Skip to main content

Advertisement

SpringerLink
Log in

A rare genetic variant in the manganese transporter SLC30A10 and elevated liver enzymes in the general population

  • Original Article
  • Published:
Hepatology International Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Abbreviations

CCHS:

Copenhagen City Heart Study

CGPS:

Copenhagen General Population Study

PDFF:

Proton density fat fraction

PNPLA3:

Patatin-like phospholipase domain-containing protein 3

SLC30A10:

Solute Carrier Family 30 Member 10

UKB:

UK Biobank

References

  1. Schwimmer JB, Celedon MA, Lavine JE, Salem R, Campbell N, Schork NJ, et al. Heritability of nonalcoholic fatty liver disease. Gastroenterology. 2009;136(5):1585–1592

    Article  PubMed  Google Scholar 

  2. Loomba R, Schork N, Chen CH, Bettencourt R, Bhatt A, Ang B, et al. Heritability of hepatic fibrosis and steatosis based on a prospective twin study. Gastroenterology. 2015;149(7):1784–1793

    Article  PubMed  Google Scholar 

  3. Jamialahmadi O, Mancina RM, Ciociola E, Tavaglione F, Luukkonen PK, Baselli G, et al. Exome-wide association study on alanine aminotransferase identifies sequence variants in the GPAM and APOE associated with fatty liver disease. Gastroenterology. 2021;160:1634–1646

    Article  CAS  PubMed  Google Scholar 

  4. Parisinos CA, Wilman HR, Thomas EL, Kelly M, Nicholls RC, McGonigle J, et al. Genome-wide and Mendelian randomisation studies of liver MRI yield insights into the pathogenesis of steatohepatitis. J Hepatol. 2020;73(2):241–251

    Article  CAS  PubMed  Google Scholar 

  5. Emdin CA, Haas M, Ajmera V, Simon TG, Homburger J, Neben C, et al. Association of genetic variation with cirrhosis: a multi-trait genome-wide association and gene-environment interaction study. Gastroenterology. 2020;160:1620-1633.e13

    Article  PubMed  Google Scholar 

  6. Anstee QM, Darlay R, Cockell S, Meroni M, Govaere O, Tiniakos D, et al. Genome-wide association study of non-alcoholic fatty liver and steatohepatitis in a histologically characterised cohort. J Hepatol. 2020;73(3):505–515

    Article  CAS  PubMed  Google Scholar 

  7. Abul-Husn NS, Cheng X, Li AH, Xin Y, Schurmann C, Stevis P, et al. A protein-truncating HSD17B13 variant and protection from chronic liver disease. N Engl J Med. 2018;378(12):1096–1106

    Article  CAS  PubMed  Google Scholar 

  8. Buch S, Stickel F, Trepo E, Way M, Herrmann A, Nischalke HD, et al. A genome-wide association study confirms PNPLA3 and identifies TM6SF2 and MBOAT7 as risk loci for alcohol-related cirrhosis. Nat Genet. 2015;47(12):1443–1448

    Article  CAS  PubMed  Google Scholar 

  9. Kozlitina J, Smagris E, Stender S, Nordestgaard BG, Zhou HH, Tybjaerg-Hansen A, et al. Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease. Nat Genet. 2014;46(4):352–356

    Article  CAS  PubMed  Google Scholar 

  10. Romeo S, Kozlitina J, Xing C, Pertsemlidis A, Cox D, Pennacchio LA, et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet. 2008;40(12):1461–1465

    Article  CAS  PubMed  Google Scholar 

  11. Sinnott-Armstrong N, Tanigawa Y, Amar D, Mars N, Benner C, Aguirre M, et al. Genetics of 35 blood and urine biomarkers in the UK Biobank. Nat Genet. 2021;53(2):185–194

    Article  CAS  PubMed  Google Scholar 

  12. Sudlow C, Gallacher J, Allen N, Beral V, Burton P, Danesh J, et al. UK biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age. PLoS Med. 2015;12(3):e1001779

    Article  PubMed  Google Scholar 

  13. Bycroft C, Freeman C, Petkova D, Band G, Elliott LT, Sharp K, et al. The UK Biobank resource with deep phenotyping and genomic data. Nature. 2018;562(7726):203–209

    Article  CAS  PubMed  Google Scholar 

  14. Stender S, Kozlitina J, Nordestgaard BG, Tybjaerg-Hansen A, Hobbs HH, Cohen JC. Adiposity amplifies the genetic risk of fatty liver disease conferred by multiple loci. Nat Genet. 2017;49(6):842–847

    Article  CAS  PubMed  Google Scholar 

  15. Gellert-Kristensen H, Richardson TG, Davey Smith G, Nordestgaard BG, Tybjaerg-Hansen A, Stender S. Combined effect of PNPLA3, TM6SF2, and HSD17B13 variants on risk of cirrhosis and hepatocellular carcinoma in the general population. Hepatology. 2020;72:845–856

    Article  CAS  PubMed  Google Scholar 

  16. Wechphanich S, Thammarat P. A survey of metal contamination in blood collection tubes on toxicology assays. BKK Med J. 2017. https://doi.org/10.31524/bkkmedj.2017.09.002

    Article  Google Scholar 

  17. Tietz Textbook of Clinical Chemistry and Molecular Diagnostics, 4th ed. Elsevier Saunders, New York; 2006.

  18. Wilman HR, Parisinos CA, Atabaki-Pasdar N, Kelly M, Thomas EL, Neubauer S, et al. Genetic studies of abdominal MRI data identify genes regulating hepcidin as major determinants of liver iron concentration. J Hepatol. 2019;71(3):594–602

    Article  CAS  PubMed  Google Scholar 

  19. Mojtahed A, Kelly CJ, Herlihy AH, Kin S, Wilman HR, McKay A, et al. Reference range of liver corrected T1 values in a population at low risk for fatty liver disease—a UK Biobank sub-study, with an appendix of interesting cases. Abdom Radiol (NY). 2019;44(1):72–84

    Article  CAS  Google Scholar 

  20. Wilman HR, Kelly M, Garratt S, Matthews PM, Milanesi M, Herlihy A, et al. Characterisation of liver fat in the UK Biobank cohort. PLoS ONE. 2017;12(2):e0172921

    Article  PubMed  Google Scholar 

  21. Seidelin AS, Nordestgaard BG, Tybjaerg-Hansen A, Stender S. Genetic variation at PPP1R3B increases hepatic CT attenuation and interacts with prandial status on plasma glucose. J Clin Endocrinol Metab. 2020;105(6):dgaa151

    Article  PubMed  Google Scholar 

  22. Fuchs A, Mejdahl MR, Kuhl JT, Stisen ZR, Nilsson EJ, Kober LV, et al. Normal values of left ventricular mass and cardiac chamber volumes assessed by 320-detector computed tomography angiography in the Copenhagen general population study. Eur Heart J Cardiovasc Imaging. 2016;17(9):1009–1017

    Article  PubMed  Google Scholar 

  23. Ruhl CE, Everhart JE. Upper limits of normal for alanine aminotransferase activity in the United States population. Hepatology. 2012;55(2):447–454

    Article  CAS  PubMed  Google Scholar 

  24. Lawrence EM, Pooler BD, Pickhardt PJ. Opportunistic screening for hereditary hemochromatosis with unenhanced CT: determination of an optimal liver attenuation threshold. AJR Am J Roentgenol. 2018;211(6):1206–1211

    Article  PubMed  Google Scholar 

  25. Quadri M, Federico A, Zhao T, Breedveld GJ, Battisti C, Delnooz C, et al. Mutations in SLC30A10 cause parkinsonism and dystonia with hypermanganesemia, polycythemia, and chronic liver disease. Am J Hum Genet. 2012;90(3):467–477

    Article  CAS  PubMed  Google Scholar 

  26. Tuschl K, Clayton PT, Gospe SM Jr, Gulab S, Ibrahim S, Singhi P, et al. Syndrome of hepatic cirrhosis, dystonia, polycythemia, and hypermanganesemia caused by mutations in SLC30A10, a manganese transporter in man. Am J Hum Genet. 2012;90(3):457–466

    Article  CAS  PubMed  Google Scholar 

  27. Ward LD, Tu HC, Quenneville CB, Tsour S, Flynn-Carroll AO, Parker MM, et al. GWAS of serum ALT and AST reveals an association of SLC30A10 Thr95Ile with hypermanganesemia symptoms. Nat Commun. 2021;12(1):4571

    Article  CAS  PubMed  Google Scholar 

  28. Tavasoli A, Arjmandi Rafsanjani K, Hemmati S, Mojbafan M, Zarei E, Hosseini S. A case of dystonia with polycythemia and hypermanganesemia caused by SLC30A10 mutation: a treatable inborn error of manganese metabolism. BMC Pediatr. 2019;19(1):229

    Article  PubMed  Google Scholar 

  29. Anagianni S, Tuschl K. Genetic disorders of manganese metabolism. Curr Neurol Neurosci Rep. 2019;19(6):33

    Article  CAS  PubMed  Google Scholar 

  30. Mercadante CJ, Prajapati M, Conboy HL, Dash ME, Herrera C, Pettiglio MA, et al. Manganese transporter Slc30a10 controls physiological manganese excretion and toxicity. J Clin Investig. 2019;129(12):5442–5461

    Article  CAS  PubMed  Google Scholar 

  31. Hutchens S, Liu C, Jursa T, Shawlot W, Chaffee BK, Yin W, et al. Deficiency in the manganese efflux transporter SLC30A10 induces severe hypothyroidism in mice. J Biol Chem. 2017;292(23):9760–9773

    Article  CAS  PubMed  Google Scholar 

  32. Pilling LC, Tamosauskaite J, Jones G, Wood AR, Jones L, Kuo CL, et al. Common conditions associated with hereditary haemochromatosis genetic variants: cohort study in UK Biobank. BMJ. 2019;364:k5222

    Article  PubMed  Google Scholar 

  33. Skowronska M, Litwin T, Kurkowska-Jastrzebska I, Czlonkowska A. Transcranial sonography changes in heterozygotic carriers of the ATP7B gene. Neurol Sci. 2020;41(9):2605–2612

    Article  PubMed  Google Scholar 

  34. Lambrianides S, Nicolaou P, Michaelidou M, Kakouris P, Votsi C, Petrou PP, et al. A novel SLC30A10 missense variant associated with parkinsonism and dystonia without hypermanganesemia. J Neurol Sci. 2020;418:117101

    Article  CAS  PubMed  Google Scholar 

  35. Ng E, Lind PM, Lindgren C, Ingelsson E, Mahajan A, Morris A, et al. Genome-wide association study of toxic metals and trace elements reveals novel associations. Hum Mol Genet. 2015;24(16):4739–4745

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

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

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.

Author information

Authors and Affiliations

  1. Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, 2100, Copenhagen, Denmark

    Anne-Sofie Seidelin, Anne Tybjærg-Hansen & Stefan Stender

  2. Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark

    Børge Grønne Nordestgaard

  3. Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Børge Grønne Nordestgaard & Anne Tybjærg-Hansen

  4. Department of Life Sciences, Centre for Inflammation Research and Translational Medicine (CIRTM), Brunel University London, Uxbridge, UK

    Hanieh Yaghootkar

  5. Research Centre for Optimal Health, School of Life Sciences, University of Westminster, London, UK

    Hanieh Yaghootkar

  6. Department of Clinical Biochemistry, Bispebjerg and Frederiksberg Hospital, Copenhagen University Hospital, Copenhagen, Denmark

    Stefan Stender

Authors
  1. Anne-Sofie Seidelin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Børge Grønne Nordestgaard
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Anne Tybjærg-Hansen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hanieh Yaghootkar
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Stefan Stender
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

AS: data curation, formal analysis, investigation, visualization, writing—original draft, writing—review and editing. BGN: resources, writing—review and editing. ATH: resources, writing—review and editing. HY: resources, formal analysis, writing—review and editing. SS: conceptualization, data curation, formal analysis, investigation, visualization, funding acquisition, supervision, writing—original draft, writing—review and editing. All authors approved the final version of the manuscript.

Corresponding author

Correspondence to Stefan Stender.

Ethics declarations

Conflict of interest

Anne-Sofie Seidelin, Børge Grønne Nordestgaard, Anne Tybjærg-Hansen, Hanieh Yaghootkar and Stefan Stender have no relevant financial or non-financial interests to disclose.

Animal research

Not applicable.

Consent to participate

All participants in the Copenhagen cohort and UK Biobank provided written consent.

Consent to publish

All co-authors agreed to the final version of the manuscript, and to the decision to submit for publication.

Plant reproducibility

Not applicable.

Clinical trials registration

No applicable.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 3808 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Seidelin, AS., Nordestgaard, B.G., Tybjærg-Hansen, A. et al. A rare genetic variant in the manganese transporter SLC30A10 and elevated liver enzymes in the general population. Hepatol Int 16, 702–711 (2022). https://doi.org/10.1007/s12072-022-10331-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12072-022-10331-w

Keywords

Search

Navigation