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

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Abstract

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).

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Acknowledgements

This research was supported by the Intramural Research Program at the National Institutes of Health (NIH), Bethesda, Maryland. We would like to thank Dr. Ninet Sinaii for her statistical advice.

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Authors and Affiliations

  1. National Institutes of Health Clinical Center, 10 Center Drive, Room 1-2740, Bethesda, MD, 20892-1932, USA

    Qizong Lao, Marcia Des Jardin, Rahul Jayakrishnan & Deborah P. Merke

  2. National Institute of Mental Health, National Institutes of Health, Bethesda, MD, 20892, USA

    Monique Ernst

  3. Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, 20892, USA

    Deborah P. Merke

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  1. Qizong Lao
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  2. Marcia Des Jardin
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  3. Rahul Jayakrishnan
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  5. Deborah P. Merke
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Correspondence to Deborah P. Merke.

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Lao, Q., Jardin, M.D., Jayakrishnan, R. et al. Complement component 4 variations may influence psychopathology risk in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Hum Genet 137, 955–960 (2018). https://doi.org/10.1007/s00439-018-1959-z

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  • DOI: https://doi.org/10.1007/s00439-018-1959-z

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