Genetically Determined Partial Complement C4 Deficiency States Are Not Independent Risk Factors for SLE in UK and Spanish Populations

Lora Boteva,David L Morris,Josefina Cortés-Hernández,Javier Martin,Timothy J Vyse,Michelle M.A Fernando

doi:10.1016/j.ajhg.2012.01.012

Abstract

Systemic lupus erythematosus (SLE) is a chronic, multisystem autoimmune disease. Complete deficiency of complement component C4 confers strong genetic risk for SLE. Partial C4 deficiency states have also shown association with SLE, but despite much effort over the last 30 years, it has not been established whether this association is primarily causal or secondary to long-range linkage disequilibrium. The complement C4 locus, located in the major histocompatibility complex (MHC) class III region, exhibits copy-number variation (CNV) and C4 itself exists as two paralogs, C4A and C4B. In order to determine whether partial C4 deficiency is an independent genetic risk factor for SLE, we investigated C4 CNV in the context of HLA-DRB1 and MHC region SNP polymorphism in the largest and most comprehensive complement C4 study to date. Specifically, we genotyped 2,207 subjects of northern and southern European ancestry (1,028 SLE cases and 1,179 controls) for total C4, C4A, and C4B gene copy numbers, and the loss-of-function C4 exon 29 CT indel. We used multiple logistic regression to determine the independence of C4 CNV from known SNP and HLA-DRB1 associations. We clearly demonstrate that genetically determined partial C4 deficiency states are not independent risk factors for SLE in UK and Spanish populations. These results are further corroborated by the lack of association shown by the C4A exon 29 CT insertion in either cohort. Thus, although complete homozygous deficiency of complement C4 is one of the strongest genetic risk factors for SLE, partial C4 deficiency states do not independently predispose to the disease.

Highlights

Systemic lupus erythematosus ([SLE] known as lupus [MIM 152700]) is a chronic, multisystem, clinically heterogeneous autoimmune disease characterized by the presence of autoantibodies directed against nuclear and cellular components, complement activation, and immune complex deposition resulting in tissue inflammation and organ damage
We performed multiple logistic regression (MLR) to determine independent effects for each of the five chosen markers at the major histocompatibility complex (MHC); every marker was tested for association conditional on PC1 as a covariate and each of the other four markers as a covariate, resulting in four tests for every marker used as a covariate
We looked for interactions between C4A and C4B and independently associated variants across the MHC by using the glm function in R

Summary

Introduction

Systemic lupus erythematosus ([SLE] known as lupus [MIM 152700]) is a chronic, multisystem, clinically heterogeneous autoimmune disease characterized by the presence of autoantibodies directed against nuclear and cellular components, complement activation, and immune complex deposition resulting in tissue inflammation and organ damage. SNP-based genome-wide association studies have shown that polymorphisms within the major histocompatibility complex (MHC) region, located on the short arm of chromosome 6, confer the greatest genetic risk for SLE.[1,2,3] The classical MHC region comprises three subregions: the telomeric class I region, the centromeric class II region, and the intervening class III region. The MHC class I and class II regions encode the human leucocyte antigen (HLA) class I and class II molecules involved in antigen presentation to T lymphocytes.[4] Genetic variants within classical HLA class I and HLA class II molecules as well as deficiency states of complement C4, encoded in the class III region of the MHC, were among the first to show association with SLE in the early 1970s.5–7. The most consistent HLA associations with SLE reside within the class II alleles, HLA-DRB1*03:01 (DR3) and HLA-DRB1*15:01 (DR2) and their respective extended haplotypes in European populations.[8]

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Conclusion