Poster Display B Cell Biology

APPROACH TO GENETIC ANALYSIS OF NON-MONOGENIC ANTIBODY DEFICIENCY

Lecture Time
10:00 - 10:01
Presenter
  • Hassan Abolhassani, Sweden
Room
Poster Area
Date
19.09.2019, Thursday
Session Time
10:00 - 17:00
Board Number
10
Presentation Topic
B Cell Biology

Abstract

Background and Aims

Primary antibody deficiencies (PAD) are caused by developmental or functional defects of humoral immunity, resulting in increased susceptibility to bacterial and viral infections. Etiology of 40-80% of patients with PAD, the second most common type of human immune system disorders after human immunodeficiency virus infection, is yet unknown.

Methods

Monogenic patients were identified in a CVID cohort using whole exome sequencing and full-resolution MHC typing. Exome-wide polygenic scores were developed using significantly different variants and multi-variant Mendelian-randomization (MR) analyses were used to test the causality of significant genetic variants on antibody levels and susceptibility to infectious diseases.

Results

Among 83 CVID patients (44.5% females), monogenic defects were found in 40 individuals. Evaluation of the remaining patients with non-monogenic CVID showed 13 and 27 significantly associated MHC-class I and II alleles, respectively. The most significant partial haplotype linked with the non-monogenic from of CVID was W*01:01:01-DMA*01:01:01-DMB*01:03:01:02-TAP1*01:01:01 (P<0.001), where carriers had a late onset of the disease, an infections only clinical phenotype, a sporadic form of CVID, post-germinal center defects and a non-progressive form of their disease. Exclusion of monogenic diseases allowed MR analyses to identify significant genetic variants associated with bacterial infections and improved discrepancies observed in MR analyses of previous studies with low pleiotropy mainly for a lower respiratory infection, bacterial infection and Streptococcal infection.

Conclusions

The full-resolution MHC typing and polygenic scores on CVID patients showed that exclusion of monogenic forms of the disease unraveled an independent role of MHC genes and common genetic variants in the pathogenesis of CVID.

Hide