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 language | English |
|---|---|
| Journal | Journal of Allergy and Clinical Immunology |
| DOIs | |
| State | Accepted/In press - Mar 4 2014 |
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Keywords
- Genome-wide association study
- Immunodeficiency
- Immunogenetics
- ITGAM
- Rare variants
ASJC Scopus subject areas
- Immunology and Allergy
- Immunology
Cite this
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 journal › Article
}
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
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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UR - http://www.scopus.com/inward/citedby.url?scp=84922570729&partnerID=8YFLogxK
U2 - 10.1016/j.jaci.2014.12.1939
DO - 10.1016/j.jaci.2014.12.1939
M3 - Article
JO - Journal of Allergy and Clinical Immunology
JF - Journal of Allergy and Clinical Immunology
SN - 0091-6749
ER -