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Genome-wide association identifies diverse causes of common variable immunodeficiency.

Publication ,  Journal Article
Orange, JS; Glessner, JT; Resnick, E; Sullivan, KE; Lucas, M; Ferry, B; Kim, CE; Hou, C; Wang, F; Chiavacci, R; Kugathasan, S; Sleasman, JW ...
Published in: J Allergy Clin Immunol
June 2011

BACKGROUND: Common variable immunodeficiency (CVID) is a heterogeneous immune defect characterized by hypogammaglobulinemia, failure of specific antibody production, susceptibility to infections, and an array of comorbidities. OBJECTIVE: To address the underlying immunopathogenesis of CVID and comorbidities, we conducted the first genome-wide association and gene copy number variation (CNV) study in patients with CVID. METHODS: Three hundred sixty-three patients with CVID from 4 study sites were genotyped with 610,000 single nucleotide polymorphisms (SNPs). Patients were divided into a discovery cohort of 179 cases in comparison with 1,917 control subjects and a replication cohort of 109 cases and 1,114 control subjects. RESULTS: Our analyses detected strong association with the MHC region and association with a disintegrin and metalloproteinase (ADAM) genes (P combined = 1.96 × 10(-7)) replicated in the independent cohort. CNV analysis defined 16 disease-associated deletions and duplications, including duplication of origin recognition complex 4L (ORC4L) that was unique to 15 cases (P = 8.66 × 10(-16)), as well as numerous unique rare intraexonic deletions and duplications suggesting multiple novel genetic causes of CVID. Furthermore, the 1,000 most significant SNPs were strongly predictive of the CVID phenotype by using a Support Vector Machine algorithm with positive and negative predictive values of 1.0 and 0.957, respectively. CONCLUSION: Our integrative genome-wide analysis of SNP genotypes and CNVs has uncovered multiple novel susceptibility loci for CVID, both common and rare, which is consistent with the highly heterogeneous nature of CVID. These results provide new mechanistic insights into immunopathogenesis based on these unique genetic variations and might allow for improved diagnosis of CVID based on accurate prediction of the CVID clinical phenotypes by using our Support Vector Machine model.

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Published In

J Allergy Clin Immunol

DOI

EISSN

1097-6825

Publication Date

June 2011

Volume

127

Issue

6

Start / End Page

1360 / 7.e6

Location

United States

Related Subject Headings

  • Polymorphism, Single Nucleotide
  • Humans
  • Genome-Wide Association Study
  • Genetic Predisposition to Disease
  • Gene Frequency
  • DNA Copy Number Variations
  • Common Variable Immunodeficiency
  • Cohort Studies
  • Case-Control Studies
  • Artificial Intelligence
 

Citation

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Orange, J. S., Glessner, J. T., Resnick, E., Sullivan, K. E., Lucas, M., Ferry, B., … Hakonarson, H. (2011). Genome-wide association identifies diverse causes of common variable immunodeficiency. J Allergy Clin Immunol, 127(6), 1360-7.e6. https://doi.org/10.1016/j.jaci.2011.02.039
Orange, Jordan S., Joseph T. Glessner, Elena Resnick, Kathleen E. Sullivan, Mary Lucas, Berne Ferry, Cecilia E. Kim, et al. “Genome-wide association identifies diverse causes of common variable immunodeficiency.J Allergy Clin Immunol 127, no. 6 (June 2011): 1360-7.e6. https://doi.org/10.1016/j.jaci.2011.02.039.
Orange JS, Glessner JT, Resnick E, Sullivan KE, Lucas M, Ferry B, et al. Genome-wide association identifies diverse causes of common variable immunodeficiency. J Allergy Clin Immunol. 2011 Jun;127(6):1360-7.e6.
Orange, Jordan S., et al. “Genome-wide association identifies diverse causes of common variable immunodeficiency.J Allergy Clin Immunol, vol. 127, no. 6, June 2011, pp. 1360-7.e6. Pubmed, doi:10.1016/j.jaci.2011.02.039.
Orange JS, Glessner JT, Resnick E, Sullivan KE, Lucas M, Ferry B, Kim CE, Hou C, Wang F, Chiavacci R, Kugathasan S, Sleasman JW, Baldassano R, Perez EE, Chapel H, Cunningham-Rundles C, Hakonarson H. Genome-wide association identifies diverse causes of common variable immunodeficiency. J Allergy Clin Immunol. 2011 Jun;127(6):1360–7.e6.
Journal cover image

Published In

J Allergy Clin Immunol

DOI

EISSN

1097-6825

Publication Date

June 2011

Volume

127

Issue

6

Start / End Page

1360 / 7.e6

Location

United States

Related Subject Headings

  • Polymorphism, Single Nucleotide
  • Humans
  • Genome-Wide Association Study
  • Genetic Predisposition to Disease
  • Gene Frequency
  • DNA Copy Number Variations
  • Common Variable Immunodeficiency
  • Cohort Studies
  • Case-Control Studies
  • Artificial Intelligence