Revisiting the association of HLA alleles and haplotypes with CYP21A2 mutations in a large cohort of patients with congenital adrenal hyperplasia

Abstract

The CYP21A2 gene encoding 21-hydroxylase is on chromosome 6p21.3 within the human leukocyte antigen (HLA) class III major histocompatibility complex and an association between congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency and HLA class I and II alleles has been shown in genetically isolated populations. One-third of CAH causing alleles are 30-kb deletions due to homologous recombination events between active and pseudogenes resulting in chimeric genes. The aim of this study was to re-visit the association between the CYP21A2 variants and HLA polymorphisms in a large ethnically diverse cohort of patients with CAH who underwent comprehensive CYP21A2 genotyping, including specification of chimeric gene subtypes (CAH CH-1 through CH-9 of CYP21A1P/CYP21A2 chimeras; CAH-X CH-1 through CH-3 of TNXA/TNXB chimeras) in alleles with 30-kb deletions. The study population included 201 patients (86 males, 115 females, age 3–75 years) with CAH due to 21-hydroxylase deficiency (159 classic, 42 nonclassic) and 194 parents. Based on the availability of parental genotype, we determined the haplotypes of CYP21A2 mutations and HLA types in 95 probands (190 alleles). Five prevalent haplotype associations were found: p.V281L and B*14-C*08 (P <0.0001); p.I172N and DQB1*03 (P = 0.035); and of the chimeric genes caused by 30-kb deletions: CH-1 and A*03 (P =0.033); CH-5 and C*06-DRB1*07 (P < 0.0001); and CAH-X CH-1 and DQB1*03 (P = 0.004). Our findings show that a number of associations between HLA alleles and haplotypes and CYP21A2 mutations, including large 30-kb deletions, exist commonly across ethnicities. These HLA associations may have clinical implications for patients with CAH and may provide insight into the genetics of this highly complex region of the human genome.

High Throughput Genetic Characterisation of Caucasian Patients Affected by Multi-Drug Resistant Rheumatoid or Psoriatic Arthritis

“…In detail, three subjects (SP4, SN2 and SN3) carry this HLA haplotype, which has been associated with the development of autosomal dominant frontal fibrosing alopecia, a disorder characterised by the recession of the hairline, co-occurrence of autoimmune diseases (e.g., thyroid disorders and Sjögren’s syndrome) and sex-hormonal imbalance [ 26 ]. This haplotype is known for being in linkage disequilibrium with the c.844G>T, p.Val282Leu variant within the CYP21A2 (NM_000500.7) gene [ 27 ], whose presence at the heterozygous state has been confirmed in the three patients. The CYP21A2 gene is located within the human leukocyte antigen complex, and it encodes for the enzyme steroid 21-hydroxylase that converts pregnenolone into cortisol [ 26 , 27 ].…”

“…This haplotype is known for being in linkage disequilibrium with the c.844G>T, p.Val282Leu variant within the CYP21A2 (NM_000500.7) gene [ 27 ], whose presence at the heterozygous state has been confirmed in the three patients. The CYP21A2 gene is located within the human leukocyte antigen complex, and it encodes for the enzyme steroid 21-hydroxylase that converts pregnenolone into cortisol [ 26 , 27 ].…”

“…The most interesting novel “drug-resistance” RA and PsA candidate genes ( CYP21A2, UGT2B17 , DVL1 , PRKDC, ORAI1 and MSR1) are those in which a variant was identified in more than one patient. In detail, the CYP21A2 gene is associated with the signalling of cortisol [ 27 ], while UGT2B17 is involved in drug metabolism and sex hormone homeostasis [ 36 ]. To our knowledge, whether UGT2B17 mediates DMARDs metabolism is unknown and cannot be excluded.…”

Trastorno de diferenciación sexual por hiperplasia suprarrenal congénita. Reporte de un caso

“…La hiperplasia suprarrenal congénita consiste en una serie de trastornos hereditarios de la esteroidegenésis, existe un déficit enzimático que da como resultado siete diferentes formas clínicas, la más frecuente es el déficit de 21-hidroxilasa, el cual presenta la paciente (12).…”

Selective IgA deficiency and congenital adrenal hyperplasia. Is there a relationship?

“…Известно, что ген 21-гидроксилаза находится на 6-й хромосоме в непосредственной близости от локусов HLA-B и DR [4]. Известны аллели высокого риска развития заболевания -HLA-В14, HLA-DR3 [4,5]. Селективный дефицит иммуноглобулина А -полигенное заболевание.…”