Common genetic variants of the human steroid 21-hydroxylase gene (CYP21A2) are related to differences in circulating hormone levels

Abstract

Purpose: Systematic evaluation of the potential relationship between the common genetic variants of CYP21A2 and hormone levels.

Methods: The relationships of CYP21A2 intron 2 polymorphisms and haplotypes with diverse baseline and stimulated blood hormone levels were studied in 106 subjects with non-functioning adrenal incidentaloma (NFAI). The rationale for using NFAI subjects is dual: i) their baseline hormone profiles do not differ from those of healthy subjects and ii) hormone levels after stimulation tests are available.

Results: The carriers (N = 27) of a well-defined CYP21A2 haplotype cluster (c5) had significantly elevated levels of cortisol (p = 0.0110), and 17-hydroxyprogesterone (p = 0.0001) after ACTH stimulation, and 11-deoxycortisol after metyrapone administration (p = 0.0017), but the hormone values were in normal ranges. In addition, the carriers (N = 33) of the C allele of the rs6462 polymorphism had a higher baseline aldosterone level (p = 0.0006). The prevalence of these genetic variants of CYP21A2 did not differ between NFAI and healthy subjects.

Conclusions: The common CYP21A2 variants presumably exert the same effect on hormone levels in the healthy and disease-affected populations. Therefore, they may contribute to complex diseases such as some cardiovascular diseases, and may influence the genotype-phenotype correlation in patients with congenital adrenal hyperplasia (CAH) including the individual need for hormone substitution.

Figure 1. Haplotype tree of CYP21A2 intron 2 and the 5′-part of exon 3, and the CYP21A2 haplotype clusters with multiple significances found by tree scanning, and p-values of the haplotype clusters related to different steroid hormone levels in subjects with non-functioning adrenal incidentaloma.

Circles represent the CYP21A2 intron 2 and the 5′-part of exon 3 haplotypes, lines with or without small black circles indicate the allele differences (character-state changes) between haplotype variants and gray shapes encompass the haplotype clusters with multiple significances. The values without parentheses are uncorrected p-values, and the values with parentheses are the corrected step-down permutational p-value after enforcing monotonicity. ACTH – adrenocorticotrophic hormone.

Figure 2. Concentrations of hormones in blood decomposed by CYP21A2 intron 2 haplotype carrier groups in subjects with non-functioning adrenal incidentaloma.

c5/o and c8/o indicate the carriers (heterozygotes) of c5 and c8 haplotypes, respectively, and o/o abbreviates the genotypes of other haplotypes. Boxes indicate interquartile ranges, lines in boxes show the medians, whiskers represent the 5^th–95^th percentiles, asterisks above the boxes indicate the significant differences between the hormone levels of genotypes. One, two and three asterisks indicate p<0.05, p<0.01 and p<0.001 respectively (t-test or Mann-Whitney test). A) Serum cortisol level after adrenocorticotropic hormone (ACTH) stimulation. B) Serum aldosterone level after ACTH stimulation. C) Serum 17-OH-progesterone level after ACTH stimulation. D) Serum corticosterone level after ACTH stimulation. E) Serum 11-deoxycortisol level after metyrapone administration. F) Baseline ACTH level.