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Effects of Complement C4 Gene Copy Number Variations, Size Dichotomy, and C4A Deficiency on Genetic Risk and Clinical

Ji Yih Chen1, Yee Ling Wu2, Mo Yin Mok3

  • 1Department of Medicine, Division of Allergy, Immunology and Rheumatology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taiwan, Republic of China.

Arthritis & Rheumatology (Hoboken, N.J.)
|January 28, 2016
PubMed

Insights

Copy number variations in complement C4 (C4) influence systemic lupus erythematosus (SLE) risk. High C4 gene copy numbers protect against SLE in East Asians, while C4A deficiency is a significant risk factor, differing in genetic basis between ethnic groups.

Area of Science:

  • Immunogenetics
  • Molecular Biology
  • Human Genetics

Background:

  • Human complement C4 (C4) exhibits complex diversity with multiple layers of variation.
  • Understanding C4 copy number variations (CNVs) and their association with disease risk, particularly in systemic lupus erythematosus (SLE), is crucial.
  • Investigating racial differences in C4A deficiency mechanisms can provide insights into SLE pathogenesis.

Purpose of the Study:

  • To elucidate the role of C4A and C4B copy number variations (CNVs) in systemic lupus erythematosus (SLE) risk.
  • To compare the genetic basis of C4A deficiency between East Asian and European populations.
  • To identify genetic factors contributing to C4 deficiency and its clinical manifestations.

Main Methods:

  • Genotyping technologies were employed to determine gene copy numbers (GCNs) of total C4, C4A, and C4B in 999 SLE patients and 1,347 healthy East Asian subjects.
  • Analysis included variations in C4-Long and C4-Short genes, and investigation of genomic regions with C4B96.
  • Comparison of C4 CNV and deficiency patterns with European populations, including HLA linkage analysis.

Main Results:

  • High GCNs of total C4 and C4A demonstrated a protective effect against SLE in East Asians; low/medium GCNs and absence of C4-Short genes were risk factors.
  • Homozygous C4A deficiency, though infrequent, significantly increased SLE susceptibility (OR 12.4). Low serum complement levels correlated with low C4 GCNs and were associated with anti-dsDNA antibodies, hemolytic anemia, and renal disease.
  • Distinct C4 haplotypes underlie C4A deficiency in East Asians (recombinant, bimodular C4-Long/C4-Short, linked to HLA-DRB1*1501) compared to Europeans (monomodular-Short, linked to HLA-DRB1*0301), with C4B96 showing an E920K polymorphism.

Conclusions:

  • C4 CNVs and C4A deficiency are significant contributors to SLE risk and disease manifestations in both East Asian and European populations.
  • Genetic variations in C4 influence susceptibility to SLE and its associated clinical features.
  • Understanding these genetic underpinnings is vital for comprehending SLE pathogenesis across diverse ethnic groups.
Abstract

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