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Clinical features of patients with homozygous complement C4A or C4B deficiency
Inka Liesmaa1, Riitta Paakkanen2,3, Asko Järvinen1
1Division of Infectious Diseases, Inflammation Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
Insights
Homozygous deficiencies of complement C4A or C4B are linked to increased risks of lymphoma, celiac disease, and sarcoidosis. These C4 gene deficiencies also correlate with adverse drug reactions, highlighting potential new disease associations.
Area of Science:
- Immunology
- Genetics
Background:
- Homozygous deficiencies of complement C4A or C4B affect 1-10% of the population.
- Genetic variations in C4 are complex, often leading to C4 deficiencies being missed in genome-wide association studies.
- Clinical presentations of patients with C4 deficiencies have not been previously analyzed.
Purpose of the Study:
- To characterize the clinical features of patients with homozygous C4A or C4B deficiency.
- To identify potential disease associations with C4 deficiencies.
Main Methods:
- Genomic quantitative real-time PCR was used to assess C4A and C4B gene numbers.
- Medical histories of 32 C4A-deficient, 87 C4B-deficient, and 120 control patients were retrospectively analyzed.
Main Results:
- Novel associations were found between C4A deficiency and lymphoma, celiac disease, and sarcoidosis (12.5% of patients vs. 0.8-2.5% in controls).
- Both C4A and C4B deficiencies were associated with a higher incidence of adverse drug reactions leading to discontinuation (34.4% for C4A, 28.7% for C4B vs. 14.2% in controls).
Conclusions:
- Homozygous C4A or C4B deficiencies are associated with various unrecorded disease associations.
- The C4 gene should be considered a candidate gene in the study of these specific disease associations.
Introduction:
Homozygous deficiencies of complement C4A or C4B are detected in 1-10% of populations. In genome-wide association studies C4 deficiencies are missed because the genetic variation of C4 is complex. There are no studies where the clinical presentation of these patients is analyzed. This study was aimed to characterize the clinical features of patients with homozygous C4A or C4B deficiency.
Material And Methods:
Thirty-two patients with no functional C4A, 87 patients with no C4B and 120 with normal amount of C4 genes were included. C4A and C4B numbers were assessed with genomic quantitative real-time PCR. Medical history was studied retrospectively from patients' files.
Results:
Novel associations between homozygous C4A deficiency and lymphoma, coeliac disease and sarcoidosis were detected. These conditions were present in 12.5%, (4/32 in patients vs. 0.8%, 1/120, in controls, OR = 17.00, 95%CI = 1.83-158.04, p = 0.007), 12.5% (4/32 in patients vs. 0%, 0/120 in controls, OR = 1.14, 95%CI = 1.00-1.30, p = 0.002) and 12.5%, respectively (4/32 in patients vs. 2.5%, 3/120 in controls, OR = 5.571, 95%CI = 1.79-2.32, p = 0.036). In addition, C4A and C4B deficiencies were both associated with adverse drug reactions leading to drug discontinuation (34.4%, 11/32 in C4A-deficient patients vs. 14.2%, 17/120 in controls, OR = 3.174, 95%CI = 1.30-7.74, p = 0.009 and 28.7%, 25/87 in C4B-deficient patients, OR = 2.44, 95%CI = 1.22-4.88, p = 0.010).
Conclusion:
This reported cohort of homozygous deficiencies of C4A or C4B suggests that C4 deficiencies may have various unrecorded disease associations. C4 gene should be considered as a candidate gene in studying these selected disease associations.
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