Background and Aims:
Hereditary haemochromatosis (HHC) is an autosomal recessive disorder of iron metabolism; the most common genetic mutation underlying this condition is a Cys282Tyr (C282Y) substitution in the HFE gene. However, there is considerable phenotypic variability in the clinical presentation of this disorder most likely representing the effects of additional disease modifier genes. Carriage of rs236918 in Proprotein Convertase Subtilisin/Kexin type 7 (PCSK7) has been identified as a risk factor for the development of cirrhosis in C282Y homozygotes; recently rs738409 in Patatin-like Phospholipase Domain-containing 3 (PNPLA3); rs58542926 in Transmembrane 6 Superfamily Member 2 (TM6SF2) and rs641738 in Membrane Bound O-Acyltransferase Domain-Containing 7 (MBOAT7) have been identified as risk variants for the development of cirrhosis in people misusing alcohol and those with non-alcoholic fatty liver disease (NAFLD); it is not known if these genetic variants modulate cirrhosis risk in C282Y homozygotes. The aim of this study was to determine whether the development of significant liver damage in C282Y homozygotes is associated with carriage of variants in PNPLA3, TM6SF2, MBOAT7 and PCSK7.
Methods:
The study involved 1266 C282Y homozygotes recruited from centres in Italy (n = 166), Austria (n = 399), Germany (n = 101), Switzerland (n = 69), England (n = 150) and Ireland (n = 381); none had evidence of other potential causes of chronic liver disease. Of these, 182 had confirmed cirrhosis and were classified as cases while the remaining 1084 had no evident liver disease and were classified as controls. Allelic association analysis for each of the genetic variants was undertaken in the individual subpopulations using a logistic regression model conditioning on age and sex. A meta-analysis of the data from the six individual constituent cohorts was performed.
Results:
The overall incidence of cirrhosis was 14.4% (range 8.3 – 39.1%). Significant associations were observed between PCSK7 rs236918 (OR 1.62; 95% [CI 1.29 – 1.94], P = 0.0040; I2= 23.51), PNPLA3 rs738409 (OR 1.55; 95% [CI 1.31 – 1.78], P = 0.00035; I2= 56.95) and TM6SF2 rs58542926 (OR 1.66; 95% [CI 1.29 – 2.02], P = 0.0063; I2= 25.94) and the risk for developing cirrhosis; there was no association with MBOAT7 rs641738 (OR 1.11; 95% [CI 0.88 – 1.34], P = 0.37; I2= 2.84).
Conclusion:
This study confirms the association of PCSK7 rs236918 and the risk for developing cirrhosis in C282Y homozygotes, and further identifies PNPLA3 rs738409 and TM6SF2 rs58542926 as additional risk loci for this association. The latter are novel findings and indicate similarities in the pathophysiology of HHC progression and that of alcohol- and NAFLD-related liver disease.
