CENTRAL ADIPOSITY AND HAEMOCHROMATOSIS CLINICAL PENETRANCE IN HFE P.C282Y HOMOZYGOTES IN UK BIOBANK

Background: Haemochromatosis, primarily caused by HFE p.C282Y homozygosity (+/+), is associated with similar clinical outcomes to obesity, including liver disease and diabetes. We assessed central adiposity's impact on clinical penetrance in p.C282Y+/+ in a large community cohort.



Methods: We studied 2,899 p.C282Y+/+ UK Biobank participants of European genetic ancestry, with a mean 13.3-year follow-up. Cox models assessed the association between high waist-to-hip ratio (WHR; >=0.96 for men, >=0.85 for women) and risk of incident outcomes, stratified by sex and adjusted for age and genetic components. Cumulative incidence of outcomes was estimated to age 80 years.



Results: Male p.C282Y+/+ with high WHR had greater liver fibrosis/cirrhosis risk compared to normal WHR (HR=4.13, 95%CI: 2.04-8.39, p=8.4*10-5); cumulative incidence to age 80 was 15.00% [95%CI: 9.81-22.57] vs 3.85% [95%CI: 1.93-7.60] in normal WHR, and also liver cancer (HR=2.57, 95%CI: 1.24-5.33, p=1.10*10-2; 9.15% [95%CI: 5.68-14.57] vs 3.57% [95%CI: 1.92-6.58]), non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes.

Female p.C282Y+/+ with high WHR had greater risk and cumulative incidences of liver fibrosis/cirrhosis (HR=9.17, 95%CI: 2.51-33.50, p=3.8x10-7; 4.59% [95%CI: 2.54-8.24] vs 0.58% [95%CI:0.19-1.80]), NAFLD (HR=5.17, 95%CI: 2.48-10.78, p=1.2x10-5), and joint replacement (HR 1.42, 95%CI: 1.03-1.96, p=0.03).

In a model analysing the whole cohort (all HFE genotype groups, n=451,270), there was a significant interaction between having a high WHR and p.C282Y+/+ genotype for risk of all statistically significant outcomes.

 

Conclusion: In p.C282Y+/+ males and females, high WHR strongly predicts clinical penetrance. Interventions to reduce central adiposity should be tested in p.C282Y+/+ to improve associated clinical outcomes.