TY - JOUR
T1 - A rare genetic variant in the manganese transporter SLC30A10 and elevated liver enzymes in the general population
AU - Seidelin, Anne Sofie
AU - Nordestgaard, Børge Grønne
AU - Tybjærg-Hansen, Anne
AU - Yaghootkar, Hanieh
AU - Stender, Stefan
N1 - Funding Information:
We thank the staff and participants of the UKB, CGPS, and CCHS. This research has been conducted using the UK Biobank Resource (application identifiers 9914 and 15825). We thank Per Bo Jensen for help with the ICP-MS analyses of manganese.
Funding Information:
This work was supported by Independent Research Fund Denmark and the Research Fund at Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. Stefan Stender is supported by a Sapere Aude Research Leader grant from Independent Research Fund Denmark (9060-00012B). Hanieh Yaghootkar is funded by Diabetes UK RD Lawrence fellowship (grant: 17/0005594). The funding organizations had no role in any of the following: design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript.
PY - 2022
Y1 - 2022
N2 - Background: A genetic variant in the manganese transporter SLC30A10 (rs188273166, p.Thr95Ile) was associated with increased plasma alanine transaminase (ALT) in a recent genome-wide association study in the UK Biobank (UKB). The aims of the present study were to test the association of rs188273166 with ALT in an independent cohort, and to begin to assess the clinical, hepatic, and biochemical phenotypes associated with the variant. Methods: We included n = 334,886 white participants from UKB, including 14,462 with hepatic magnetic resonance imaging (MRI), and n = 113,612 individuals from the Copenhagen City Heart Study and the Copenhagen General Population Study combined. Results: Genotyping SLC30A10 p.Thr95Ile identified 816 heterozygotes in the UKB and 111 heterozygotes in the Copenhagen cohort. Compared to noncarriers, heterozygotes had 4 and 5 U/L higher levels of ALT in the UKB and Copenhagen cohort, respectively, and 3 U/L higher plasma aspartate transaminase and gamma-glutamyl transferase in the UKB. Heterozygotes also had higher corrected T1 on liver MRI, a marker of hepatic inflammation (p = 4 × 10–7), but no change in MRI-quantified steatosis (p = 0.57). Plasma manganese was within the normal range in nine heterozygotes that provided new blood samples. SLC30A10 p.Thr95Ile heterozygotes had an eightfold increased risk of biliary tract cancer in UKB (p = 4 × 10–7), but this association was not replicated in the Copenhagen cohort. Conclusions: SLC30A10 p.Thr95Ile was associated with elevated liver enzymes in two large general population cohorts, and with MRI-quantified hepatic inflammation. Graphical abstract: A rare genetic variant (p.Thr95Ile) in the manganese transporter SLC30A10 is associated with elevated plasma alanine transaminase (ALT) and higher corrected T1 on liver MRI, markers of liver inflammation. These data support that the variant may increase the risk of liver disease. [Figure not available: see fulltext.]
AB - Background: A genetic variant in the manganese transporter SLC30A10 (rs188273166, p.Thr95Ile) was associated with increased plasma alanine transaminase (ALT) in a recent genome-wide association study in the UK Biobank (UKB). The aims of the present study were to test the association of rs188273166 with ALT in an independent cohort, and to begin to assess the clinical, hepatic, and biochemical phenotypes associated with the variant. Methods: We included n = 334,886 white participants from UKB, including 14,462 with hepatic magnetic resonance imaging (MRI), and n = 113,612 individuals from the Copenhagen City Heart Study and the Copenhagen General Population Study combined. Results: Genotyping SLC30A10 p.Thr95Ile identified 816 heterozygotes in the UKB and 111 heterozygotes in the Copenhagen cohort. Compared to noncarriers, heterozygotes had 4 and 5 U/L higher levels of ALT in the UKB and Copenhagen cohort, respectively, and 3 U/L higher plasma aspartate transaminase and gamma-glutamyl transferase in the UKB. Heterozygotes also had higher corrected T1 on liver MRI, a marker of hepatic inflammation (p = 4 × 10–7), but no change in MRI-quantified steatosis (p = 0.57). Plasma manganese was within the normal range in nine heterozygotes that provided new blood samples. SLC30A10 p.Thr95Ile heterozygotes had an eightfold increased risk of biliary tract cancer in UKB (p = 4 × 10–7), but this association was not replicated in the Copenhagen cohort. Conclusions: SLC30A10 p.Thr95Ile was associated with elevated liver enzymes in two large general population cohorts, and with MRI-quantified hepatic inflammation. Graphical abstract: A rare genetic variant (p.Thr95Ile) in the manganese transporter SLC30A10 is associated with elevated plasma alanine transaminase (ALT) and higher corrected T1 on liver MRI, markers of liver inflammation. These data support that the variant may increase the risk of liver disease. [Figure not available: see fulltext.]
KW - Biliary tract cancer
KW - Cholangiocarcinoma
KW - Cirrhosis
KW - Epidemiology
KW - General population
KW - Hypermanganesemia
KW - Magnetic resonance spectroscopy
KW - NAFLD
KW - PNPLA3
KW - UK Biobank
U2 - 10.1007/s12072-022-10331-w
DO - 10.1007/s12072-022-10331-w
M3 - Journal article
C2 - 35397106
AN - SCOPUS:85127726314
VL - 16
SP - 702
EP - 711
JO - Hepatology International
JF - Hepatology International
SN - 1936-0533
IS - 3
ER -