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The Roles of Complement C4A and C4B Genetic Diversity and HLA DRB1 Variants on Disease Associations with Juvenile Dermatomyositis and Systemic Lupus Erythematosus

Lintner, Katherine E
http://rave.ohiolink.edu/etdc/view?acc_num=osu1460986052

Abstract Details

2016, Doctor of Philosophy, Ohio State University, Molecular, Cellular and Developmental Biology.
Complement C4 is an immune protein with a wide range of effector functions, including disposal of apoptotic materials, clearance of immune complexes, and activation of the classical complement pathway resulting in cytolysis of microbes. Homozygous deficiencies of C4 or early complement components (C1q, C1r, or C1s), albeit rare, are strongly associated with the autoimmune disease systemic lupus erythematosus (SLE). Much more common than a complete genetic deficiency is “low” gene copy number (GCN) of C4, which varies among human genomes from two to eight copies. Low GCN of C4, specifically of the isotype C4A, is associated with SLE disease risk. However, it is known that C4A-deficient haplotypes in European Americans are in strong linkage disequilibrium (LD) with HLA allele DRB1*0301 on chromosome 6, which has been associated with other autoimmune diseases, including juvenile dermatomyositis (JDM). It remains a puzzle whether C4A deficiency, DRB1*0301, or both are responsible for the primary disease association because of the strong LD exhibited between the two genetic variants. We assessed GCNs for C4A, C4B, and HLA-DRB1 alleles in genetic risk of JDM. C4A deficiency was a risk factor for JDM independent of DRB1*0301, but the effect size was stronger when C4A deficiency and DRB1*0301 were present together. JDM patients with C4A deficiency had higher prevalence of elevated serum muscle enzymes at disease diagnosis and elevated erythrocyte-bound C4-derived activation products (E-C4d). We also observed that C4A deficiency is a strong risk factor for pediatric SLE susceptibility as is the case for adult SLE reported previously, but the effect size was greater in pediatric populations. Our regression analyses of Caucasian SLE patients and controls suggested that DRB1*0301 was likely secondary to C4A deficiency on disease susceptibility. Given the common observation of C4A deficiency in patients afflicted with JDM or SLE, a logical step forward would be the establishment of C4-based therapy for these patients. In a series of luciferase reporter assays, we confirmed the 3’ long terminal repeat (3’LTR) that flanks a retroviral insertion in intron 9 of C4 displays promoter activity, which could possibly initiate an antisense C4 transcript from exon 9 to exon 1. Moreover, we demonstrated the 3’LTR, in both orientations, enhanced C4 promoter activity in different human cultured cells. In healthy subjects from three different races, we showed a significant, negative correlation between the retroviral insert and C4 plasma protein levels. Cell culture assays and genotype-phenotype data indicate that the retroviral 3’LTR may interfere with C4 gene expression, possibly through antisense inhibition. Several observations here require thoughtful and investigative extensions of this work. It is of interest to study the 3’LTR and other cis-acting elements that may affect C4 gene expression. Furthermore, increasing the sample size of the study population and analyzing complement and HLA genetic risk factors in autoimmune diseases in other races will allow for a greater understanding of disease pathways, identify any common or race-specific genetic factors, and impact the field of human health by strengthening the prevention, treatment, maintenance, or cure of JDM, SLE, or other human immune-mediated diseases.
Chack-Yung Yu, D.Phil. (Advisor)
Carlos Alvarez, Ph.D. (Committee Member)
Heithem El-Hodiri, Ph.D. (Committee Member)
Wael Jarjour, M.D. (Committee Member)
Yusen Liu, Ph.D. (Committee Member)
209 p.
Genetics; Immunology; Molecular Biology
autoimmune diseases; systemic lupus erythematosus; juvenile dermatomyositis; complement system; complement C4; human leukocyte antigen region

Recommended Citations

Citations

  • Lintner, K. E. (2016). The Roles of Complement C4A and C4B Genetic Diversity and HLA DRB1 Variants on Disease Associations with Juvenile Dermatomyositis and Systemic Lupus Erythematosus [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1460986052

    APA Style (7th edition)

  • Lintner, Katherine. The Roles of Complement C4A and C4B Genetic Diversity and HLA DRB1 Variants on Disease Associations with Juvenile Dermatomyositis and Systemic Lupus Erythematosus . 2016. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1460986052.

    MLA Style (8th edition)

  • Lintner, Katherine. "The Roles of Complement C4A and C4B Genetic Diversity and HLA DRB1 Variants on Disease Associations with Juvenile Dermatomyositis and Systemic Lupus Erythematosus ." Doctoral dissertation, Ohio State University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=osu1460986052

    Chicago Manual of Style (17th edition)

osu1460986052
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This open access ETD is published by The Ohio State University and OhioLINK.