Complement Component C4 in Human Systemic Lupus Erythematosus: from Genetic Deficiencies to Copy-Number Variations
Year: 2009
Type: article
Study design: Observational Study
Abstract: A new paradigm in human genetics is the presence of frequent interindividual variations in copy-number (CNV) of specific genomic DNA segments.One such CNV locus encodes an immune effector protein, complement component C4.Located in the major histocompatibility complex (MHC), human C4 is a constituent of the RP-C4-CYP21-TNX module that exhibits a copynumber variation ranging from 2-10 per diploid genome.C4 CNV leads to parallel quantitative and qualitative variations of C4 proteins.The polymorphic C4 protein can be classified into two isotypes: the acidic C4A and the basic C4B.This dissertation focuses on investigating the quantitative and qualitative diversities of C4 in human systemic lupus erythematosus (SLE).The molecular defects of two North African patients with complete C4 deficiency who developed SLE were determined.These cases underscore the importance of C4 protein in the protection against SLE.To investigate if C4 CNV contributes to differential SLE risk, we developed specific and sensitive quantitative real-time PCR assays to interrogate the copynumbers of C4A and C4B.Large cohorts of SLE patients and race-matched controls of European, African and Asian ancestries were studied.The mean total iv C4 copy-numbers in SLE were consistently lower compared to those in controls.Such decrease was mainly due to homozygous and heterozygous deficiencies of C4A.We further genotyped C4 CNV and its closely linked DRB1 gene in the MHC in over 1,000 Caucasian subjects.We obtained evidence for that lower C4A copy-number and HLA-DR3 are overlapping but can be independent risk factors for SLE in Caucasians.The phenotypic serial changes of serum complement proteins C3 and C4, and RBC-bound C4d were characterized in a pilot cohort of SLE patients with defined C4 genotypes.Three distinct C4 protein profiles corresponding to different degrees of disease presentations were observed.In conclusion, low copy-numbers of C4A is a risk factor for SLE among different races.Elucidating C4 genotypes and classifying C4 protein profiles may be beneficial for diagnosis and management of SLE.v Dedicated to my beloved parents and grandparents vi ACKNOWLEDGEMENTS As I am reflecting on what I have accomplished in the past few years to prepare for this dissertation, I have also come to realize that I have been extremely lucky to have encountered so many wonderful people in my graduate school years.These people are undoubtedly the "良师益友"(good mentors and beneficial friends) in my life.They have contributed more than a fair share in my growth as a graduate student, as a scientist, and I must say that I am deeply grateful and indebted to all of them.First and foremost, I thank my advisor Dr. C. Yung Yu.He has provided me with every valuable learning opportunity, encouraged me to dream big, constantly challenged me for independent thinking, and believed in that "Yee Ling can do it" more than Yee Ling believed in it herself at times.Speaking with his actions, he has shown me what it takes to be a real scientist besides intellectual competence, and that is total dedication, extreme perseverance, and sometimes, stubborn optimism.It is difficult to list what he has taught me in science, and how much I have actually been able to absorb, but one thing is for sure: if I have not learned anything at all in science from him in the past five years, at least I have learned a thing or two about politics and college football.vii I also thank all my committee advisors for actively involving in my academic well-being.I thank Dr. Haikady Nagaraja for patiently teaching me statistics and showing me how to analyze complicated data.I thank Dr. Brad Rovin and Dr. Kim McBride for giving me valuable inputs on my projects from the perspective of medicine and genetics.They have constantly reminded me to think about the medical relevance of my studies.I thank all my committee members for taking time from their busy schedules to attend my committee meetings, my IBGP seminar, and my defense, and for carefully reading my dissertation and giving me helpful advise on not only the scientific aspects but also grammatical improvements.As one proceeds to read the following chapters, one will inevitably notice the magnitude of the amount of work involved.No bridge was built by one man.
Author: Yee Ling Wu
Institution: The Ohio State University
Language: English
Subfield: Rheumatology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2471338683