Relationship between copy number of genes (C4A, C4B) encoding the fourth component of complement and the clinical course of hereditary angioedema (HAE)

In order to study if in patients with hereditary angioedema (HAE), copy number of the two genes (C4A and C4A) encoded in the central region of main histocompatibility complex (MHC) influences the diagnostically important C4 serum concentration as well as the clinical course of the disease, we determined copy number of the complement C4A and C4B genes in DNA samples of 95 HAE patients and 246 healthy controls. Distribution of both the C4A and C4B copy numbers significantly (p=0.0183 and 0.0318, respectively) differed between the two groups, the most marked difference we observed was the lower frequency of the high (3 or 4) C4A copy numbers in the patients. As it expected, the dosage of both C4A and C4B genes positively correlated to the longitudinally measured serum C4 concentrations. Moreover, we found an unexpected clinical correlation with the dosage of the C4B gene. The course of the disease was milder in the 9/95 patients carrying 3 or 4 copies of C4B gene, compared to the rest of patients, i.e. diagnosis was established at significantly (p=0.0052) older age (36.0 (31.0-39.5)) years versus 20.5 (7.5-31.5 years), bi-yearly attack rate was significantly (p=0.0145) lower (1.0 (0.0-11.0)) versus 11.0 (3.5-21.5), and the over-all activity of the classical pathway and the enzyme-inhibitor activity of the C1-inhibitor (C1-INH) was closer to the normal values. These observations indicate that high copy number of the C4B gene can be a protective factor against disease severity in HAE and therefore its determination is warranted