FUT2-ABO epistasis increases the risk of early childhood asthma and Streptococcus pneumoniae respiratory illnesses

被引：34

作者：

Ahluwalia, Tarunveer S. ^{[1
,2
,3
]}

Eliasen, Anders U. ^{[1
,4
]}

Sevelsted, Astrid ^{[1
]}

Pedersen, Casper-Emil T. ^{[1
]}

Stokholm, Jakob ^{[1
]}

Chawes, Bo ^{[1
]}

Bork-Jensen, Jette ^{[5
]}

Grarup, Niels ^{[5
]}

Pedersen, Oluf ^{[5
]}

Hansen, Torben ^{[5
]}

Linneberg, Allan ^{[6
,7
]}

Sharma, Amitabh ^{[8
]}

Weiss, Scott T. ^{[8
]}

Evans, Michael D. ^{[9
]}

Jackson, Daniel J. ^{[10
]}

Morin, Andreanne ^{[11
]}

Krogfelt, Karen A. ^{[12
,13
]}

Schjorring, Susanne ^{[12
]}

Mortensen, Preben B. ^{[14
,15
,16
]}

Hougaard, David M. ^{[14
,17
,18
]}

Bybjerg-Grauholm, Jonas ^{[14
,17
,18
]}

Baekvad-Hansen, Marie ^{[14
,17
,18
]}

Mors, Ole ^{[14
,19
]}

Nordentoft, Merete ^{[14
,20
]}

Borglum, Anders D. ^{[14
,21
,22
,23
]}

Werge, Thomas ^{[14
,20
,24
,25
]}

Agerbo, Esben ^{[14
,15
,16
]}

Gern, James E. ^{[10
]}

Lemanske, Robert F., Jr. ^{[10
]}

Ober, Carole ^{[11
]}

Pedersen, Anders G. ^{[4
]}

Bisgaard, Hans ^{[1
]}

Bonnelykke, Klaus ^{[1
]}

机构：

[1] Univ Copenhagen, Herlev & Gentofte Hosp, Copenhagen Prospect Studies Asthma Childhood, COPSAC, Copenhagen, Denmark

[2] Steno Diabet Ctr Copenhagen, Gentofte, Denmark

[3] Univ Copenhagen, Dept Biol, Bioinformat Ctr, Copenhagen, Denmark

[4] Tech Univ Denmark, Sect Bioinformat, Dept Hlth Technol, Copenhagen, Denmark

[5] Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn, Ctr Basic Metab Res, Copenhagen, Denmark

[6] Bispebjerg & Frederiksberg Hosp, Ctr Clin Res & Dis Prevent, Copenhagen, Denmark

[7] Univ Copenhagen, Dept Clin Med, Copenhagen, Denmark

[8] Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA

[9] Univ Minnesota, Clin & Translat Sci Inst, Minneapolis, MN USA

[10] Univ Wisconsin, Dept Pediat, Madison, WI USA

[11] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA

[12] Statens Serum Inst, Dept Bacteria Parasites & Fungi, Copenhagen, Denmark

[13] Roskilde Univ, Dept Sci & Environm, Roskilde, Denmark

[14] Lundbeck Fdn Initiat Integrated Psychiat Res, IPSYCH, Copenhagen, Denmark

[15] Aarhus Univ, Natl Ctr Register Based Res Business & Social Sci, NCRR, Aarhus C, Denmark

[16] Aarhus Univ, CIRRAU Ctr Integrated Register Based Res, Aarhus C, Denmark

[17] Statens Serum Inst, Dept Congenital Disorders, Copenhagen, Denmark

[18] SSI, Den Neonatale Screenings Biobank, Copenhagen, Denmark

[19] Aarhus Univ Hosp Psychiat, Psychosis Res Unit, Risskov, Denmark

[20] Copenhagen Univ Hosp, Mental Hlth Ctr Copenhagen, Capital Reg Denmark, Copenhagen, Denmark

[21] Aarhus Univ, Ctr Integrat Sequencing, Dept Biomed, Aarhus C, Denmark

[22] Aarhus Univ, Ctr Integrat Sequencing, ISEQ, Aarhus C, Denmark

[23] Cent Reg Denmark, Ctr Genom & Personalized Med, Aarhus C, Denmark

[24] Copenhagen Mental Hlth Serv, Inst Biol Psychiat, Copenhagen, Denmark

[25] Univ Copenhagen, GLOBE Inst, Ctr GeoGenet, Copenhagen, Denmark

来源：

NATURE COMMUNICATIONS | 2020年 / 11卷 / 01期

关键词：

ABO/SECRETOR GENETIC COMPLEX; GENOMEWIDE ASSOCIATION; HERITABILITY; METAANALYSIS; SUSCEPTIBILITY; INFECTION; ANTIGENS; SEQUENCE; DISEASE; ONSET;

D O I：

10.1038/s41467-020-19814-6

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Asthma with severe exacerbation is the most common cause of hospitalization among young children. We aim to increase the understanding of this clinically important disease entity through a genome-wide association study. The discovery analysis comprises 2866 children experiencing severe asthma exacerbation between ages 2 and 6 years, and 65,415 non-asthmatic controls, and we replicate findings in 918 children from the Copenhagen Prospective Studies on Asthma in Childhood (COPSAC) birth cohorts. We identify rs281379 near FUT2/MAMSTR on chromosome 19 as a novel risk locus (OR=1.18 (95% CI=1.11-1.25), P-discovery=2.6 x 10(-9)) as well as a biologically plausible interaction between functional variants in FUT2 and ABO. We further discover and replicate a potential causal mechanism behind this interaction related to S. pneumoniae respiratory illnesses. These results suggest a novel mechanism of early childhood asthma and demonstrates the importance of phenotype-specificity for discovery of asthma genes and epistasis. Genetic variants discovered through genome-wide association studies for asthma together account for a small portion of the heritability. Here, the authors identify a possible epistatic relationship between coding variants in FUT2 and ABO, especially pronounced in severe and early onset asthma.

引用

页数：12

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