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. 2021 Apr;53(7):830-843.
doi: 10.1111/apt.16252. Epub 2021 Feb 10.

Variants in PCSK7, PNPLA3 and TM6SF2 are risk factors for the development of cirrhosis in hereditary haemochromatosis

Stephan Buch  1 , Aneesh Sharma  2 , Eleanor Ryan  3 , Christian Datz  4 , William J H Griffiths  5 , Michael Way  2 , Thomas W M Buckley  2 , John D Ryan  3 , Stephen Stewart  3 , Callum Wright  5 , Paola Dongiovanni  6 , Anna Fracanzani  6 , Jochen Zwerina  7   8 , Uta Merle  9 , Karl Heinz Weiss  9 , Elmar Aigner  4 , Elisabeth Krones  10 , Christian Dejaco  10   11 , Janett Fischer  12 , Thomas Berg  12 , Luca Valenti  6 , Heinz Zoller  13 , Andrew McQuillin  2 , Jochen Hampe  1 , Felix Stickel  14 , Marsha Y Morgan  2
Affiliations

Variants in PCSK7, PNPLA3 and TM6SF2 are risk factors for the development of cirrhosis in hereditary haemochromatosis

Stephan Buch et al. Aliment Pharmacol Ther. 2021 Apr.

Abstract

Background: Cirrhosis develops in <10% of individuals homozygous for the C282Y variant in the homeostatic iron regulator (HFE) gene. Carriage of PCSK7:rs236918 is associated with an increased risk of cirrhosis in this population.

Aim: To determine if genetic variants significantly associated with the risk of alcohol- and NAFLD-related cirrhosis also modulate the cirrhosis risk in C282Y homozygotes.

Methods: Variants in PCSK7, PNPLA3, TM6SF2, MBOAT7 and HSD17B13 were genotyped in 1319 C282Y homozygotes, from six European countries, of whom 171 (13.0%) had cirrhosis. Genotypic and allelic associations with the risk for developing cirrhosis were assessed, adjusting for age and sex. Fixed effects meta-analyses of the adjusted summary data for each country were performed. Post hoc association testing was undertaken in the 131 (76.6%) cases and 299 (26.0%) controls with available liver histology.

Results: Significant associations were observed between PCSK7:rs236918 (OR = 1.52 [95% CI 1.06-2.19]; P = 0.022; I2 = 0%); PNPLA3:rs738409 (OR = 1.60 [95% CI 1.22-2.11]; P = 7.37 × 10-4 ; I2 = 45.5%) and TM6SF2:rs58542926 (OR = 1.94 [95% CI 1.28-2.95]; P = 1.86 × 10-3 ; I2 = 0%) and the cirrhosis risk in C282Y homozygotes. These findings remained significant in the subpopulation with available liver histology. The population-attributable fractions were 5.6% for PCSK7:rs236918, 13.8% for PNPLA3:rs738409, 6.5% for TM6SF2:rs58542926 and 24.0% for carriage of all three variants combined.

Conclusions: The risk of cirrhosis associated with carriage of PCSK7:rs236918 was confirmed in this much larger population of C282Y homozygotes. In addition, PNPLA3:rs738409 and TM6SF2:rs58542926 were established as significant additional risk factors. More detailed genetic testing of C282Y homozygotes would allow risk stratification and help guide future management.

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References

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