Hormonal profiles in Italian late-onset adrenal hyperplasia correlate with HLA class III polymorphisms.
To investigate the genetic polymorphisms of the HLA region in late-onset adrenal hyperplasia, 13 Italian patients affected by the disease were analyzed for: (1) HLA-A and -B typing; (2) restriction fragment length polymorphism (RFLP) of DR beta, DQ beta, DQ alpha, 21-hydroxylase A and B genes; (3) fourth complement fraction loci A and B (C4A and C4B), second complement fraction (C2) and properdin B factor (Bf) complement typing; (4) hormonal characteristics associated with some HLA haplotypes. HLA alleles B14 and DR beta 1 were found to be significantly more frequent in patients with respect to controls (relative risk: 8.7 and 7.2, p less than 0.001 and p less than 0.0001, respectively). Also C4B*2, 1 duplication was more frequent in patients than in normal subjects (23% vs. 1.5%, p less than 0.0001). Moreover, patients carrying a duplicated C4B (as well as those having the B14 antigen) showed higher 17-hydroxyprogesterone levels after ACTH stimulation. RFLP analysis of 21-hydroxylase genes with a specific probe revealed a duplication of 21-hydroxylase A gene in 40% of patients. All these individuals carried the C4A*2 B*2,1 phenotype and 75% of them displayed a clearly recognizable duplication at the C4B locus. These data support the hypothesis that in late-onset adrenal hyperplasia the 21-hydroxylase A pseudogene, even if inactive, may play a negative role in the regulation of 21-hydroxylase biosynthesis. Furthermore, we suggest analyzing class III phenotypes to screen the enzymatic defect.
Division of Endocrinology and Laboratory, Mauriziano Umberto I Hospital, Turin, Italy.
A
A
Balsamo
A
A
Revelli
I
I
Borelli
A
A
Amoroso
G
G
Cenderelli
G
G
De Sanso
G
G
Mazzola
E S
ES
Curtoni
G
G
Zoppetti
M
M
Massobrio
D019326:17-alpha-Hydroxyprogesterone; D000293:Adolescent; D000312:Adrenal Hyperplasia, Congenital / Q000235:genetics* / Q000276:immunology; D000324:Adrenocorticotropic Hormone; D000328:Adult; D015935:Complement C4b / Q000235:genetics; D003165:Complement System Proteins / Q000235:genetics; D005260:Female; D012739:Gonadal Steroid Hormones / Q000097:blood / Q000378:metabolism*; D006680:HLA Antigens / Q000235:genetics*; D015235:HLA-B Antigens / Q000235:genetics; D059909:HLA-B14 Antigen; D006683:HLA-DQ Antigens / Q000235:genetics; D006684:HLA-DR Antigens / Q000235:genetics; D059811:HLA-DRB1 Chains; D000949:Histocompatibility Antigens Class II / Q000235:genetics; D006801:Humans; D006908:Hydroxyprogesterones / Q000097:blood; D007558:Italy; D010641:Phenotype; D012150:Polymorphism, Restriction Fragment Length; D013255:Steroid 21-Hydroxylase / Q000235:genetics
D012739:Gonadal Steroid Hormones; D006680:HLA Antigens; D015235:HLA-B Antigens; D059909:HLA-B14 Antigen; D006683:HLA-DQ Antigens; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D000949:Histocompatibility Antigens Class II; D006908:Hydroxyprogesterones; D019326:17-alpha-Hydroxyprogesterone; D015935:Complement C4b; D000324:Adrenocorticotropic Hormone; D003165:Complement System Proteins; D013255:Steroid 21-Hydroxylase