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Genome-wide association study of circulating liver enzymes reveals an expanded role for manganese transporter SLC30A10 in liver health

View ORCID ProfileLucas D. Ward, Ho-Chou Tu, Chelsea Quenneville, Alexander O. Flynn-Carroll, Margaret M. Parker, View ORCID ProfileAimee M. Deaton, Patrick A. J. Haslett, Gregory Hinkle, View ORCID ProfilePaul Nioi
doi: https://doi.org/10.1101/2020.05.19.104570
Lucas D. Ward
1Alnylam Pharmaceuticals, Cambridge, MA 02142
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  • For correspondence: lward@alnylam.com
Ho-Chou Tu
1Alnylam Pharmaceuticals, Cambridge, MA 02142
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Chelsea Quenneville
1Alnylam Pharmaceuticals, Cambridge, MA 02142
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Alexander O. Flynn-Carroll
1Alnylam Pharmaceuticals, Cambridge, MA 02142
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Margaret M. Parker
1Alnylam Pharmaceuticals, Cambridge, MA 02142
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Aimee M. Deaton
1Alnylam Pharmaceuticals, Cambridge, MA 02142
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Patrick A. J. Haslett
1Alnylam Pharmaceuticals, Cambridge, MA 02142
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Gregory Hinkle
1Alnylam Pharmaceuticals, Cambridge, MA 02142
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Paul Nioi
1Alnylam Pharmaceuticals, Cambridge, MA 02142
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Abstract

To better understand molecular pathways underlying liver health and disease, we performed genome-wide association studies (GWAS) on circulating levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) across 408,300 subjects from four ethnic groups in the UK Biobank, focusing on variants associating with both enzymes. Of these variants, the strongest effect is a rare (MAF in White British = 0.12%) missense variant in the gene encoding manganese efflux transporter SLC30A10, Thr95Ile (rs188273166), associating with a 5.9% increase in ALT and a 4.2% increase in AST. Carriers have higher prevalence of all-cause liver disease (OR = 1.70; 95% CI = 1.24 to 2.34) and higher prevalence of extrahepatic bile duct cancer (OR = 23.8; 95% CI = 9.1 to 62.1) compared to non-carriers. Over 4% of the cases of extrahepatic cholangiocarcinoma in the UK Biobank carry SLC30A10 Thr95Ile. Unlike variants in SLC30A10 known to cause the recessive syndrome hypermanganesemia with dystonia-1 (HMNDYT1), the Thr95Ile variant has a detectable effect even in the heterozygous state. Also unlike HMNDYT1-causing variants, Thr95Ile results in a protein that is properly trafficked to the plasma membrane when expressed in HeLa cells. These results suggest that coding variation in SLC30A10 impacts liver health in more individuals than the small population of HMNDYT1 patients.

Competing Interest Statement

The authors are employees of Alnylam Pharmaceuticals, Inc.

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Posted May 20, 2020.
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Genome-wide association study of circulating liver enzymes reveals an expanded role for manganese transporter SLC30A10 in liver health
Lucas D. Ward, Ho-Chou Tu, Chelsea Quenneville, Alexander O. Flynn-Carroll, Margaret M. Parker, Aimee M. Deaton, Patrick A. J. Haslett, Gregory Hinkle, Paul Nioi
bioRxiv 2020.05.19.104570; doi: https://doi.org/10.1101/2020.05.19.104570
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Genome-wide association study of circulating liver enzymes reveals an expanded role for manganese transporter SLC30A10 in liver health
Lucas D. Ward, Ho-Chou Tu, Chelsea Quenneville, Alexander O. Flynn-Carroll, Margaret M. Parker, Aimee M. Deaton, Patrick A. J. Haslett, Gregory Hinkle, Paul Nioi
bioRxiv 2020.05.19.104570; doi: https://doi.org/10.1101/2020.05.19.104570

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