Polymorphic variants of the IL2RA gene and susceptibility to type 1 diabetes in the Polish population.

Polymorphic variants of the IL2RA gene, which encodes high-affinity alpha subunit (CD25) of the interleukin-2 receptor, were recently found to affect the risk of several autoimmune disorders. This study was aimed to investigate the association of selected IL2RA polymorphisms (rs11594656, rs3118470, rs2104286 and rs7093069) with type 1 diabetes (T1D) in a Polish cohort comprising 445 patients and 671 healthy control subjects. The minor A allele at rs11594656 was found significantly less frequently among T1D subjects, compared with the control group [P = 0.011; odds ratio (OR) = 0.77; 95% confidence interval (CI) = 0.629-0.942]. In contrast, the minor C allele at rs3118470 appeared to be significantly associated with the occurrence of T1D (P = 0.003; OR = 1.30; 95% CI = 1.094-1.550). Two other IL2RA single nucleotide polymorphisms (SNPs) did not show significant differences among investigated groups. In conclusion, the study confirms the association of the IL2RA locus with T1D in the Polish population.

Increased serum osteoprotegerin in patients with primary adrenal insufficiency receiving conventional hydrocortisone substitution.

Patients treated for primary adrenal insufficiency (PAI) are at risk of steroid over-replacement, which may affect their skeleton. The study was aimed to investigate the effect of steroid substitution on serum osteoprotegerin and receptor activator of nuclear factor kappa-beta ligand (RANKL) levels in relation to bone mineral density (BMD) in PAI. Eighty patients (mean age 47.2±14.5 years, mean hydrocortisone dose 0.49±0.14 mg/kg/day) and 63 healthy subjects were included. Serum osteoprotegerin, RANKL, 25-hydroxyvitamin D3, calcium, phosphate, alkaline phosphatase, intact parathormone, and dehydroepiandrosterone-sulfate levels were evaluated in patients and controls. BMD was assessed in affected subjects using dual-energy X-ray absorptiometry. Mean osteoprotegerin concentration in PAI patients appeared significantly higher vs. controls (p=0.002), while RANKL levels were similar (p=0.430). Serum osteoprotegerin increased with age (p<0.001), but showed no correlation with daily hydrocortisone dose. Osteoprotegerin was negatively correlated with serum dehydroepiandrosterone-sulfate (p=0.008) and with BMD at the lumbar spine (p<0.001) and femoral neck (p=0.003). RANKL correlated negatively with PAI duration (p=0.029) and positively with daily hydrocortisone dose (p=0.018). Lumbar spine osteoporosis and osteopenia were found in 12 and 31 patients, respectively, whereas in femoral neck: in 5 and 33 individuals. Patients with osteoporosis displayed higher osteoprotegerin levels, but after the age-adjustment the correlation was lost. In conclusion, increased osteoprotegerin in PAI might reflect a compensatory response to enhanced bone resorption due to exogenous steroid excess and/or result from a deficit in adrenal androgens. RANKL levels remain within normal range on standard steroid replacement.

PTPN22, PDCD1 and CYP27B1 polymorphisms and susceptibility to type 1 diabetes in Polish patients.

Type 1 diabetes (T1DM) is a common autoimmune disease with a complex genetic background. This study was aimed to investigate the association of PTPN22 G(-1123)C and C1858T, PDCD1 G7146A and CYP27B1 C(-1260)A polymorphisms with T1DM among Polish subjects. The PTPN22 gene encodes lymphoid tyrosine phosphatase, a potent negative regulator of T cell activation. PDCD1 gene gives rise to an inhibitory cell-surface receptor, expressed on activated lymphocytes. CYP27B1 encodes 1-alpha hydroxylase, responsible for conversion of the vitamin D(3) precursor into its active form, involved in the immune function. Polymorphic variants of these genes have previously been associated with various autoimmune disorders. The four polymorphisms were genotyped by PCR-restriction fragment assays in a case-control study comprising 215 T1DM patients and 236 healthy controls. The PTPN22 T1858 allele appeared significantly increased in T1DM compared to the control group (P=0.004), yielding an OR of 1.73 (95% CI 1.19-2.51). The difference in distribution of C1858T genotypes also demonstrated statistical significance (P=0.015). The frequencies of PTPN22 G(-1123)C alleles and genotypes did not differ between T1DM cases and controls, although the haplotype comprising both mutant PTPN22 alleles, C(-1123) and T1858, was significantly more frequent in affected individuals (P=0.003). G(-1123)C and C1858T were in linkage disequilibrium (D' = 0.98; r(2) =0.61 in T1DM and D' = 0.97; r(2) =0.41 in controls). No significant differences in the allele and genotype frequencies of PDCD1 and CYP27B1 polymorphisms were found between patients and controls. This study confirms the association of PTPN22 C1858T polymorphism with T1DM, whereas the effects of PTPN22 G(-1123)C, PDCD1 G7146A and CYP27B1 C(-1260)A seem unlikely, at least in the Polish population.

Adrenal hypoplasia congenita - an uncommon reason of primary adrenal insufficiency.

Adrenal hypoplasia congenita (AHC) is a rare inherited condition characterised by primary adrenal failure and hypogonadotropic hypogonadism. Most cases arise from mutations in the NR0B1 gene (Xp21.3), which encodes an orphan nuclear receptor DAX-1. A 20-year-old patient was recently diagnosed with AHC. Adrenal failure had been recognized and treated since his infancy. During adolescence, gradual decrease in growth velocity and low body mass were noted. Lack of puberty and skeletal immaturity were observed. Serum DHEA-S and testosterone were undetectable. Low gonadotropin levels failed to rise after stimulation. Neither dysfunction of the somatotropic nor pituitary-thyroid axis was found and no hypothalamo-pituitary pathology was visible on MRI. Androgen replacement therapy induced the development of secondary sexual characteristics, remarkably improved patient's growth and advanced his bone age. NR0B1 mutation screening revealed nucleotide transversion C>A, resulting in premature stop codon (Y399X). Same mutation was previously identified in a Scottish family, however, phenotypic differences suggest the role of additional factors modifying the disease course. Although it does not change therapeutic strategy, accurate molecular diagnosis allows genetic counselling in family members. Autoimmunity remains the major cause of adrenal failure; however, other rare conditions should always be considered.

Association of the CYP27B1 C(-1260)A polymorphism with autoimmune Addison's disease.

Autoimmune Addison's disease (AAD) is a complex endocrine disorder with several susceptibility loci. This study was aimed to investigate the associations of CYP27B1 C(-1260)A and PDCD1 G7146A polymorphisms with AAD in a Polish cohort, comprising 101 AAD patients and 251 healthy controls. CYP27B1 encodes 1alpha-hydroxylase, responsible for conversion of the vitamin D (3) precursor into its active form, involved in the immune function. PDCD1 gene gives rise to an inhibitory immune receptor, expressed on activated lymphocytes. Polymorphic variants of these genes had previously been associated with various autoimmune disorders. Genotyping was performed by PCR-RFLP method. The CYP27B1 C(-1260) allele appeared significantly more frequent in AAD compared to controls ( P=0.020), yielding an OR of 1.53 (95% CI 1.07-2.19). The distribution of C(-1260)A genotypes also demonstrated significant difference ( P=0.003). Stratification according to the presence of concomitant autoimmune disorders revealed an association of the C(-1260) allele with the polyendocrine cases of AAD ( P=0.031), while no significance was found for the isolated ADD compared with healthy controls ( P=0.253). Overall, the association between AAD and C(-1260)A was confirmed in a meta-analysis of 325 AAD patients and 952 controls from three different European populations. Under a fixed-effect model, C(-1260) allele and CC genotype were associated with AAD susceptibility with a pooled OR of 1.44 (95% CI 1.18-1.75) and 1.88 (95% CI 1.42-2.36), respectively. No differences were observed for the PDCD1 G7146A between affected subjects and controls (p>0.05). In conclusion, this study confirms the association of the CYP27B1 C(-1260)A polymorphism with AAD, whereas the contribution of PDCD1 G7146A seems less likely.