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

被引：23

作者：

Maggadottir, S. Melkorka ^{[1
,2
]}

Li, Jin ^{[2
]}

Glessner, Joseph T. ^{[2
]}

Li, Yun Rose ^{[2
]}

Wei, Zhi ^{[4
]}

Chang, Xiao ^{[2
]}

Mentch, Frank D. ^{[2
]}

Thomas, Kelly A. ^{[2
]}

Kim, Cecilia E. ^{[2
]}

Zhao, Yan ^{[2
]}

Hou, Cuiping ^{[2
]}

Wang, Fengxiang ^{[2
]}

Jorgensen, Silje F. ^{[5
]}

Perez, Elena E. ^{[6
]}

Sullivan, Kathleen E. ^{[1
]}

Orange, Jordan S. ^{[7
]}

Karlsen, Tom H. ^{[5
]}

Chapel, Helen ^{[8
,9
]}

Cunningham-Rundles, Charlotte ^{[10
,11
]}

Hakonarson, Hakon ^{[2
,3
,12
,13
]}

机构：

[1] Childrens Hosp Philadelphia, Div Allergy & Immunol, Philadelphia, PA USA

[2] Childrens Hosp Philadelphia, Ctr Appl Genom, Abramson Res Ctr, Philadelphia, PA USA

[3] Childrens Hosp Philadelphia, Div Human Genet, Philadelphia, PA USA

[4] New Jersey Inst Technol, Dept Comp Sci, Newark, NJ 07102 USA

[5] Oslo Univ Hosp, Rikshosp, Div Canc Med Surg & Transplantat, Internal Med Res Inst,KG Jebsen Inflammat Res Ctr, N-0450 Oslo, Norway

[6] Univ S Florida, Dept Pediat, Div Rheumatol Allergy & Immunol, St Petersburg, FL USA

[7] Texas Childrens Hosp, Sect Immunol Allergy & Rheumatol, Houston, TX 77030 USA

[8] Univ Oxford, Nuffield Dept Med, Oxford OX1 2JD, England

[9] Oxford Radcliffe Hosp, Oxford, England

[10] Mt Sinai Sch Med, Inst Immunol, New York, NY USA

[11] Mt Sinai Sch Med, Dept Med, New York, NY USA

[12] Univ Penn, Perelman Sch Med Philadelphia, Dept Pediat, Philadelphia, PA 19104 USA

[13] Univ Penn, Perelman Sch Med Philadelphia, Med Scientist Training Program, Philadelphia, PA 19104 USA

来源：

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY | 2015年 / 135卷 / 06期

关键词：

Immunodeficiency; immunogenetics; genome-wide association study; ITGAM; rare variants; SYSTEMIC-LUPUS-ERYTHEMATOSUS; AMYOTROPHIC-LATERAL-SCLEROSIS; ANTIBODY-DEFICIENCY SYNDROME; GENOME-WIDE ASSOCIATION; NF-KAPPA-B; COMPLEMENT RECEPTOR-3; T-CELLS; FUNCTIONAL VARIANT; CRITICAL REGULATOR; DENDRITIC CELLS;

D O I：

10.1016/j.jaci.2014.12.1939

中图分类号：

R392 [医学免疫学];

学科分类号：

100102 ;

摘要：

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 Bead Chip from Il lumina 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 x 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 x 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 FUSIITGAM (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.

引用

页码：1569 / 1577

页数：9