A Protein-Truncating HSD17B13 Variant and Protection from Chronic Liver Disease

被引：626

作者：

Abul-Husn, N. S. ^{[1
]}

Cheng, X. ^{[2
]}

Li, A. H. ^{[1
]}

Xin, Y. ^{[2
]}

Schurmann, C. ^{[1
]}

Stevis, P. ^{[2
]}

Liu, Y. ^{[2
]}

Kozlitina, J. ^{[3
]}

Stender, S. ^{[3
]}

Wood, G. C. ^{[4
]}

Stepanchick, A. N. ^{[4
]}

Still, M. D. ^{[4
,5
]}

McCarthy, S. ^{[1
]}

O'Dushlaine, C. ^{[1
]}

Packer, J. S. ^{[1
]}

Balasubramanian, S. ^{[1
]}

Gosalia, N. ^{[1
]}

Esopi, D. ^{[2
]}

Kim, S. Y. ^{[2
]}

Mukherjee, S. ^{[1
]}

Lopez, A. E. ^{[1
]}

Fuller, E. D. ^{[1
]}

Penn, J. ^{[1
]}

Chu, X. ^{[4
]}

Luo, J. Z. ^{[4
]}

Mirshahi, U. L. ^{[4
]}

Carey, D. J. ^{[4
]}

Still, C. D. ^{[4
]}

Feldman, M. D. ^{[5
]}

Small, A. ^{[5
]}

Damrauer, S. M. ^{[5
]}

Rader, D. J. ^{[5
]}

Zambrowicz, B. ^{[2
]}

Olson, W. ^{[2
]}

Murphy, A. J. ^{[2
]}

Borecki, I. B. ^{[1
]}

Shuldiner, A. R. ^{[1
]}

Reid, J. G. ^{[1
]}

Overton, J. D. ^{[1
]}

Yancopoulos, G. D. ^{[2
]}

Hobbs, H. H. ^{[3
]}

Cohen, J. C.

Gottesman, O. ^{[1
]}

Teslovich, T. M. ^{[1
]}

Baras, A. ^{[1
]}

Mirshahi, T. ^{[4
]}

Gromada, J. ^{[2
]}

Dewey, F. E. ^{[1
]}

机构：

[1] Regeneron Genet Ctr, 777 Old Saw Mill River Rd, Tarrytown, NY 10591 USA

[2] Regeneron Pharmaceut, Tarrytown, NY USA

[3] Univ Texas Southwestern Med Ctr Dallas, Dallas, TX 75390 USA

[4] Geisinger Hlth Syst, Danville, PA USA

[5] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA

来源：

NEW ENGLAND JOURNAL OF MEDICINE | 2018年 / 378卷 / 12期

关键词：

GENOME-WIDE ASSOCIATION; UNITED-STATES; CONFERS SUSCEPTIBILITY; GENETIC-VARIATION; PNPLA3; TM6SF2; PREVALENCE; EXPRESSION; SECRETION; RISK;

D O I：

10.1056/NEJMoa1712191

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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 = 4.2x10(-12)) and AST (P = 6.2x10(-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.

引用

页码：1096 / 1106

页数：11

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