Deficiency of Complement C4A or Low Copy Number of Total C4 Genes, HLA-DRB1*15 and HLA-DRB1*03 Are Strong Genetic Risk Factors for Pediatric SLE of European Descent

Stacy Ardoin¹, Pinar Ozge Avar Aydin², Lai Hin Kimi Chan³, Katherine Lintner⁴, Yee Ling Wu^5,6, Rabheh Aziz¹, Anjali Patwardhan^7,8, Evan Mulvihill¹, Gakit Yu⁹, Bi Zhou¹⁰, Emeli Lundstrom¹¹, Leonid Padyukov¹², Kyla Driest¹³, Cagri Yildirim-Toruner¹³, Sharon Bout-Tabaku¹³, Charles Spencer¹⁴, Gloria Higgins¹, Sampath Prahalad¹⁵, Hermine Brunner¹⁶ and Chack-Yung Yu^10,17, ¹Pediatrics and Rheumatology, Nationwide Children's Hospital and The Ohio State University, Columbus, OH, ²Rheumatology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, ³Pediatrics, Emory University School of Medicine, Atlanta, GA, ⁴Pediatrics, Nationwide Children's Hospital, Columbus, OH, ⁵The Research Institute at Nationwide Children's Hospital and The Ohio State University, Columbus, OH, ⁶Center for Molecular and Human Genetics, The Research Institute at Nationwide Children's Hospital, Columbus, OH, ⁷Pediatric Rheumatology, Nationwide Childrens Hospital, Columbus, OH, ⁸Pediatric Rheumatology, Nationwide Children's Hospital, Columbia, MO, ⁹Center for Molecular and Human Genetics, Nationwide Children's Hospital, Columbus, OH, ¹⁰Center for Molecular and Human Genetics, The Research Institute at Nationwide Children's Hospital and The Ohio State University, Columbus, OH, ¹¹Rheumatology, Karolinska Institute, Stockholm, Switzerland, ¹²Rheumatology Unit, Department of Medicine, Karolinska Institutet and Karolinska Hospital, Stockholm, Sweden, ¹³Rheumatology, Nationwide Children's Hospital, Columbus, OH, ¹⁴Rheumatology, Nationwide Childrens Hospital/OSU, Columbus, OH, ¹⁵Pediatrics, Emory Children's Center, Atlanta, GA, ¹⁶Rheumatology, PRCSG, Cincinnati, OH, ¹⁷Pediatrics, Ohio State Univ, Columbus, OH

Meeting: 2017 Pediatric Rheumatology Symposium

Keywords: complement, complement deficiency and genetics, SLE

Session Information

Date: Thursday, May 18, 2017

Title: Genetics and Pathogenesis Poster Session

Session Type: Abstract Submissions

Session Time: 5:30PM-7:00PM

Background/Purpose: A complete genetic deficiency of complement C4 almost always leads to the pathogenesis of systemic lupus erythematosus (SLE) with childhood onset, although its prevalence is extremely low. On the other hand, low gene copy number (GCN) of total C4 and genetic deficiency of C4A occur between 33 and 40% in adult SLE (aSLE) of European ancestry. Located centromeric to C4 on chromosome 6 is another SLE risk factor, specific alleles of HLA-DRB1. The objective of this study is to determine the effects of complement C4 gene copy number variations, C4A deficiency and HLA-DRB1 variants on the risk of pediatric SLE (pSLE).

Methods: Pediatric SLE patients and control subjects were recruited from Ohio and Atlanta, which included 105 Caucasian patients and 937 race-matched healthy subjects. The female to male ratio of pSLE was 5.7 to 1. GCNs of total C4, C4A, C4B, long and short C4 genes were determined by genomic Southern blot analyses, and/or TaqMan-based, quantitative realtime PCR using five amplicons. HLA-DRB1 variants were determined by 20 sets of specific PCR, and gel electrophoresis. Published data from 373 White aSLE were used for comparison.

Results: The copy number of total C4 genes varies from 2 to 8 copies in a diploid genome. Each of those C4 genes may code for an acidic C4A or a basic C4B protein. Low GCN of total C4 (C4T≤3) was present in 45.7% of pSLE, 42.9% of aSLE and 28.4% of healthy controls. The odds ratios and 95% confidence interval for C4T≤3 was 2.1 (1.4-3.2) in pSLE (p=0.0004), and 1.9 (1.5-2.5) in aSLE (p=4.4×10^-7). Homozygous and heterozygous deficiency of C4A (C4A≤1) occurred in 39.8% of pSLE, 32.7% of aSLE, and 18.6% of healthy controls. The odds ratios for C4A deficiency were 2.9 (1.6-4.9) in pSLE (p=2.6×10^-6), and 2.1 (1.6-2.8) in aSLE (p=9.9×10^-8). HLA-DRB1*15 (DR2) has a frequency of 45.7% in pSLE, 31.7% in aSLE and 27.9% in controls. The odds ratios of DRB1*15 were 2.2 (1.2-4.0) for pSLE (p=0.015), but only 1.2 (0.89-1.6) for aSLE (p=0.23). Another DRB1 allele *03 (DR3) had similar frequencies in pSLE (37.0%) and aSLE (38.6%), but a significantly lower frequency in controls (26.7%). Subjects with a homozygosity of C4A deficiency, or HLA-DRB1*15, or HLA-DRB1*03 together are present in 6.0% of healthy controls, but 26.7% of pSLE [OR=5.7 (2.7-12.2), p=4×10^-5] and 15.9% of aSLE [OR=3.0 (1.9-4.70), p=2.5×10^-6].

Conclusion: C4A deficiency and low GCN of total C4 are significant risk factors for pediatric and adult SLE of European ancestry, but their effect sizes are consistently larger for pSLE. HLA-DRB1*15 plays an important role on the risk of pSLE. C4A deficiency, HLA-DRB1*15 and HLA-DRB1*03 have strong effects on conferring high risk of pSLE.

Disclosure: S. Ardoin, None; P. O. Avar Aydin, None; L. H. K. Chan, None; K. Lintner, None; Y. L. Wu, None; R. Aziz, None; A. Patwardhan, None; E. Mulvihill, None; G. Yu, None; B. Zhou, None; E. Lundstrom, None; L. Padyukov, None; K. Driest, None; C. Yildirim-Toruner, None; S. Bout-Tabaku, None; C. Spencer, None; G. Higgins, None; S. Prahalad, None; H. Brunner, None; C. Y. Yu, None.

To cite this abstract in AMA style:

Ardoin S, Avar Aydin PO, Chan LHK, Lintner K, Wu YL, Aziz R, Patwardhan A, Mulvihill E, Yu G, Zhou B, Lundstrom E, Padyukov L, Driest K, Yildirim-Toruner C, Bout-Tabaku S, Spencer C, Higgins G, Prahalad S, Brunner H, Yu CY. Deficiency of Complement C4A or Low Copy Number of Total C4 Genes, HLA-DRB1*15 and HLA-DRB1*03 Are Strong Genetic Risk Factors for Pediatric SLE of European Descent [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 4). https://acrabstracts.org/abstract/deficiency-of-complement-c4a-or-low-copy-number-of-total-c4-genes-hla-drb115-and-hla-drb103-are-strong-genetic-risk-factors-for-pediatric-sle-of-european-descent/. Accessed .

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