A Neanderthal OAS1 isoform protects individuals of European ancestry against COVID-19 susceptibility and severity

被引：178

作者：

Zhou, Sirui ^{[1
,2
]}

Butler-Laporte, Guillaume ^{[1
,2
]}

Nakanishi, Tomoko ^{[1
,3
,4
,5
]}

Morrison, David R. ^{[1
]}

Afilalo, Jonathan ^{[1
,2
,6
]}

Afilalo, Marc ^{[1
,7
]}

Laurent, Laetitia ^{[1
]}

Pietzner, Maik ^{[8
]}

Kerrison, Nicola ^{[8
]}

Zhao, Kaiqiong ^{[1
,2
]}

Brunet-Ratnasingham, Elsa ^{[9
,10
]}

Henry, Danielle ^{[1
]}

Kimchi, Nofar ^{[1
]}

Afrasiabi, Zaman ^{[1
]}

Rezk, Nardin ^{[1
]}

Bouab, Meriem ^{[1
]}

Petitjean, Louis ^{[1
]}

Guzman, Charlotte ^{[1
]}

Xue, Xiaoqing ^{[1
]}

Tselios, Chris ^{[1
]}

Vulesevic, Branka ^{[1
]}

Adeleye, Olumide ^{[1
]}

Abdullah, Tala ^{[1
]}

Almamlouk, Noor ^{[1
]}

Chen, Yiheng ^{[1
,3
]}

Chasse, Michael ^{[9
]}

Durand, Madeleine ^{[9
]}

Paterson, Clare ^{[11
]}

Normark, Johan ^{[12
,13
]}

Frithiof, Robert ^{[14
]}

Lipcsey, Miklos ^{[14
,15
]}

Hultstrom, Michael ^{[14
,16
]}

Greenwood, Celia M. T. ^{[1
,2
,17
]}

Zeberg, Hugo ^{[18
]}

Langenberg, Claudia ^{[8
,19
]}

Thysell, Elin ^{[20
]}

Pollak, Michael ^{[1
,21
,22
]}

Mooser, Vincent ^{[3
]}

Forgetta, Vincenzo ^{[1
]}

Kaufmann, Daniel E. ^{[9
,23
]}

Richards, J. Brent ^{[1
,2
,3
,24
]}

机构：

[1] McGill Univ, Lady Davis Inst, Jewish Gen Hosp, Montreal, PQ, Canada

[2] McGill Univ, Dept Epidemiol Biostat & Occupat Hlth, Montreal, PQ, Canada

[3] McGill Univ, Dept Human Genet, Montreal, PQ, Canada

[4] Kyoto Univ, Grad Sch Med, Kyoto McGill Int Collaborat Sch Genom Med, Kyoto, Japan

[5] Japan Soc Promot Sci, Tokyo, Japan

[6] McGill Univ, Div Cardiol, Dept Med, Montreal, PQ, Canada

[7] McGill Univ, Jewish Gen Hosp, Dept Emergency Med, Montreal, PQ, Canada

[8] Univ Cambridge, MRC Epidemiol Unit, Sch Clin Med, Cambridge, England

[9] Ctr Hosp Univ Montreal, Res Ctr, Montreal, PQ, Canada

[10] Univ Montreal, Dept Microbiol Infectiol & Immunol, Montreal, PQ, Canada

[11] SomaLog Inc, Boulder, CO USA

[12] Umea Univ, Mol Infect Med Sweden MIMS, Umea, Sweden

[13] Umea Univ, Sect Infect & Immunol, Dept Clin Microbiol, Wallenberg Ctr Mol Med, Umea, Sweden

[14] Uppsala Univ, Dept Surg Sci, Anaesthesiol & Intens Care Med, Uppsala, Sweden

[15] Uppsala Univ, Dept Surg Sci, Hedenstierna Lab, CIRRUS,Anaesthesiol & Intens Care Med, Uppsala, Sweden

[16] Uppsala Univ, Dept Med Cell Biol, Integrat Physiol, Uppsala, Sweden

[17] McGill Univ, Gerald Bronfman Dept Oncol, Montreal, PQ, Canada

[18] Karolinska Inst, Dept Neurosci, Stockholm, Sweden

[19] Charite Univ Med Berlin, Berlin Inst Hlth, Computat Med, Berlin, Germany

[20] Umea Univ, Dept Med Biosci, Pathol, Umea, Sweden

[21] McGill Univ, Dept Med, Montreal, PQ, Canada

[22] McGill Univ, Dept Oncol, Montreal, PQ, Canada

[23] Univ Montreal, Dept Med, Montreal, PQ, Canada

[24] Kings Coll London, Dept Twin Res, London, England

来源：

NATURE MEDICINE | 2021年 / 27卷 / 04期

基金：

瑞典研究理事会; 日本学术振兴会; 加拿大健康研究院; 英国医学研究理事会;

关键词：

RNASE L; PROTEINS; GENOME; GENES;

D O I：

10.1038/s41591-021-01281-1

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

To identify circulating proteins influencing Coronavirus Disease 2019 (COVID-19) susceptibility and severity, we undertook a two-sample Mendelian randomization (MR) study, rapidly scanning hundreds of circulating proteins while reducing bias due to reverse causation and confounding. In up to 14,134 cases and 1.2 million controls, we found that an s.d. increase in OAS1 levels was associated with reduced COVID-19 death or ventilation (odds ratio (OR) = 0.54, P = 7 x 10(-8)), hospitalization (OR = 0.61, P = 8 x 10(-8)) and susceptibility (OR = 0.78, P = 8 x 10(-6)). Measuring OAS1 levels in 504 individuals, we found that higher plasma OAS1 levels in a non-infectious state were associated with reduced COVID-19 susceptibility and severity. Further analyses suggested that a Neanderthal isoform of OAS1 in individuals of European ancestry affords this protection. Thus, evidence from MR and a case-control study support a protective role for OAS1 in COVID-19 adverse outcomes. Available pharmacological agents that increase OAS1 levels could be prioritized for drug development. A variant of the OAS1 gene, which encodes an enzyme that is critical for the innate immune response to viral infections, is associated with decreased risk of death in patients with COVID-19.

引用

页码：659 / 667

页数：24

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