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@article{Buch:2021:10.1111/apt.16252,
author = {Buch, S and Sharma, A and Ryan, E and Datz, C and Griffiths, WJH and Way, M and Buckley, TWM and Ryan, JD and Stewart, S and Wright, C and Dongiovanni, P and Fracanzani, A and Zwerina, J and Merle, U and Weiss, KH and Aigner, E and Krones, E and Dejaco, C and Fischer, J and Berg, T and Valenti, L and Zoller, H and McQuillin, A and Hampe, J and Stickel, F and Morgan, MY},
doi = {10.1111/apt.16252},
journal = {Aliment Pharmacol Ther},
pages = {830--843},
title = {Variants in PCSK7, PNPLA3 and TM6SF2 are risk factors for the development of cirrhosis in hereditary haemochromatosis.},
url = {http://dx.doi.org/10.1111/apt.16252},
volume = {53},
year = {2021}
}

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TY  - JOUR
AB  - 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.
AU  - Buch,S
AU  - Sharma,A
AU  - Ryan,E
AU  - Datz,C
AU  - Griffiths,WJH
AU  - Way,M
AU  - Buckley,TWM
AU  - Ryan,JD
AU  - Stewart,S
AU  - Wright,C
AU  - Dongiovanni,P
AU  - Fracanzani,A
AU  - Zwerina,J
AU  - Merle,U
AU  - Weiss,KH
AU  - Aigner,E
AU  - Krones,E
AU  - Dejaco,C
AU  - Fischer,J
AU  - Berg,T
AU  - Valenti,L
AU  - Zoller,H
AU  - McQuillin,A
AU  - Hampe,J
AU  - Stickel,F
AU  - Morgan,MY
DO  - 10.1111/apt.16252
EP  - 843
PY  - 2021///
SP  - 830
TI  - Variants in PCSK7, PNPLA3 and TM6SF2 are risk factors for the development of cirrhosis in hereditary haemochromatosis.
T2  - Aliment Pharmacol Ther
UR  - http://dx.doi.org/10.1111/apt.16252
UR  - https://www.ncbi.nlm.nih.gov/pubmed/33565643
VL  - 53
ER  -

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