Jongkeun Park

Adiponectin concentrations: a genome-wide association study.

Adiponectin is associated with obesity and insulin resistance. To date, there has been no genome-wide association study (GWAS) of adiponectin levels in Asians. Here we present a GWAS of a cohort of Korean volunteers. A total of 4,001 subjects were genotyped by using a genome-wide marker panel in a two-stage design (979 subjects initially and 3,022 in a second stage). Another 2,304 subjects were used for follow-up replication studies with selected markers. In the discovery phase, the top SNP associated with mean log adiponectin was rs3865188 in CDH13 on chromosome 16 (p = 1.69 × 10(-15) in the initial sample, p = 6.58 × 10(-39) in the second genome-wide sample, and p = 2.12 × 10(-32) in the replication sample). The meta-analysis p value for rs3865188 in all 6,305 individuals was 2.82 × 10(-83). The association of rs3865188 with high-molecular-weight adiponectin (p = 7.36 × 10(-58)) was even stronger in the third sample. A reporter assay that evaluated the effects of a CDH13 promoter SNP in complete linkage disequilibrium with rs3865188 revealed that the major allele increased expression 2.2-fold. This study clearly shows that genetic variants in CDH13 influence adiponectin levels in Korean adults.

Polymorphism p53 codon‐72 and invasive cervical cancer: a meta‐analysis

Objectives: Although some studies have reported that the arginine isoform on codon 72 of p53 increases the susceptibility to invasive cervical cancer, such data remain controversial. The objective of this study was to quantitatively summarize the evidence for such a relationship. Methods: Our data sources consisted of a MEDLINE search of the literature published before December 2002, bibliography review, and expert consultation. Thirty‐seven studies met the inclusion criteria. Information on sample size, study design, Hardy–Weinberg equilibrium, and method of genotype determination was abstracted by two reviewers using a standardized protocol. The overall odds ratio (OR) of the p53 gene on invasive cervical cancer was estimated using the Mantel–Haenzel method. Results: The overall OR (95% confidence interval) for cervical cancer among those with the homozygous mutant (Arg/Arg) was 1.2 (1.1–1.3, P=0.001) compared with those with the heterozygous mutant (Arg/Pro). By a cellular type of cervical cancer, the overall OR among those with Arg/Arg was statistically significant in adenocarcinomas (1.7, 1.1–2.6, P=0.024), but not in squamous cell carcinomas (1.1, 0.9–1.2, P=0.960), compared with Pro/Pro. Compared with Arg/Pro, the OR among those with Arg/Arg was statistically significant in HPV types 16 (1,5, 1.2–2.0, P=0.002). Conclusions: Overall, the p53 gene was associated with increased risk for invasive cervical cancer. However, the risk varied by country, cellular, and HPV type.

Downregulation of Foxe1 by HR suppresses Msx1 expression in the hair follicles of Hr Hp mice

Hairless (HR), a transcriptional cofactor, is highly expressed in the skin and brain. To characterize the effects of HR expression in the skin, we examined its capacity for transcriptional regulation of its target genes in mouse skin and keratinocytes. We found that Foxe1 mRNA expression was suppressed in HR-overexpressing skin, as well as in HR-expressing keratinocytes. In turn, Msx1 expression was downregulated contingent on Foxe1 downregulation in skin and keratinocytes. We also found that expression of Sfrp1 was also correlated with that of Foxe1. Further investigation of the mechanisms involved in the transcriptional regulation of these genes will facilitate our understanding of the relationship among genes involved in hair follicle morphogenesis and cycling.

Poly(rC) binding protein 2 acts as a negative regulator of IRES-mediated translation of Hr mRNA

During the hair follicle (HF) cycle, HR protein expression is not concordant with the presence of the Hr mRNA transcript, suggesting an elaborate regulation of Hr gene expression. Here we present evidence that the 5′ untranslated region (UTR) of the Hr gene has internal ribosome entry site (IRES) activity and this activity is regulated by the binding of poly (rC) binding protein 2 (PCBP2) to Hr mRNA. Overexpression and knockdown of PCBP2 resulted in a decrease in Hr 5′ UTR IRES activity and an increase in HR protein expression without changing mRNA levels. We also found that this regulation was disrupted in a mutant Hr 5′ UTR that has a mutation responsible for Marie Unna hereditary hypotrichosis (MUHH) in both mice and humans. These findings suggest that Hr mRNA expression is regulated at the post-transcriptional level via IRES-mediated translation control through interaction with PCPB2, but not in MUHH.

A nucleotide variant in promoter of the human CDH13 gene which affects its transcription activity is associated with colorectal cancer

T-cadherin is frequently down regulated in various cancers, however, the underlying mechanisms responsible have yet to be elucidated. A genome wide association study of a cohort of Korean adults revealed that the T-cadherin rs3865188 single nucleotide polymorphism (SNP) was associated with serum Adiponectin levels and that its genotypic variants were correlated with risk for colorectal cancer (CRC). To test the function of rs12444338, a SNP tightly linked to the rs3865188 SNP, in T-cadherin transcriptional regulation in colorectal cancer, its effect on transcriptional activity and the capacity of binding activity attributable to allelic variation of the rs12444338 SNP was investigated. An electrophoretic-mobility-shift assay (EMSA) revealed a specific nucleoprotein complex unique to the T allele probe, which displayed lower promoter activity when compared to the G allele. Based on the results of the EMSA using mutant probes, the consensus sequence of the putative transcription factor binding site was determined. Additionally, candidates for putative binding factors to the T allele were also identified. Collectively, the study data suggested that the rs12444338 SNP was involved in transcriptional regulation of T-cadherin gene (CDH13) and that the differential binding of transcription factors at the rs12444338 SNP resulted in altered gene expression. These results elucidate, at least in part, the regulation of T-cadherin expression in CRC and provide further information regarding the effect of nucleotide variation in its promoter region.

The Hairless Gene: A Putative Navigator of Hair Follicle Development

Abstract The Hairless (HR) gene regulates the expression of sev-eral target genes as a transcriptional corepressor of nu-clear receptors. The hair follicle (HF), a small independ-ent organ of the skin, resides in the epidermis and un-dergoes regenerative cycling for normal hair formation. HF development requires many genes and signaling pathways to function properly in time and space, one of them being the HR gene. Various mutations of the HR gene have been reported to cause the hair loss pheno-type in rodents and humans. In recent studies, it has been suggested that the HR gene is a critical player in the regulation of the hair cycle and, thus, HF develop-ment. Furthermore, the HR gene is associated with the Wnt signaling pathway, which regulates proliferation and differentiation of cells and plays an essential role in hair and skin development. In this review, we summarize the mutations responsible for human hair disorders and dis-cuss the roles of the HR gene in HF development. Keywords: hairless, corepressor, hair follicle, hair cycle, hair loss