Susceptibility for Lupus Nephritis by Low Copy Number of theFCGR3BGene Is Linked to Increased Levels of Pathogenic Autoantibodies

Abstract

Low copy number (CN) of the FCGR3B gene reduces FCGR3B membrane expression on neutrophils and results in clearance of a smaller amount of immune complex. We investigated FCGR3B CN in relation to the clinical phenotype in a Caucasian SLE cohort (n = 107). FCGR3B CN was determined by three different qPCR parameter estimations (Ct−, Cy0, and cpD1) and confirmed by the FCGR2C/FCGR2A paralog ratio test. Clinical and serological data were then analyzed for their association with FCGR3B CN. Low FCGR3B CN (<2) was more frequent in SLE patients than in healthy controls (n = 162) (20% versus 6%, OR 4.15, P = 0.003) and associated with higher disease activity scores (SLEDAI 10.4 versus 6.1, P = 0.03), lupus nephritis (LN) (25 versus 5%, P = 0.03), and increased levels of antibodies against dsDNA (81 versus 37 IU, P = 0.03), C1q (22 versus 6 IU, P = 0.003), and ribosomal P (10 versus 5 IU, P = 0.01). No such associations were seen with antibodies against extractable nuclear antigens or high FCGR3B CN (>2). In multivariate analyses, LN was independently associated with anti-C1q-Ab levels (P = 0.03) and low FCGR3B CN (P = 0.09). We conclude that the susceptibility for LN in patients with low FCGR3B CN is linked to increased levels of pathogenic autoantibodies.

Low copy number of FCGR3B is associated with lupus nephritis in a Chinese population

“…The association between a low copy number of FCGR3B and LN is in accordance with studies in Afro-Caribbean and Caucasian populations (11)(12)(13)(14)(15) and is consistent with Chen et al's (8) and Niederer et al's (28) studies of Chinese populations. Furthermore, one previously published meta-analysis indicated that a low copy number of FCGR3B was a risk factor for LN (30), suggesting that there is a positive association between low copy number of FCGR3B and a risk of developing LN.…”

“…Previous studies regarded FCGR3B CNV as a risk factor for a range of autoimmune diseases, including rheumatoid arthritis and SLE (11)(12)(13)(14)(15)27). A copy number <2 of FCGR3B has emerged as a susceptibility factor in Caucasian patients with SLE.…”

“…Reduced FCGR3B expression is thus, likely to contribute to the impaired clearance of immune complexes, which is a feature of LN, explaining the association between low FCGR3B CN and LN. A study by Nossent et al (15) demonstrated that a low copy number of FCGR3B was associated with SLEDAI, increased levels of anti-dsDNA antibody and ribosomal P. Furthermore, Chen et al (8) revealed that FCGR3B low copy number genotypes were significantly enriched in SLE patients with ulcer and nephritis. However, the present study failed to find any association between FCGR3B CNV and the clinical features of LN.…”

Omics technologies for kidney disease research

“…These association studies usually compare SLEassociated loci between those individuals with and without LN. Most of the susceptibility loci discovered by these strategies are related to immunity, such as complementmediated phagocytosis, antibody-mediated cytotoxicity, and T-cell function (Kim-Howard et al, 2009;Nossent et al, 2013;Qin et al, 2010;Zhou et al, 2010). While candidate gene association studies have provided important findings, this approach is based on assumptions about the pathogenesis of the disease, and is limited in its ability to identify new disease loci and pathways.…”

Genetics of Lupus Nephritis: Clinical Implications

“…46 The NA1 and NA2 alleles may also affect interactions with other cell surface receptors, such as the β2-integrin, CD11b/CD18 46 (ITGAM), whose genetic variants have also been linked to LN. 26,47,48 Low copy number of FCGR3A 49 and FCGR3B 50 have also been linked to LN.…”