Variants of DENND1B associated with asthma in children

Patrick M A Sleiman; James Flory; Marcin Imielinski; Jonathan P Bradfield; Kiran Annaiah; Saffron A G Willis-Owen; Kai Wang; Nicholas M Rafaels; Sven Michel; Klaus Bønnelykke; Haitao Zhang; Cecilia E Kim; Edward C Frackelton; Joseph T Glessner; Cuiping Hou; F George Otieno; Erin Santa; Kelly Thomas; Ryan M Smith; Wendy R Glaberson; Maria Garris; Rosetta M Chiavacci; Terri H Beaty; Ingo Ruczinski; Jordan M Orange; Julian Allen; Jonathan M Spergel; Robert Grundmeier; Rasika A Mathias; Jason D Christie; Erika von Mutius; William O C Cookson; Michael Kabesch; Miriam F Moffatt; Michael M Grunstein; Kathleen C Barnes; Marcella Devoto; Mark Magnusson; Hongzhe Li; Struan F A Grant; Hans Bisgaard; Hakon Hakonarson

doi:10.1056/nejmoa0901867

Variants of DENND1B associated with asthma in children

Patrick M A Sleiman, James Flory, Marcin Imielinski, Jonathan P Bradfield, Kiran Annaiah, Saffron A G Willis-Owen, Kai Wang, Nicholas M Rafaels, Sven Michel, Klaus Bønnelykke, Haitao Zhang, Cecilia E Kim, Edward C Frackelton, Joseph T Glessner, Cuiping Hou, F George Otieno, Erin Santa, Kelly Thomas, Ryan M Smith, Wendy R GlabersonMaria Garris, Rosetta M Chiavacci, Terri H Beaty, Ingo Ruczinski, Jordan M Orange, Julian Allen, Jonathan M Spergel, Robert Grundmeier, Rasika A Mathias, Jason D Christie, Erika von Mutius, William O C Cookson, Michael Kabesch, Miriam F Moffatt, Michael M Grunstein, Kathleen C Barnes, Marcella Devoto, Mark Magnusson, Hongzhe Li, Struan F A Grant, Hans Bisgaard, Hakon Hakonarson

249 Citations (Scopus)

Abstract

BACKGROUND: Asthma is a complex disease that has genetic and environmental causes. The genetic factors associated with susceptibility to asthma remain largely unknown. METHODS: We carried out a genomewide association study involving children with asthma. The sample included 793 North American children of European ancestry with persistent asthma who required daily inhaled glucocorticoid therapy and 1988 matched controls (the discovery set). We also tested for genomewide association in an independent cohort of 917 persons of European ancestry who had asthma and 1546 matched controls (the replication set). Finally, we tested for an association between 20 single-nucleotide polymorphisms (SNPs) at chromosome 1q31 and asthma in 1667 North American children of African ancestry who had asthma and 2045 ancestrally matched controls. RESULTS: In our meta-analysis of all samples from persons of European ancestry, we observed an association, with genomewide significance, between asthma and SNPs at the previously reported locus on 17q21 and an additional eight SNPs at a novel locus on 1q31. The SNP most strongly associated with asthma was rs2786098 (P=8.55×10^-9). We observed replication of the association of asthma with SNP rs2786098 in the independent series of persons of European ancestry (combined P=9.3×10^-11). The alternative allele of each of the eight SNPs on chromosome 1q31 was strongly associated with asthma in the children of African ancestry (P=1.6×10 ^-13 for the comparison across all samples). The 1q31 locus contains DENND1B, a gene that is expressed by natural killer cells and dendritic cells and that encodes a protein that interacts with the tumor necrosis factor a receptor. CONCLUSIONS: We have identified a locus containing DENND1B on chromosome 1q31.3 that is associated with susceptibility to asthma.

Original language	English
Journal	New England Journal of Medicine
Volume	362
Issue number	1
Pages (from-to)	36-44
Number of pages	9
ISSN	0028-4793
DOIs	https://doi.org/10.1056/nejmoa0901867
Publication status	Published - 7 Jan 2010

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Sleiman, P. M. A., Flory, J., Imielinski, M., Bradfield, J. P., Annaiah, K., Willis-Owen, S. A. G., Wang, K., Rafaels, N. M., Michel, S., Bønnelykke, K., Zhang, H., Kim, C. E., Frackelton, E. C., Glessner, J. T., Hou, C., Otieno, F. G., Santa, E., Thomas, K., Smith, R. M., ... Hakonarson, H. (2010). Variants of DENND1B associated with asthma in children. New England Journal of Medicine, 362(1), 36-44. https://doi.org/10.1056/nejmoa0901867

Sleiman, PMA, Flory, J, Imielinski, M, Bradfield, JP, Annaiah, K, Willis-Owen, SAG, Wang, K, Rafaels, NM, Michel, S, Bønnelykke, K, Zhang, H, Kim, CE, Frackelton, EC, Glessner, JT, Hou, C, Otieno, FG, Santa, E, Thomas, K, Smith, RM, Glaberson, WR, Garris, M, Chiavacci, RM, Beaty, TH, Ruczinski, I, Orange, JM, Allen, J, Spergel, JM, Grundmeier, R, Mathias, RA, Christie, JD, von Mutius, E, Cookson, WOC, Kabesch, M, Moffatt, MF, Grunstein, MM, Barnes, KC, Devoto, M, Magnusson, M, Li, H, Grant, SFA, Bisgaard, H & Hakonarson, H 2010, 'Variants of DENND1B associated with asthma in children', New England Journal of Medicine, vol. 362, no. 1, pp. 36-44. https://doi.org/10.1056/nejmoa0901867

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title = "Variants of DENND1B associated with asthma in children",

abstract = "BACKGROUND: Asthma is a complex disease that has genetic and environmental causes. The genetic factors associated with susceptibility to asthma remain largely unknown. METHODS: We carried out a genomewide association study involving children with asthma. The sample included 793 North American children of European ancestry with persistent asthma who required daily inhaled glucocorticoid therapy and 1988 matched controls (the discovery set). We also tested for genomewide association in an independent cohort of 917 persons of European ancestry who had asthma and 1546 matched controls (the replication set). Finally, we tested for an association between 20 single-nucleotide polymorphisms (SNPs) at chromosome 1q31 and asthma in 1667 North American children of African ancestry who had asthma and 2045 ancestrally matched controls. RESULTS: In our meta-analysis of all samples from persons of European ancestry, we observed an association, with genomewide significance, between asthma and SNPs at the previously reported locus on 17q21 and an additional eight SNPs at a novel locus on 1q31. The SNP most strongly associated with asthma was rs2786098 (P=8.55×10-9). We observed replication of the association of asthma with SNP rs2786098 in the independent series of persons of European ancestry (combined P=9.3×10-11). The alternative allele of each of the eight SNPs on chromosome 1q31 was strongly associated with asthma in the children of African ancestry (P=1.6×10 -13 for the comparison across all samples). The 1q31 locus contains DENND1B, a gene that is expressed by natural killer cells and dendritic cells and that encodes a protein that interacts with the tumor necrosis factor a receptor. CONCLUSIONS: We have identified a locus containing DENND1B on chromosome 1q31.3 that is associated with susceptibility to asthma.",

author = "Sleiman, {Patrick M A} and James Flory and Marcin Imielinski and Bradfield, {Jonathan P} and Kiran Annaiah and Willis-Owen, {Saffron A G} and Kai Wang and Rafaels, {Nicholas M} and Sven Michel and Klaus B{\o}nnelykke and Haitao Zhang and Kim, {Cecilia E} and Frackelton, {Edward C} and Glessner, {Joseph T} and Cuiping Hou and Otieno, {F George} and Erin Santa and Kelly Thomas and Smith, {Ryan M} and Glaberson, {Wendy R} and Maria Garris and Chiavacci, {Rosetta M} and Beaty, {Terri H} and Ingo Ruczinski and Orange, {Jordan M} and Julian Allen and Spergel, {Jonathan M} and Robert Grundmeier and Mathias, {Rasika A} and Christie, {Jason D} and {von Mutius}, Erika and Cookson, {William O C} and Michael Kabesch and Moffatt, {Miriam F} and Grunstein, {Michael M} and Barnes, {Kathleen C} and Marcella Devoto and Mark Magnusson and Hongzhe Li and Grant, {Struan F A} and Hans Bisgaard and Hakon Hakonarson",

note = "2010 Massachusetts Medical Society",

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T1 - Variants of DENND1B associated with asthma in children

AU - Sleiman, Patrick M A

AU - Flory, James

AU - Imielinski, Marcin

AU - Bradfield, Jonathan P

AU - Annaiah, Kiran

AU - Willis-Owen, Saffron A G

AU - Wang, Kai

AU - Rafaels, Nicholas M

AU - Michel, Sven

AU - Bønnelykke, Klaus

AU - Zhang, Haitao

AU - Kim, Cecilia E

AU - Frackelton, Edward C

AU - Glessner, Joseph T

AU - Hou, Cuiping

AU - Otieno, F George

AU - Santa, Erin

AU - Thomas, Kelly

AU - Smith, Ryan M

AU - Glaberson, Wendy R

AU - Garris, Maria

AU - Chiavacci, Rosetta M

AU - Beaty, Terri H

AU - Ruczinski, Ingo

AU - Orange, Jordan M

AU - Allen, Julian

AU - Spergel, Jonathan M

AU - Grundmeier, Robert

AU - Mathias, Rasika A

AU - Christie, Jason D

AU - von Mutius, Erika

AU - Cookson, William O C

AU - Kabesch, Michael

AU - Moffatt, Miriam F

AU - Grunstein, Michael M

AU - Barnes, Kathleen C

AU - Devoto, Marcella

AU - Magnusson, Mark

AU - Li, Hongzhe

AU - Grant, Struan F A

AU - Bisgaard, Hans

AU - Hakonarson, Hakon

N1 - 2010 Massachusetts Medical Society

PY - 2010/1/7

Y1 - 2010/1/7

N2 - BACKGROUND: Asthma is a complex disease that has genetic and environmental causes. The genetic factors associated with susceptibility to asthma remain largely unknown. METHODS: We carried out a genomewide association study involving children with asthma. The sample included 793 North American children of European ancestry with persistent asthma who required daily inhaled glucocorticoid therapy and 1988 matched controls (the discovery set). We also tested for genomewide association in an independent cohort of 917 persons of European ancestry who had asthma and 1546 matched controls (the replication set). Finally, we tested for an association between 20 single-nucleotide polymorphisms (SNPs) at chromosome 1q31 and asthma in 1667 North American children of African ancestry who had asthma and 2045 ancestrally matched controls. RESULTS: In our meta-analysis of all samples from persons of European ancestry, we observed an association, with genomewide significance, between asthma and SNPs at the previously reported locus on 17q21 and an additional eight SNPs at a novel locus on 1q31. The SNP most strongly associated with asthma was rs2786098 (P=8.55×10-9). We observed replication of the association of asthma with SNP rs2786098 in the independent series of persons of European ancestry (combined P=9.3×10-11). The alternative allele of each of the eight SNPs on chromosome 1q31 was strongly associated with asthma in the children of African ancestry (P=1.6×10 -13 for the comparison across all samples). The 1q31 locus contains DENND1B, a gene that is expressed by natural killer cells and dendritic cells and that encodes a protein that interacts with the tumor necrosis factor a receptor. CONCLUSIONS: We have identified a locus containing DENND1B on chromosome 1q31.3 that is associated with susceptibility to asthma.

AB - BACKGROUND: Asthma is a complex disease that has genetic and environmental causes. The genetic factors associated with susceptibility to asthma remain largely unknown. METHODS: We carried out a genomewide association study involving children with asthma. The sample included 793 North American children of European ancestry with persistent asthma who required daily inhaled glucocorticoid therapy and 1988 matched controls (the discovery set). We also tested for genomewide association in an independent cohort of 917 persons of European ancestry who had asthma and 1546 matched controls (the replication set). Finally, we tested for an association between 20 single-nucleotide polymorphisms (SNPs) at chromosome 1q31 and asthma in 1667 North American children of African ancestry who had asthma and 2045 ancestrally matched controls. RESULTS: In our meta-analysis of all samples from persons of European ancestry, we observed an association, with genomewide significance, between asthma and SNPs at the previously reported locus on 17q21 and an additional eight SNPs at a novel locus on 1q31. The SNP most strongly associated with asthma was rs2786098 (P=8.55×10-9). We observed replication of the association of asthma with SNP rs2786098 in the independent series of persons of European ancestry (combined P=9.3×10-11). The alternative allele of each of the eight SNPs on chromosome 1q31 was strongly associated with asthma in the children of African ancestry (P=1.6×10 -13 for the comparison across all samples). The 1q31 locus contains DENND1B, a gene that is expressed by natural killer cells and dendritic cells and that encodes a protein that interacts with the tumor necrosis factor a receptor. CONCLUSIONS: We have identified a locus containing DENND1B on chromosome 1q31.3 that is associated with susceptibility to asthma.

U2 - 10.1056/nejmoa0901867

DO - 10.1056/nejmoa0901867

M3 - Journal article

SN - 0028-4793

VL - 362

SP - 36

EP - 44

JO - New England Journal of Medicine

JF - New England Journal of Medicine

IS - 1

ER -

Variants of DENND1B associated with asthma in children

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