计了英国生物银行社区队列中 p.C282Y+/+ 参与者的腰臀比 (WHR) 与常规护理中事件临床结果的关联。方法和结果：1,297 名男性和 1,602 名女性 p.C282Y+/+ 的基线腰臀比，诊断平均随访时间为 13.3 年。样条回归和 Cox 比例风险模型根据年龄和遗传主成分进行了调整。累积发病年龄为40岁至80岁。在 p.C282Y+/+ 男性中，住院患者诊断的肝纤维化/肝硬化 (p=2.4*10−5)、肝癌 (p=0.007)、非酒精性脂肪肝 (NAFLD) 之间存在正线性 WHR 关系（ p=7.7*10−11) 和 2 型糖尿病 (T2D) (p=5.1*10−16)。 p.C282Y+/+ 男性（≥0.96；33.9%）高 WHR 的肝纤维化/肝硬化风险比（HR）为 HR=4.13（95%CI：2.04-8.39，p=8.4*10−5 vs.正常腰臀比）； 80 岁累计发病率为 15.0% (95%CI: 9.8%-22.6%) 对比 3.9% (95%CI: 1.9%-7.6%)；肝癌的累积发病率为 9.2% (95%CI: 5.7%-14.6%) 和 3.6% (95%CI: 1.9%-6.6%)。 24 名患有纤维化/肝硬化的高 WHR p.C282Y+/+ 男性中，有 23 名 (96%) 被诊断为血色素沉着症。高腰臀比 (≥0.85; 30.0%) p.C282Y+/+ 女性增加了肝纤维化/肝硬化 (HR=9.17, 95%CI: 2.51-33.50, p=3.8*10−7) 和 NAFLD (HR=5.17) 的风险，95%CI：2.48-10.78，p=1.2*10−5）。在具有额外初级保健诊断的子集中，纤维化/肝硬化关联相似。结论：在 p.C282Y+/+ 男性和女性中，腰臀比增加与肝脏并发症的风险显着升高相关。 应测试减少中心性肥胖以改善这些结果的干预措施。