Complement Component 4 Copy Number Variation and.pdf

Complement Component 4 Copy Number Variation and CYP21A2 Genotype Associations in Patients with Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency Wuyan Chen1, Zhi Xu1, Miki Nishitani2, Carol Van Ryzin2, Nazli B. McDonnell1,4, and Deborah P. Merke2,3 1Laboratory of Clinical Investigation, National Institute on Aging, Baltimore, Maryland, USA 2National Institutes of Health, Clinical Center, Bethesda, Maryland, USA 3National Institutes of Health, Program in Developmental Endocrinology and Genetics (PDEGEN), The Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland, USA 4Clinical Research Branch, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, USA Abstract Background—Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21- OHD) is an autosomal recessive disorder of cortisol biosynthesis caused by CYP21A2 mutations. An increase in gene copy number variation (CNV) exists at the CYP21A2 locus. CNV of C4, a neighboring gene that encodes complement component 4, is associated with autoimmune disease susceptibility. Methods—Comprehensive genetic analysis of the RCCX (RP-C4-CYP21-TNX) region was conducted in 127 unrelated 21-OHD patients (100 classic, 27 nonclassic). C4 copy number was determined by Southern blot. C4 CNV and serum C4 levels were evaluated in relation to CYP21A2 mutations and relevant phenotypes. Results—The most common CYP21A2 mutation associated with the nonclassic form of CAH, V281L, was associated with high C4 copy number (p=7.13×10 ?16 ). Large CYP21A2 deletion was associated with low C4 copy number (p=1.61×10 ?14 ). Monomodular RCCX with a short C4 gene, a risk factor for autoimmune disease, was significantly less frequent in CAH patients compared to population estimates (2.8 vs. 10.6%; p=1.08×10 ?4 ). Conclusions—CAH patients have increased C4 CNV, with mutation-specific associations that may be protective for autoimmune disease. The study of CYP