205-P Immunogenetics of complement C4 deficiencies

S144

Abstracts

204-P

DRB1*07:01 INCREASES RISK FOR BACTERIAL VAGINOSIS IN BLACK WOMEN. Janelle A. Noble,1 Jill Hollenbach,1 Julie A. Lane,1 Jenifer Allsworth.2 1Research, Children’s Hospital Oakland Research Institute, Oakland, CA, USA; 2Obstetrics and Gynecology, Washington University in St. Louis School of Medicine, St. Louis, MO, USA. Aim: The prevalence of BV is higher in Black women than in White women, even after accounting for cofounders, such as socioeconomic status and sexual behavior. Because of its role in immune system recognition of pathogens, classical HLA alleles are associated with most autoimmune and infectious disease. HLA allele frequencies and haplotypic combinations vary among populations. The aim of this study is to test the hypothesis that alleles at the HLA-DRB1 locus are associated with risk for Bacterial Vaginosis (BV) and that HLA association in BV may help explain ethnic disparities. Methods: Subjects were selected from the contraceptive CHOICE study in the St. Louis metropolitan area. All subjects (144 patients and 110 controls) were Black. HLA DRB1 genotyping was performed either by SSO or by next generation sequencing (Roche 454). Chi-square tests for heterogeneity between patient and control allele frequencies were performed, with rare alleles combined into a common class. Results: While the allele frequency distribution for the control group conformed to expectations under Hardy-Weinberg Equilibrium proportions, the patient group did not. Overall allele distribution of DRB1 alleles did not differ significantly in patients vs. controls (p ⫽ 0.1). However, DRB1*07:01 was significantly overrepresented in the patient population vs. the controls (p ⫽ 0.01). Conclusions: These data suggest that the allele DRB1*07:01, or something in linkage disequilibrium with it, is associated with BV in Black women. Further testing, including genotyping of the DQ-encoding loci, is required to determine whether or not this association is with an African-specific DR7 haplotype, which could help explain the disproportionately high number of Black women affected with BV.

205-P

IMMUNOGENETICS OF COMPLEMENT C4 DEFICIENCIES. Riitta Paakkanen,1,2 Annika Wennerström,1 Inka Liesmaa,3 Jari Suvilehto,4,5 Mikko Seppänen,3 Asko Järvinen,3 Ville Valtonen,3 Markku S. Nieminen,2 Juha Sinisalo,2 Marja-Liisa Lokki.1 1Haartman Institute, Transplantation Laboratory, University of Helsinki, Helsinki, Finland; 2Department of Medicine, Division of Cardiology, Helsinki University Central Hospital, Helsinki, Finland; 3Department of Medicine, Division of Infectious Diseases, Helsinki University Central Hospital, Helsinki, Finland; 4Haartman Institute, Department of Bacteriology and Immunology, University of Helsinki, Helsinki, Finland; 5Department of Otorhinolaryngology, Helsinki University Central Hospital, Helsinki, Finland. Aim: Complement activation acts as immune surveillance system on healthy and altered host cells and foreign intruders. C4 is a component of C3 convertase in classical and lectin complement pathways, expressed in two polymorphic isotypes, C4A and C4B. Most humans have two copies of C4A and C4B genes at MHC class III region. We are focusing on the C4 deficiencies (less than two copies) that are common and have been associated with a variety of infections and immunologically mediated diseases. Methods: We have developed SYBR® Green labeled real-time quantitative PCR for detection of genomic copy numbers of C4A, C4B and C4A silencing mutation CTins (in exon 29). We have analyzed C4 deficiencies together with HLA-A, -B, -DRB1 and other class III genes in chronic C. pneumoniae and recurrent herpes simplex virus 1 and 2 infections, chronic rhinosinuitis, severe periodontitis, sarcoidosis and in coronary artery disease. Results: 1600 patients studied for suffering from recurrent infections had more C4A deficiencies than subjects in the general population (OR⫽1.93, 95% CI⫽1.13-3.29, P⫽0.014). Complete deficiency (no copies) of C4A (n⫽21) and C4B (n⫽70) were collected from these patients and characterized using clinical parameters and detailed patient history. In case-control studies of altogether 750 Finnish patients and more than 400 controls, partial C4 deficiencies (only one copy) associated independently with recurrent, chronic infections, served as a pharmacological marker for secondary antibiotic treatment of coronary artery disease and associated with elevated autoantibody concentrations. Conclusions: Our studies show that C4 deficiencies, in interaction with HLA, subject to chronic and infectious conditions and are related to inflammatory diseases. Our observations weight the importance to study multiple MHC functions simultaneously to identify the predisposing and protective immunity components.