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

Research output: Contribution to journalArticle

11 Citations (Scopus)

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. Astrong 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 languageEnglish
JournalJournal of Allergy and Clinical Immunology
DOIs
StateAccepted/In press - Mar 4 2014

Fingerprint

Common Variable Immunodeficiency
Single Nucleotide Polymorphism
Genes
Integrins
Sarcoma
Nucleotide Mapping
Healthy Volunteers
Macrophage-1 Antigen
Wiskott-Aldrich Syndrome
Meta-Analysis
Immunoglobulins
B-Lymphocytes
Cell Count
Genome
Morbidity

Keywords

  • Genome-wide association study
  • Immunodeficiency
  • Immunogenetics
  • ITGAM
  • Rare variants

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Maggadottir, S. M., Li, J., Glessner, J. T., Li, Y. R., Wei, Z., Chang, X., ... Hakonarson, H. (Accepted/In press). Rare variants at 16p11.2 are associated with common variable immunodeficiency. Journal of Allergy and Clinical Immunology. https://doi.org/10.1016/j.jaci.2014.12.1939

Rare variants at 16p11.2 are associated with common variable immunodeficiency. / Maggadottir, S. Melkorka; Li, Jin; Glessner, Joseph T.; Li, Yun Rose; Wei, Zhi; Chang, Xiao; Mentch, Frank D.; Thomas, Kelly A.; Kim, Cecilia E.; Zhao, Yan; Hou, Cuiping; Wang, Fengxiang; Jørgensen, Silje F.; Perez, Elena E.; Sullivan, Kathleen E.; Orange, Jordan S.; Karlsen, Tom H.; Chapel, Helen; Cunningham-Rundles, Charlotte; Hakonarson, Hakon.

In: Journal of Allergy and Clinical Immunology, 04.03.2014.

Research output: Contribution to journalArticle

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 2014, 'Rare variants at 16p11.2 are associated with common variable immunodeficiency', Journal of Allergy and Clinical Immunology. https://doi.org/10.1016/j.jaci.2014.12.1939
Maggadottir, S. Melkorka ; Li, Jin ; Glessner, Joseph T. ; Li, Yun Rose ; Wei, Zhi ; Chang, Xiao ; Mentch, Frank D. ; Thomas, Kelly A. ; Kim, Cecilia E. ; Zhao, Yan ; Hou, Cuiping ; Wang, Fengxiang ; Jørgensen, Silje F. ; Perez, Elena E. ; Sullivan, Kathleen E. ; Orange, Jordan S. ; Karlsen, Tom H. ; Chapel, Helen ; Cunningham-Rundles, Charlotte ; Hakonarson, Hakon. / Rare variants at 16p11.2 are associated with common variable immunodeficiency. In: Journal of Allergy and Clinical Immunology. 2014.
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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. Astrong 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.",
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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

PY - 2014/3/4

Y1 - 2014/3/4

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. Astrong 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. Astrong 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 - Genome-wide association study

KW - Immunodeficiency

KW - Immunogenetics

KW - ITGAM

KW - Rare variants

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