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 -