Ye An Kim, Ji Won Yoon, Young Lee, Hyuk Jin Choi, Jae Won Yun, Eunsin Bae, Seung-Hyun Kwon, So Eun Ahn, Ah-Ra Do, Heejin Jin, Sungho Won, Do Joon Park, Chan Soo Shin, Je Hyun Seo
Endocrinol Metab. 2021;36(6):1189-1200. Published online December 2, 2021
Background Epidemiological data have shown that vitamin D deficiency is highly prevalent in Korea. Genetic factors influencing vitamin D deficiency in humans have been studied in Europe but are less known in East Asian countries, including Korea. We aimed to investigate the genetic factors related to vitamin D levels in Korean people using a genome-wide association study (GWAS).
Methods We included 12,642 subjects from three different genetic cohorts consisting of Korean participants. The GWAS was performed on 7,590 individuals using linear or logistic regression meta- and mega-analyses. After identifying significant single nucleotide polymorphisms (SNPs), we calculated heritability and performed replication and rare variant analyses. In addition, expression quantitative trait locus (eQTL) analysis for significant SNPs was performed.
Results rs12803256, in the actin epsilon 1, pseudogene (ACTE1P) gene, was identified as a novel polymorphism associated with vitamin D deficiency. SNPs, such as rs11723621 and rs7041, in the group-specific component gene (GC) and rs11023332 in the phosphodiesterase 3B (PDE3B) gene were significantly associated with vitamin D deficiency in both meta- and mega-analyses. The SNP heritability of the vitamin D concentration was estimated to be 7.23%. eQTL analysis for rs12803256 for the genes related to vitamin D metabolism, including glutamine-dependent NAD(+) synthetase (NADSYN1) and 7-dehydrocholesterol reductase (DHCR7), showed significantly different expression according to alleles.
Conclusion The genetic factors underlying vitamin D deficiency in Korea included polymorphisms in the GC, PDE3B, NADSYN1, and ACTE1P genes. The biological mechanism of a non-coding SNP (rs12803256) for DHCR7/NADSYN1 on vitamin D concentrations is unclear, warranting further investigations.
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Background As the genetic variants of trabecular bone microarchitecture are not well-understood, we performed a genome-wide association study to identify genetic determinants of bone microarchitecture analyzed by trabecular bone score (TBS).
Methods TBS-associated genes were discovered in the Ansung cohort (discovery cohort), a community-based rural cohort in Korea, and then validated in the Gene-Environment Interaction and Phenotype (GENIE) cohort (validation cohort), consisting of subjects who underwent health check-up programs. In the discovery cohort, 2,451 participants were investigated for 1.42 million genotyped and imputed markers.
Results In the validation cohort, identified as significant variants were evaluated in 2,733 participants. An intronic variant in iroquois homeobox 3 (IRX3), rs1815994, was significantly associated with TBS in men (P=3.74E-05 in the discovery cohort, P=0.027 in the validation cohort). Another intronic variant in mitogen-activated protein kinase kinase 5 (MAP2K5), rs11630730, was significantly associated with TBS in women (P=3.05E-09 in the discovery cohort, P=0.041 in the validation cohort). Men with the rs1815994 variant and women with the rs11630730 variant had lower TBS and lumbar spine bone mineral density. The detrimental effects of the rs1815994 variant in men and rs11630730 variant in women were also identified in association analysis (β=–0.0281, β=–0.0465, respectively).
Conclusion In this study, the rs1815994 near IRX3 in men and rs11630730 near MAP2K5 in women were associated with deterioration of the bone microarchitecture. It is the first study to determine the association of genetic variants with TBS. Further studies are needed to confirm our findings and identify additional variants contributing to the trabecular bone microarchitecture.
Hwa Young Ahn, Kwan Jae Lee, Soon Hui Kim, Eun Ky Kim, Ah Reum Kang, Jung Ah Lim, Ji Won Yoon, Kyung Won Kim, Do Joon Park, Bo Youn Cho, Young Joo Park
Endocrinol Metab. 2011;26(3):232-238. Published online September 1, 2011
BACKGROUND Bile acids were important for the regulation of cholesterol homeostasis. Thyroid hormone increased the expression of CYP7A1 (cholesterol 7alpha-hydroxylase), catalyzing the first step in the biosynthesis of bile acids. However, the effect of thyroid hormone on bile acid export has not been previously assessed. The principal objective of this study is to evaluate the effects of thyroid hormone on the bile salt export pump (BSEP). METHODS: Thyroid hormone, T3 (1 mg/g) was administered to male mice via intraperitoneal injection. After 6 hours and 5 days of T3 treatment, we measured serum total and LDL cholesterol and hepatobiliary bile acid concentrations. We assessed the changes associated with bile acid synthesis and transport. In order to evaluate the direct effect of thyroid hormone, we assessed the changes in the levels of BSEP protein after T3 administration in human hepatoma cells. RESULTS: Serum total and LDL cholesterol were reduced and hepatobiliary bile acid concentrations were increased following T3 treatment. Expressions of Cyp7a1 and BSEP mRNA were increased following T3 treatment. The levels of the BSEP protein in the mouse liver as well as in the human hepatoma cells were increased after T3 treatment. CONCLUSION: Thyroid hormone can regulate LDL cholesterol metabolism. It increases bile acid synthesis and the excretion of bile acids via increased BSEP expression.
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Ji Won Yoon, Mi Yeon Kang, Hwa Young Ahn, Jee Hyun An, Sang Wan Kim, Chan Soo Shin, Kyong Soo Park, Hak Chul Jang, Bo Youn Cho, Hong Kyu Lee, Seong Yeon Kim
J Korean Endocr Soc. 2008;23(6):395-403. Published online December 1, 2008
BACKGROUND This study was performed to evaluate the frequency and clinical characteristics of patients with active acromegaly and who show discordance of the growth hormone (GH) level and the insulin-like growth factor-I (IGF-I) level. METHODS: We reviewed the medical records of the patients who were diagnosed with acromegaly between 01/01/1995 and 6/30/2007 at Seoul National University Hospital. We selected only the patients whose basal GH and IGF-I levels were available. We investigated the pre- and post-operative clinical characteristics, as well as the blood concentrations of GH and IGF-I. The concordance rate between the two hormones was examined. The patients were considered to have active disease on the basis of their IGF-I levels above the normal range, after adjustment for age and gender, and their mean basal GH value was > or = 2.5 microgram/L. The hormone levels and the clinical parameters were compared between the hormone concordant and discordant groups. RESULTS: We reviewed the preoperative records of 103 acromegalic patients, and these patients met the above-mentioned criteria. 53 postoperative patients who were not cured by operation were monitored without them receiving radiation or medical therapy. Both the basal GH and IGF-I levels were above normal in 103 patients preoperatively, and the discordant rate was 0% (0/103 cases). Postoperatively, the discordant rate between the two hormones was increased to 30.2% (16/53 cases). Age, gender, body mass index and tumor size were insignificantly different between the concordant and discordant groups. However, postoperative residual tumors were less frequently observed in the discordant group (P = 0.006). CONCLUSION: For the patients with acromegaly, unlike the 0% discordance preoperatively, 30.2% of patients showed a discrepancy between their GH and IGF-I levels postoperatively. The patients who had hormonal discrepancy were less likely to have residual tumors after operation. Considering the frequency of this hormonal discrepancy, both hormone levels should be measured to evaluate the disease activity after treatment. Further, oral glucose tolerance testing should be performed and especially for the patients with an increased GH level, but who have a normal IGF-I concentration.
Patients with adrenocortical carcinoma (ACC) present with evidence of excessive adrenal steroid hormone in approximately 60% of cases, in which rapidly progressing Cushing's syndrome with or without virilization is the most frequent presentation. Some patients experience an increase or a decline in cortisol production through the progression of their ACC. We report on an unusual case of a cortisol-producing ACC, and the patient presented with a decline in cortisol production, followed by an increase in cortisol production, through the progression of the tumor. A 65-year-old woman who manifested with facial edema and weight gain was diagnosed with Cushing's syndrome, caused by cortisol producing ACC. The patient was treated with adrenalectomy. However, 8 months later, a metastatic hepatic tumor of recurred ACC was detected. At that time, the hormonal evaluation revealed that the liver mass did not produce any hormones. The patient was treated with metastatectomy. Four months later, a relapsed tumor was detected. Increased cortisol production was observed at that time. We speculate there was a change in the clonal dominance within the ACC and this change might cause such a difference. This is the first case report of ACC that showed variable hormone production during progression.