Clinical and Molecular Characteristics of GNAS Inactivation Disorders Observed in 18 Korean Patients.

BACKGROUND: The GNAS gene on chromosome 20q13.3 is a complex, imprinted locus regulated in a tissue-specific manner. GNAS inactivation disorders are a heterogeneous group of rare disorders caused by mutations and methylation defects. These are divided into pseudohypoparathyroidism (PHP) types 1A and 1B, pseudo-pseudohypoparathyroidism (PPHP), and progressive osseous heteroplasia (POH), depending on the presence or absence of hormone resistance, Albright's hereditary osteodystrophy (AHO), and ectopic ossification. METHODS: This study analyzed the clinical characteristics and molecular genetic backgrounds of 18 Korean patients from 16 families with a genetically confirmed GNAS defect. Auxological parameters, AHO phenotypes, types of hormonal resistance, family history, and molecular genetic disturbances were reviewed retrospectively. RESULTS: Nine (90%) patients with PHP1A showed resistance to parathyroid hormone (PTH) and all patients showed elevated thyroid-stimulating hormone (TSH) levels at diagnosis. Eight (80%) patients were managed with levothyroxine supplementation. Three of six patients with PHP1B had elevated TSH levels, but none of whom needed levothyroxine medication. AHO features were absent in PHP1B. Patients with PPHP and POH did not show any hormone resistance, and both of them were born as small for gestational age. Among the 11 families with PHP1A, PPHP, and POH, eight different (three novel) mutations in the GNAS gene were identified. Among the six patients with PHP1B, two were sporadic cases and four showed isolated loss of methylation at GNAS A/B:TSS-DMR. CONCLUSIONS: Clinical and molecular characteristics of Korean patients with GNAS inactivation disorders were described in this study. Also, we reaffirmed heterogeneity of PHP, contributing to further accumulation and expansion of current knowledge of this complex disease.

Evidence for the role of STAT4 as a general autoimmunity locus in the Korean population.

BACKGROUND: Recently, the association of a common STAT4 haplotype with type 1 diabetes (T1D) as well as rheumatoid arthritis has been documented in Caucasians and Koreans. STAT4 is involved in the signalling of interleukin-12 and γIFN, as well as interleukin-23. To discover genes affecting the susceptibility of common autoimmune diseases, we studied the association of polymorphisms in STAT4 with autoimmune thyroid disease (AITD) as well as T1D in the Korean population. SUBJECTS AND METHODS: Four single-nucleotide polymorphisms on the chromosome 2q (rs11889341, rs7574865, rs8179673, and rs10181656), which were found to associate with rheumatoid arthritis were examined for association in a Korean sample of 428 AITD, 418 T1D patients, and 1060 controls. RESULTS: The minor alleles of all four single-nucleotide polymorphisms and the reconstructed STAT4 haplotypes conferred significant degree of risk for AITD (p=10(-2) to 10(-4)). Although we found a weak association of rs11889341 with T1D (p<0.05), the same haplotypes were not associated with T1D susceptibility. When we stratified T1D patients according to the age of onset, the minor alleles of all four single-nucleotide polymorphisms and the same haplotypes showed significant association with the susceptibility of T1D in the early-onset subgroup (p<0.01), not in the late-onset subgroup. CONCLUSION: STAT4 alleles and the same haplotypes might influence cytokine signalling, and therefore the development of AITD as well as T1D. These results reinforce the influence of STAT4 gene as a general autoimmune gene.

Susceptibility influence of a PTPN22 haplotype with thyroid autoimmunity in Koreans.

BACKGROUND: Considerable amount of evidences in the Caucasians have suggested the association of a missense single-nucleotide polymorphism (SNP) in the protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene (rs2476601) with several autoimmune diseases including autoimmune thyroid diseases (AITD) and type 1 diabetes (T1D). As the SNP was reported to be non-polymorphic in Asians, we attempt to explore an association of PTPN22 without restricting to the rs2476601 with AITD or T1D in Korean population. METHODS: We studied 389 T1D, 212 AITD (84 Graves' disease and 128 Hashimoto's thyroiditis) patients and 225 controls. In addition to the rs2476601, we selected five testing SNPs spanning 58 kb over the PTPN22 gene using the previous resequencing data and International HapMap Project. RESULTS: We found that neither alleles, genotypes among all five SNPs, nor reconstructed haplotypes of five SNPs were associated with T1D. Interestingly, a minor allele of a SNP (rs12730735) and a haplotype (GGCTT) showed significant association with the susceptibility of AITD, especially with that of Hashimoto's thyroiditis (p<0.01). CONCLUSIONS: These results indicate that the PTPN22 gene polymorphism independent of the SNP rs2476601 might be a supplementary risk factor to AITD, but not in T1D in Koreans, contradicting a major contributory influence of the PTPN22 gene in explaining common mechanism underlying multiple autoimmune diseases.

Determination of the BMI threshold that predicts cardiovascular risk and insulin resistance in late childhood.

AIMS: Body mass index (BMI, kg/m(2)) thresholds of children predicting cardiovascular risk, reported in previous studies were inconsistent and that predicting increased insulin resistance is lacking. We determined the BMI threshold that predicts increased cardiovascular risk and insulin resistance in children. METHODS: The entire 4th grade students (187 boys and 218 girls) from 5 schools were included. Cardiovascular risk was defined as the presence of three or more of cardiovascular risk factors. Increased insulin resistance was estimated using homeostasis model assessment of insulin resistance and fasting insulin level. RESULTS: The BMI percentile predicting cardiovascular risk was the 71.3th percentile for boys and the 77.1th percentile for girls. The BMI value was 21.4 kg/m(2) for boys and 20.6 kg/m(2) for girls. 34% of boys and 42% of girls with a BMI above the cut-off values had cardiovascular risk. The BMI percentile predicting increased insulin resistance was the 66.3th percentile for boys and the 67.9th percentile for girls. The children with cardiovascular risk had significantly greater (P<0.01) insulin resistance than those without risk. CONCLUSION: This study demonstrated that the BMI thresholds at which cardiovascular risk and insulin resistance begin to increase in Korean children were lower than current definition of childhood obesity, proposed by the international obesity task force.

STAT4 polymorphism is associated with early-onset type 1 diabetes, but not with late-onset type 1 diabetes.

In an effort to discover non-HLA genes affecting susceptibility to type 1 diabetes (T1D), we have investigated the association of polymorphisms in STAT4, an important signaling molecule of IL-12, gammaIFN, and IL-23, in a sample of 389 T1D patients and 152 nondiabetic controls in Korea. Four SNPs on chromosome 2q, which were recently found to be associated with rheumatoid arthritis, were examined for association and linkage disequilibrium. We found that neither alleles or genotypes among all four SNPs nor reconstructed haplotypes of the three SNPs within the same LD block (rs7574865, rs8179673, and rs10181656) were associated with susceptibility to T1D. When we stratified T1D patients into early-onset and late-onset subgroups on the basis of fewer or more than 7.8 years of age at diagnosis, however, the minor alleles of three SNPs (rs7574865, rs8179673, and rs10181656) showed a significant association with susceptibility to T1D in the early-onset subgroup (i.e., rs7574865, OR = 1.44 [1.03-2.01], P < 0.05), but not in the late-onset subgroup, suggesting that STAT4 is related to earlier development of T1D. The analysis of genotypes and haplotypes of the same SNPs (rs7574865, rs8179673, and rs10181656) showed very comparable degrees of risk for T1D. The age at diagnosis is lowest in the patients carrying the homozygotes of a minor allele, middle in the heterozygotes, and highest in the homozygotes of a major allele, suggesting the dosage effects of risk alleles on the age of onset of disease. Recognizing that only the early-onset cases might represent the true autoimmune T1D in Asian populations, we see that STAT4 alleles and haplotype might influence cytokine signaling and, therefore, development of T1D.