Lucas Mitchell R, Pilling Luke C, Atkins Janice L, Melzer David
Epidemiology and Public Health Group, Department of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, UK.
Hepatology. 2025 May 1;81(5):1522-1534. doi: 10.1097/HEP.0000000000001056. Epub 2024 Aug 23.
The HFE p.C282Y+/+ (homozygous) genotype and central adiposity both increase liver disease and diabetes risks, but the 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.
Baseline WHR data available in 1297 male and 1602 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 ( p = 7.7 × 10 -11 ), and type 2 diabetes ( p = 5.1 × 10 -16 ). The hazard ratio for high WHR in p.C282Y+/+ males (≥0.96; 33.9%) was 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 (hazard ratio = 9.17, 95% CI: 2.51-33.50, p = 3.8 × 10 -7 ) and Non-alcoholic fatty liver disease (hazard ratio = 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.
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.
HFE基因p.C282Y+/+（纯合子）基因型和中心性肥胖均会增加肝病和糖尿病风险，但二者的联合作用尚不清楚。我们在英国生物银行社区队列中，估计了p.C282Y+/+参与者日常护理中腰臀比（WHR）与临床结局的关联。
1297名男性和1602名女性p.C282Y+/+参与者有基线WHR数据，平均随访13.3年以进行诊断。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校正。累积发病率为40至80岁。在p.C282Y+/+男性中，医院住院诊断的肝纤维化/肝硬化（p = 2.4×10⁻⁵）、肝癌（p = 0.007）、非酒精性脂肪性肝病（p = 7.7×10⁻¹¹）和2型糖尿病（p = 5.1×10⁻¹⁶）与WHR呈正线性关系。p.C282Y+/+男性中高WHR（≥0.96；33.9%）者肝纤维化/肝硬化的风险比为4.13（95%CI：2.04 - 8.39，p = 8.4×10⁻⁵，与正常WHR相比）；80岁时的累积发病率为15.0%（95%CI：9.8% - 22.6%），而正常WHR者为3.9%（95%CI：1.9% - 7.6%）；肝癌的累积发病率分别为9.2%（95%CI：5.7% - 14.6%）和3.6%（95%CI：1.9% - 6.6%）。24名发生纤维化/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。p.C282Y+/+女性中高WHR（≥0.85；30.0%）者肝纤维化/肝硬化（风险比 = 9.17，95%CI：2.51 - 33.50，p = 3.8×10⁻⁷）和非酒精性脂肪性肝病（风险比 = 5.17，95%CI：2.48 - 10.78，p = 1.2×10⁻⁵）的风险增加。在有额外初级保健诊断的亚组中，纤维化/肝硬化的关联相似。
在p.C282Y+/+男性和女性中，WHR升高与肝脏并发症风险大幅增加相关。应测试降低中心性肥胖以改善这些结局的干预措施。
