A protein-truncating HSD17B13 variant and protection from chronic liver disease

N. S. Abul-Husn, X. Cheng, A. H. Li, Y. Xin, C. Schurmann, P. Stevis, Y. Liu, J. Kozlitina, S. Stender, G. C. Wood, A. N. Stepanchick, M. D. Still, S. McCarthy, C. O'Dushlaine, J. S. Packer, S. Balasubramanian, N. Gosalia, D. Esopi, S. Y. Kim, S. Mukherjee & 28 others A. E. Lopez, E. D. Fuller, J. Penn, X. Chu, J. Z. Luo, U. L. Mirshahi, D. J. Carey, C. D. Still, M. D. Feldman, A. Small, S. M. Damrauer, D. J. Rader, B. Zambrowicz, W. Olson, A. J. Murphy, I. B. Borecki, A. R. Shuldiner, J. G. Reid, J. D. Overton, G. D. Yancopoulos, H. H. Hobbs, J. C. Cohen, O. Gottesman, T. M. Teslovich, A. Baras, T. Mirshahi, J. Gromada, F. E. Dewey

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Abstract

BACKGROUND Elucidation of the genetic factors underlying chronic liver disease may reveal new therapeutic targets. METHODS We used exome sequence data and electronic health records from 46,544 participants in the DiscovEHR human genetics study to identify genetic variants associated with serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Variants that were replicated in three additional cohorts (12,527 persons) were evaluated for association with clinical diagnoses of chronic liver disease in DiscovEHR study participants and two independent cohorts (total of 37,173 persons) and with histopathological severity of liver disease in 2391 human liver samples. RESULTS A splice variant (rs72613567:TA) in HSD17B13, encoding the hepatic lipid droplet protein hydroxysteroid 17-beta dehydrogenase 13, was associated with reduced levels of ALT (P = 4.2×10-12) and AST (P = 6.2×10-10). Among DiscovEHR study participants, this variant was associated with a reduced risk of alcoholic liver disease (by 42% [95% confidence interval {CI}, 20 to 58] among heterozygotes and by 53% [95% CI, 3 to 77] among homozygotes), nonalcoholic liver disease (by 17% [95% CI, 8 to 25] among heterozygotes and by 30% [95% CI, 13 to 43] among homozygotes), alcoholic cirrhosis (by 42% [95% CI, 14 to 61] among heterozygotes and by 73% [95% CI, 15 to 91] among homozygotes), and nonalcoholic cirrhosis (by 26% [95% CI, 7 to 40] among heterozygotes and by 49% [95% CI, 15 to 69] among homozygotes). Associations were confirmed in two independent cohorts. The rs72613567:TA variant was associated with a reduced risk of nonalcoholic steatohepatitis, but not steatosis, in human liver samples. The rs72613567:TA variant mitigated liver injury associated with the risk-increasing PNPLA3 p.I148M allele and resulted in an unstable and truncated protein with reduced enzymatic activity. CONCLUSIONS A loss-of-function variant in HSD17B13 was associated with a reduced risk of chronic liver disease and of progression from steatosis to steatohepatitis.

Original languageEnglish (US)
Pages (from-to)1096-1106
Number of pages11
JournalNew England Journal of Medicine
Volume378
Issue number12
DOIs
StatePublished - Mar 22 2018

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Liver Diseases
Chronic Disease
Confidence Intervals
Homozygote
Heterozygote
Proteins
Liver
Aspartate Aminotransferases
Alanine Transaminase
17-Hydroxysteroid Dehydrogenases
Exome
Alcoholic Liver Cirrhosis
Alcoholic Liver Diseases
Electronic Health Records
Medical Genetics
Fatty Liver
Disease Progression
Fibrosis
Alleles
Wounds and Injuries

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Abul-Husn, N. S., Cheng, X., Li, A. H., Xin, Y., Schurmann, C., Stevis, P., ... Dewey, F. E. (2018). A protein-truncating HSD17B13 variant and protection from chronic liver disease. New England Journal of Medicine, 378(12), 1096-1106. https://doi.org/10.1056/NEJMoa1712191

A protein-truncating HSD17B13 variant and protection from chronic liver disease. / Abul-Husn, N. S.; Cheng, X.; Li, A. H.; Xin, Y.; Schurmann, C.; Stevis, P.; Liu, Y.; Kozlitina, J.; Stender, S.; Wood, G. C.; Stepanchick, A. N.; Still, M. D.; McCarthy, S.; O'Dushlaine, C.; Packer, J. S.; Balasubramanian, S.; Gosalia, N.; Esopi, D.; Kim, S. Y.; Mukherjee, S.; Lopez, A. E.; Fuller, E. D.; Penn, J.; Chu, X.; Luo, J. Z.; Mirshahi, U. L.; Carey, D. J.; Still, C. D.; Feldman, M. D.; Small, A.; Damrauer, S. M.; Rader, D. J.; Zambrowicz, B.; Olson, W.; Murphy, A. J.; Borecki, I. B.; Shuldiner, A. R.; Reid, J. G.; Overton, J. D.; Yancopoulos, G. D.; Hobbs, H. H.; Cohen, J. C.; Gottesman, O.; Teslovich, T. M.; Baras, A.; Mirshahi, T.; Gromada, J.; Dewey, F. E.

In: New England Journal of Medicine, Vol. 378, No. 12, 22.03.2018, p. 1096-1106.

Research output: Contribution to journalArticle

Abul-Husn, NS, Cheng, X, Li, AH, Xin, Y, Schurmann, C, Stevis, P, Liu, Y, Kozlitina, J, Stender, S, Wood, GC, Stepanchick, AN, Still, MD, McCarthy, S, O'Dushlaine, C, Packer, JS, Balasubramanian, S, Gosalia, N, Esopi, D, Kim, SY, Mukherjee, S, Lopez, AE, Fuller, ED, Penn, J, Chu, X, Luo, JZ, Mirshahi, UL, Carey, DJ, Still, CD, Feldman, MD, Small, A, Damrauer, SM, Rader, DJ, Zambrowicz, B, Olson, W, Murphy, AJ, Borecki, IB, Shuldiner, AR, Reid, JG, Overton, JD, Yancopoulos, GD, Hobbs, HH, Cohen, JC, Gottesman, O, Teslovich, TM, Baras, A, Mirshahi, T, Gromada, J & Dewey, FE 2018, 'A protein-truncating HSD17B13 variant and protection from chronic liver disease', New England Journal of Medicine, vol. 378, no. 12, pp. 1096-1106. https://doi.org/10.1056/NEJMoa1712191
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. New England Journal of Medicine. 2018 Mar 22;378(12):1096-1106. https://doi.org/10.1056/NEJMoa1712191
Abul-Husn, N. S. ; Cheng, X. ; Li, A. H. ; Xin, Y. ; Schurmann, C. ; Stevis, P. ; Liu, Y. ; Kozlitina, J. ; Stender, S. ; Wood, G. C. ; Stepanchick, A. N. ; Still, M. D. ; McCarthy, S. ; O'Dushlaine, C. ; Packer, J. S. ; Balasubramanian, S. ; Gosalia, N. ; Esopi, D. ; Kim, S. Y. ; Mukherjee, S. ; Lopez, A. E. ; Fuller, E. D. ; Penn, J. ; Chu, X. ; Luo, J. Z. ; Mirshahi, U. L. ; Carey, D. J. ; Still, C. D. ; Feldman, M. D. ; Small, A. ; Damrauer, S. M. ; Rader, D. J. ; Zambrowicz, B. ; Olson, W. ; Murphy, A. J. ; Borecki, I. B. ; Shuldiner, A. R. ; Reid, J. G. ; Overton, J. D. ; Yancopoulos, G. D. ; Hobbs, H. H. ; Cohen, J. C. ; Gottesman, O. ; Teslovich, T. M. ; Baras, A. ; Mirshahi, T. ; Gromada, J. ; Dewey, F. E. / A protein-truncating HSD17B13 variant and protection from chronic liver disease. In: New England Journal of Medicine. 2018 ; Vol. 378, No. 12. pp. 1096-1106.
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title = "A protein-truncating HSD17B13 variant and protection from chronic liver disease",
abstract = "BACKGROUND Elucidation of the genetic factors underlying chronic liver disease may reveal new therapeutic targets. METHODS We used exome sequence data and electronic health records from 46,544 participants in the DiscovEHR human genetics study to identify genetic variants associated with serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Variants that were replicated in three additional cohorts (12,527 persons) were evaluated for association with clinical diagnoses of chronic liver disease in DiscovEHR study participants and two independent cohorts (total of 37,173 persons) and with histopathological severity of liver disease in 2391 human liver samples. RESULTS A splice variant (rs72613567:TA) in HSD17B13, encoding the hepatic lipid droplet protein hydroxysteroid 17-beta dehydrogenase 13, was associated with reduced levels of ALT (P = 4.2×10-12) and AST (P = 6.2×10-10). Among DiscovEHR study participants, this variant was associated with a reduced risk of alcoholic liver disease (by 42{\%} [95{\%} confidence interval {CI}, 20 to 58] among heterozygotes and by 53{\%} [95{\%} CI, 3 to 77] among homozygotes), nonalcoholic liver disease (by 17{\%} [95{\%} CI, 8 to 25] among heterozygotes and by 30{\%} [95{\%} CI, 13 to 43] among homozygotes), alcoholic cirrhosis (by 42{\%} [95{\%} CI, 14 to 61] among heterozygotes and by 73{\%} [95{\%} CI, 15 to 91] among homozygotes), and nonalcoholic cirrhosis (by 26{\%} [95{\%} CI, 7 to 40] among heterozygotes and by 49{\%} [95{\%} CI, 15 to 69] among homozygotes). Associations were confirmed in two independent cohorts. The rs72613567:TA variant was associated with a reduced risk of nonalcoholic steatohepatitis, but not steatosis, in human liver samples. The rs72613567:TA variant mitigated liver injury associated with the risk-increasing PNPLA3 p.I148M allele and resulted in an unstable and truncated protein with reduced enzymatic activity. CONCLUSIONS A loss-of-function variant in HSD17B13 was associated with a reduced risk of chronic liver disease and of progression from steatosis to steatohepatitis.",
author = "Abul-Husn, {N. S.} and X. Cheng and Li, {A. H.} and Y. Xin and C. Schurmann and P. Stevis and Y. Liu and J. Kozlitina and S. Stender and Wood, {G. C.} and Stepanchick, {A. N.} and Still, {M. D.} and S. McCarthy and C. O'Dushlaine and Packer, {J. S.} and S. Balasubramanian and N. Gosalia and D. Esopi and Kim, {S. Y.} and S. Mukherjee and Lopez, {A. E.} and Fuller, {E. D.} and J. Penn and X. Chu and Luo, {J. Z.} and Mirshahi, {U. L.} and Carey, {D. J.} and Still, {C. D.} and Feldman, {M. D.} and A. Small and Damrauer, {S. M.} and Rader, {D. J.} and B. Zambrowicz and W. Olson and Murphy, {A. J.} and Borecki, {I. B.} and Shuldiner, {A. R.} and Reid, {J. G.} and Overton, {J. D.} and Yancopoulos, {G. D.} and Hobbs, {H. H.} and Cohen, {J. C.} and O. Gottesman and Teslovich, {T. M.} and A. Baras and T. Mirshahi and J. Gromada and Dewey, {F. E.}",
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TY - JOUR

T1 - A protein-truncating HSD17B13 variant and protection from chronic liver disease

AU - Abul-Husn, N. S.

AU - Cheng, X.

AU - Li, A. H.

AU - Xin, Y.

AU - Schurmann, C.

AU - Stevis, P.

AU - Liu, Y.

AU - Kozlitina, J.

AU - Stender, S.

AU - Wood, G. C.

AU - Stepanchick, A. N.

AU - Still, M. D.

AU - McCarthy, S.

AU - O'Dushlaine, C.

AU - Packer, J. S.

AU - Balasubramanian, S.

AU - Gosalia, N.

AU - Esopi, D.

AU - Kim, S. Y.

AU - Mukherjee, S.

AU - Lopez, A. E.

AU - Fuller, E. D.

AU - Penn, J.

AU - Chu, X.

AU - Luo, J. Z.

AU - Mirshahi, U. L.

AU - Carey, D. J.

AU - Still, C. D.

AU - Feldman, M. D.

AU - Small, A.

AU - Damrauer, S. M.

AU - Rader, D. J.

AU - Zambrowicz, B.

AU - Olson, W.

AU - Murphy, A. J.

AU - Borecki, I. B.

AU - Shuldiner, A. R.

AU - Reid, J. G.

AU - Overton, J. D.

AU - Yancopoulos, G. D.

AU - Hobbs, H. H.

AU - Cohen, J. C.

AU - Gottesman, O.

AU - Teslovich, T. M.

AU - Baras, A.

AU - Mirshahi, T.

AU - Gromada, J.

AU - Dewey, F. E.

PY - 2018/3/22

Y1 - 2018/3/22

N2 - BACKGROUND Elucidation of the genetic factors underlying chronic liver disease may reveal new therapeutic targets. METHODS We used exome sequence data and electronic health records from 46,544 participants in the DiscovEHR human genetics study to identify genetic variants associated with serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Variants that were replicated in three additional cohorts (12,527 persons) were evaluated for association with clinical diagnoses of chronic liver disease in DiscovEHR study participants and two independent cohorts (total of 37,173 persons) and with histopathological severity of liver disease in 2391 human liver samples. RESULTS A splice variant (rs72613567:TA) in HSD17B13, encoding the hepatic lipid droplet protein hydroxysteroid 17-beta dehydrogenase 13, was associated with reduced levels of ALT (P = 4.2×10-12) and AST (P = 6.2×10-10). Among DiscovEHR study participants, this variant was associated with a reduced risk of alcoholic liver disease (by 42% [95% confidence interval {CI}, 20 to 58] among heterozygotes and by 53% [95% CI, 3 to 77] among homozygotes), nonalcoholic liver disease (by 17% [95% CI, 8 to 25] among heterozygotes and by 30% [95% CI, 13 to 43] among homozygotes), alcoholic cirrhosis (by 42% [95% CI, 14 to 61] among heterozygotes and by 73% [95% CI, 15 to 91] among homozygotes), and nonalcoholic cirrhosis (by 26% [95% CI, 7 to 40] among heterozygotes and by 49% [95% CI, 15 to 69] among homozygotes). Associations were confirmed in two independent cohorts. The rs72613567:TA variant was associated with a reduced risk of nonalcoholic steatohepatitis, but not steatosis, in human liver samples. The rs72613567:TA variant mitigated liver injury associated with the risk-increasing PNPLA3 p.I148M allele and resulted in an unstable and truncated protein with reduced enzymatic activity. CONCLUSIONS A loss-of-function variant in HSD17B13 was associated with a reduced risk of chronic liver disease and of progression from steatosis to steatohepatitis.

AB - BACKGROUND Elucidation of the genetic factors underlying chronic liver disease may reveal new therapeutic targets. METHODS We used exome sequence data and electronic health records from 46,544 participants in the DiscovEHR human genetics study to identify genetic variants associated with serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Variants that were replicated in three additional cohorts (12,527 persons) were evaluated for association with clinical diagnoses of chronic liver disease in DiscovEHR study participants and two independent cohorts (total of 37,173 persons) and with histopathological severity of liver disease in 2391 human liver samples. RESULTS A splice variant (rs72613567:TA) in HSD17B13, encoding the hepatic lipid droplet protein hydroxysteroid 17-beta dehydrogenase 13, was associated with reduced levels of ALT (P = 4.2×10-12) and AST (P = 6.2×10-10). Among DiscovEHR study participants, this variant was associated with a reduced risk of alcoholic liver disease (by 42% [95% confidence interval {CI}, 20 to 58] among heterozygotes and by 53% [95% CI, 3 to 77] among homozygotes), nonalcoholic liver disease (by 17% [95% CI, 8 to 25] among heterozygotes and by 30% [95% CI, 13 to 43] among homozygotes), alcoholic cirrhosis (by 42% [95% CI, 14 to 61] among heterozygotes and by 73% [95% CI, 15 to 91] among homozygotes), and nonalcoholic cirrhosis (by 26% [95% CI, 7 to 40] among heterozygotes and by 49% [95% CI, 15 to 69] among homozygotes). Associations were confirmed in two independent cohorts. The rs72613567:TA variant was associated with a reduced risk of nonalcoholic steatohepatitis, but not steatosis, in human liver samples. The rs72613567:TA variant mitigated liver injury associated with the risk-increasing PNPLA3 p.I148M allele and resulted in an unstable and truncated protein with reduced enzymatic activity. CONCLUSIONS A loss-of-function variant in HSD17B13 was associated with a reduced risk of chronic liver disease and of progression from steatosis to steatohepatitis.

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