Complement component 4 variations may influence psychopathology risk in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency

• Published in: Human genetics Vol. 137; no. 11-12; pp. 955 - 960
• Main Authors: Lao, Qizong, Jardin, Marcia Des, Jayakrishnan, Rahul, Ernst, Monique, Merke, Deborah P.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-12-2018; Springer Nature B.V
• Subjects: Adolescent; Adrenal glands; Adrenal Hyperplasia, Congenital - genetics; Adrenal Hyperplasia, Congenital - pathology; Adult; Autoimmune diseases; Biomedical and Life Sciences; Biomedicine; Comorbidity; Complement C4 - genetics; Complement component C4; Congenital diseases; Copy number; DNA Copy Number Variations - genetics; Female; Gene Function; Genetic diversity; Genomes; Genotype; Genotypes; Haplotypes; Hereditary diseases; Human Genetics; Humans; Hydroxylase; Hyperplasia; Isotypes; Major histocompatibility complex; Male; Metabolic Diseases; Molecular Medicine; Morbidity; Mutation; Original Investigation; Psychopathology; Steroid 21-Hydroxylase - genetics; Steroidogenesis; Young Adult
• ISSN: 0340-6717; 1432-1203
• DOI: 10.1007/s00439-018-1959-z

CYP21A2
defects result in congenital adrenal hyperplasia (CAH), an autosomal recessive disorder characterized by impaired adrenal steroidogenesis.
CYP21A2
lies within the major histocompatibility complex in an area of the genome highly susceptible to genetic variation. Alterations in the neighboring complement component 4 isotypes
C4A
and
C4B
have been associated with psychiatric and autoimmune disease. The purpose of this study was to evaluate
C4A
and
C4B
in patients with CAH in relation to
CYP21A2
genotype and psychiatric and autoimmune comorbidity. We determined the copy numbers of
C4A
and
C4B
in 145 patients with CAH (median age: 15.5 years, IQR: 16.8) and 108 carrier relatives (median age: 41.5 years, IQR: 12.0) and evaluated serum C4 concentrations. Comorbidity was determined by medical record review. Only 30% of subjects had the expected two copies each of the two
C4
genes.
C4B
copy number determined total
C4
copy number and serum C4 concentration, negatively correlated with carriership of a 30-kb deletion (
P
 < 10
− 5
), and positively correlated with carriership of p.V281L (
P
 < 10
− 5
). High
C4A
copy number (≥ 3) was associated with increased risk of having an externalizing psychiatric condition (relative risk: 2.67, 95% CI: 1.03–6.89,
P
 = 0.04). No association was found between
C4
copy number and autoimmune disease. Mutation-specific
C4
structural variations commonly occur in patients with CAH and may have important clinical consequences, including increased risk of psychiatric morbidity.
Trial registration
NCT00250159 (November 7, 2005).