Rare variants at 16p11.2 are associated with common variable immunodeficiency

S. Melkorka Maggadottir; Jin Li; Joseph T. Glessner; Yun Rose Li; Zhi Wei; Xiao Chang; Frank D. Mentch; Kelly A. Thomas; Cecilia E. Kim; Yan Zhao; Cuiping Hou; Fengxiang Wang; Silje F. Jørgensen; Elena E. Perez; Kathleen E. Sullivan; Jordan S. Orange; Tom H. Karlsen; Helen Chapel; Charlotte Cunningham-Rundles; Hakon Hakonarson

doi:10.1016/j.jaci.2014.12.1939

Rare variants at 16p11.2 are associated with common variable immunodeficiency

S. Melkorka Maggadottir, Jin Li, Joseph T. Glessner, Yun Rose Li, Zhi Wei, Xiao Chang, Frank D. Mentch, Kelly A. Thomas, Cecilia E. Kim, Yan Zhao, Cuiping Hou, Fengxiang Wang, Silje F. Jørgensen, Elena E. Perez, Kathleen E. Sullivan, Jordan S. Orange, Tom H. Karlsen, Helen Chapel, Charlotte Cunningham-Rundles, Hakon Hakonarson

Faculty of Medicine

University of Iceland

Research output: Contribution to journal › Article › peer-review

Abstract

Background Common variable immunodeficiency (CVID) is characterized clinically by inadequate quantity and quality of serum immunoglobulins with increased susceptibility to infections, resulting in significant morbidity and mortality. Only a few genes have been uncovered, and the genetic background of CVID remains elusive to date for the majority of patients. Objective We sought to seek novel associations of genes and genetic variants with CVID. Methods We performed association analyses in a discovery cohort of 164 patients with CVID and 19,542 healthy control subjects genotyped on the Immuno BeadChip from Illumina platform; replication of findings was examined in an independent cohort of 135 patients with CVID and 2,066 healthy control subjects, followed by meta-analysis. Results We identified 11 single nucleotide polymorphisms (SNPs) at the 16p11.2 locus associated with CVID at a genome-wide significant level in the discovery cohort. The most significant SNP, rs929867 (P = 6.21 × 10^-9), is in the gene fused-in-sarcoma (FUS), with 4 other SNPs mapping to integrin CD11b (ITGAM). Results were confirmed in our replication cohort. Conditional association analysis suggests a single association signal at the 16p11.2 locus. A strong trend of association was also seen for 38 SNPs (P < 5 × 10^-5) in the MHC region, supporting that this is a genuine CVID locus. Interestingly, we found that 80% of patients with the rare ITGAM variants have reduced switched memory B-cell counts. Conclusion We report a novel association of CVID with rare variants at the FUS/ITGAM (CD11b) locus on 16p11.2. The association signal is enriched for promoter/enhancer markers in the ITGAM gene. ITGAM encodes the integrin CD11b, a part of complement receptor 3, a novel candidate gene implicated here for the first time in the pathogenesis of CVID.

Original language	English
Pages (from-to)	1569-1577
Number of pages	9
Journal	Journal of allergy and clinical immunology
Volume	135
Issue number	6
DOIs	https://doi.org/10.1016/j.jaci.2014.12.1939
Publication status	Published - 1 Jun 2015

Bibliographical note

Funding Information: Disclosure of potential conflict of interest: Y. R. Li is supported by the Paul and Daisy Soros Fellowship for New Americans and the NIH F30 Individual NRSA Training Grant. E. E. Perez has received consultancy fees from Baxter and CSL Behring; research support from CSL Behring ; lecture fees from the Eastern Allergy Conference and the American College of Allergy, Asthma & Immunology (ACAAI); and royalties from UpToDate. K. E. Sullivan has received consultancy fees from the Immune Deficiency Foundation and UpToDate, research support from Baxter , and royalties from UpToDate. J. S. Orange has received consultancy fees from CSL Behring, Baxter, Atlantic Research, Viracor, Octapharma, BPL, Cangene, and Amerisource Bergen; research support from CSL Behring ; lecture fees from Baxter; and royalties from UpToDate and Unimed Publishing. H. Chapel is a board member for Baxter Healthcare and has received consultancy fees from Biotest, LFB. The rest of the authors declare that they have no relevant conflicts of interest. Funding Information: Supported by an Institute Development Fund from CHOP , U01HG006830 , and a donation from the Kubert Estate Foundation. Publisher Copyright: © 2015 American Academy of Allergy, Asthma & Immunology.

Other keywords

ITGAM
Immunodeficiency
genome-wide association study
immunogenetics
rare variants

Access to Document

10.1016/j.jaci.2014.12.1939

Cite this

Maggadottir, S. M., Li, J., Glessner, J. T., Li, Y. R., Wei, Z., Chang, X., Mentch, F. D., Thomas, K. A., Kim, C. E., Zhao, Y., Hou, C., Wang, F., Jørgensen, S. F., Perez, E. E., Sullivan, K. E., Orange, J. S., Karlsen, T. H., Chapel, H., Cunningham-Rundles, C., & Hakonarson, H. (2015). Rare variants at 16p11.2 are associated with common variable immunodeficiency. Journal of allergy and clinical immunology, 135(6), 1569-1577. https://doi.org/10.1016/j.jaci.2014.12.1939

@article{d5a6329958344d4687a17cd108123000,

title = "Rare variants at 16p11.2 are associated with common variable immunodeficiency",

abstract = "Background Common variable immunodeficiency (CVID) is characterized clinically by inadequate quantity and quality of serum immunoglobulins with increased susceptibility to infections, resulting in significant morbidity and mortality. Only a few genes have been uncovered, and the genetic background of CVID remains elusive to date for the majority of patients. Objective We sought to seek novel associations of genes and genetic variants with CVID. Methods We performed association analyses in a discovery cohort of 164 patients with CVID and 19,542 healthy control subjects genotyped on the Immuno BeadChip from Illumina platform; replication of findings was examined in an independent cohort of 135 patients with CVID and 2,066 healthy control subjects, followed by meta-analysis. Results We identified 11 single nucleotide polymorphisms (SNPs) at the 16p11.2 locus associated with CVID at a genome-wide significant level in the discovery cohort. The most significant SNP, rs929867 (P = 6.21 × 10-9), is in the gene fused-in-sarcoma (FUS), with 4 other SNPs mapping to integrin CD11b (ITGAM). Results were confirmed in our replication cohort. Conditional association analysis suggests a single association signal at the 16p11.2 locus. A strong trend of association was also seen for 38 SNPs (P < 5 × 10-5) in the MHC region, supporting that this is a genuine CVID locus. Interestingly, we found that 80\% of patients with the rare ITGAM variants have reduced switched memory B-cell counts. Conclusion We report a novel association of CVID with rare variants at the FUS/ITGAM (CD11b) locus on 16p11.2. The association signal is enriched for promoter/enhancer markers in the ITGAM gene. ITGAM encodes the integrin CD11b, a part of complement receptor 3, a novel candidate gene implicated here for the first time in the pathogenesis of CVID.",

keywords = "ITGAM, Immunodeficiency, genome-wide association study, immunogenetics, rare variants",

author = "Maggadottir, \{S. Melkorka\} and Jin Li and Glessner, \{Joseph T.\} and Li, \{Yun Rose\} and Zhi Wei and Xiao Chang and Mentch, \{Frank D.\} and Thomas, \{Kelly A.\} and Kim, \{Cecilia E.\} and Yan Zhao and Cuiping Hou and Fengxiang Wang and J{\o}rgensen, \{Silje F.\} and Perez, \{Elena E.\} and Sullivan, \{Kathleen E.\} and Orange, \{Jordan S.\} and Karlsen, \{Tom H.\} and Helen Chapel and Charlotte Cunningham-Rundles and Hakon Hakonarson",

note = "Funding Information: Disclosure of potential conflict of interest: Y. R. Li is supported by the Paul and Daisy Soros Fellowship for New Americans and the NIH F30 Individual NRSA Training Grant. E. E. Perez has received consultancy fees from Baxter and CSL Behring; research support from CSL Behring ; lecture fees from the Eastern Allergy Conference and the American College of Allergy, Asthma \& Immunology (ACAAI); and royalties from UpToDate. K. E. Sullivan has received consultancy fees from the Immune Deficiency Foundation and UpToDate, research support from Baxter , and royalties from UpToDate. J. S. Orange has received consultancy fees from CSL Behring, Baxter, Atlantic Research, Viracor, Octapharma, BPL, Cangene, and Amerisource Bergen; research support from CSL Behring ; lecture fees from Baxter; and royalties from UpToDate and Unimed Publishing. H. Chapel is a board member for Baxter Healthcare and has received consultancy fees from Biotest, LFB. The rest of the authors declare that they have no relevant conflicts of interest. Funding Information: Supported by an Institute Development Fund from CHOP , U01HG006830 , and a donation from the Kubert Estate Foundation. Publisher Copyright: {\textcopyright} 2015 American Academy of Allergy, Asthma \& Immunology.",

year = "2015",

month = jun,

day = "1",

doi = "10.1016/j.jaci.2014.12.1939",

language = "English",

volume = "135",

pages = "1569--1577",

journal = "Journal of allergy and clinical immunology",

issn = "0091-6749",

publisher = "Elsevier Inc.",

number = "6",

}

Maggadottir, SM, Li, J, Glessner, JT, Li, YR, Wei, Z, Chang, X, Mentch, FD, Thomas, KA, Kim, CE, Zhao, Y, Hou, C, Wang, F, Jørgensen, SF, Perez, EE, Sullivan, KE, Orange, JS, Karlsen, TH, Chapel, H, Cunningham-Rundles, C & Hakonarson, H 2015, 'Rare variants at 16p11.2 are associated with common variable immunodeficiency', Journal of allergy and clinical immunology, vol. 135, no. 6, pp. 1569-1577. https://doi.org/10.1016/j.jaci.2014.12.1939

TY - JOUR

T1 - Rare variants at 16p11.2 are associated with common variable immunodeficiency

AU - Maggadottir, S. Melkorka

AU - Li, Jin

AU - Glessner, Joseph T.

AU - Li, Yun Rose

AU - Wei, Zhi

AU - Chang, Xiao

AU - Mentch, Frank D.

AU - Thomas, Kelly A.

AU - Kim, Cecilia E.

AU - Zhao, Yan

AU - Hou, Cuiping

AU - Wang, Fengxiang

AU - Jørgensen, Silje F.

AU - Perez, Elena E.

AU - Sullivan, Kathleen E.

AU - Orange, Jordan S.

AU - Karlsen, Tom H.

AU - Chapel, Helen

AU - Cunningham-Rundles, Charlotte

AU - Hakonarson, Hakon

N1 - Funding Information: Disclosure of potential conflict of interest: Y. R. Li is supported by the Paul and Daisy Soros Fellowship for New Americans and the NIH F30 Individual NRSA Training Grant. E. E. Perez has received consultancy fees from Baxter and CSL Behring; research support from CSL Behring ; lecture fees from the Eastern Allergy Conference and the American College of Allergy, Asthma & Immunology (ACAAI); and royalties from UpToDate. K. E. Sullivan has received consultancy fees from the Immune Deficiency Foundation and UpToDate, research support from Baxter , and royalties from UpToDate. J. S. Orange has received consultancy fees from CSL Behring, Baxter, Atlantic Research, Viracor, Octapharma, BPL, Cangene, and Amerisource Bergen; research support from CSL Behring ; lecture fees from Baxter; and royalties from UpToDate and Unimed Publishing. H. Chapel is a board member for Baxter Healthcare and has received consultancy fees from Biotest, LFB. The rest of the authors declare that they have no relevant conflicts of interest. Funding Information: Supported by an Institute Development Fund from CHOP , U01HG006830 , and a donation from the Kubert Estate Foundation. Publisher Copyright: © 2015 American Academy of Allergy, Asthma & Immunology.

PY - 2015/6/1

Y1 - 2015/6/1

N2 - Background Common variable immunodeficiency (CVID) is characterized clinically by inadequate quantity and quality of serum immunoglobulins with increased susceptibility to infections, resulting in significant morbidity and mortality. Only a few genes have been uncovered, and the genetic background of CVID remains elusive to date for the majority of patients. Objective We sought to seek novel associations of genes and genetic variants with CVID. Methods We performed association analyses in a discovery cohort of 164 patients with CVID and 19,542 healthy control subjects genotyped on the Immuno BeadChip from Illumina platform; replication of findings was examined in an independent cohort of 135 patients with CVID and 2,066 healthy control subjects, followed by meta-analysis. Results We identified 11 single nucleotide polymorphisms (SNPs) at the 16p11.2 locus associated with CVID at a genome-wide significant level in the discovery cohort. The most significant SNP, rs929867 (P = 6.21 × 10-9), is in the gene fused-in-sarcoma (FUS), with 4 other SNPs mapping to integrin CD11b (ITGAM). Results were confirmed in our replication cohort. Conditional association analysis suggests a single association signal at the 16p11.2 locus. A strong trend of association was also seen for 38 SNPs (P < 5 × 10-5) in the MHC region, supporting that this is a genuine CVID locus. Interestingly, we found that 80% of patients with the rare ITGAM variants have reduced switched memory B-cell counts. Conclusion We report a novel association of CVID with rare variants at the FUS/ITGAM (CD11b) locus on 16p11.2. The association signal is enriched for promoter/enhancer markers in the ITGAM gene. ITGAM encodes the integrin CD11b, a part of complement receptor 3, a novel candidate gene implicated here for the first time in the pathogenesis of CVID.

AB - Background Common variable immunodeficiency (CVID) is characterized clinically by inadequate quantity and quality of serum immunoglobulins with increased susceptibility to infections, resulting in significant morbidity and mortality. Only a few genes have been uncovered, and the genetic background of CVID remains elusive to date for the majority of patients. Objective We sought to seek novel associations of genes and genetic variants with CVID. Methods We performed association analyses in a discovery cohort of 164 patients with CVID and 19,542 healthy control subjects genotyped on the Immuno BeadChip from Illumina platform; replication of findings was examined in an independent cohort of 135 patients with CVID and 2,066 healthy control subjects, followed by meta-analysis. Results We identified 11 single nucleotide polymorphisms (SNPs) at the 16p11.2 locus associated with CVID at a genome-wide significant level in the discovery cohort. The most significant SNP, rs929867 (P = 6.21 × 10-9), is in the gene fused-in-sarcoma (FUS), with 4 other SNPs mapping to integrin CD11b (ITGAM). Results were confirmed in our replication cohort. Conditional association analysis suggests a single association signal at the 16p11.2 locus. A strong trend of association was also seen for 38 SNPs (P < 5 × 10-5) in the MHC region, supporting that this is a genuine CVID locus. Interestingly, we found that 80% of patients with the rare ITGAM variants have reduced switched memory B-cell counts. Conclusion We report a novel association of CVID with rare variants at the FUS/ITGAM (CD11b) locus on 16p11.2. The association signal is enriched for promoter/enhancer markers in the ITGAM gene. ITGAM encodes the integrin CD11b, a part of complement receptor 3, a novel candidate gene implicated here for the first time in the pathogenesis of CVID.

KW - ITGAM

KW - Immunodeficiency

KW - genome-wide association study

KW - immunogenetics

KW - rare variants

UR - https://www.scopus.com/pages/publications/84941232213

U2 - 10.1016/j.jaci.2014.12.1939

DO - 10.1016/j.jaci.2014.12.1939

M3 - Article

C2 - 25678086

SN - 0091-6749

VL - 135

SP - 1569

EP - 1577

JO - Journal of allergy and clinical immunology

JF - Journal of allergy and clinical immunology

IS - 6

ER -

Rare variants at 16p11.2 are associated with common variable immunodeficiency

Abstract

Bibliographical note

Other keywords

Access to Document

Fingerprint

Cite this