Association of SOX11 Polymorphisms in distal 3'UTR with Susceptibility for Schizophrenia.

BACKGROUND: Diverse and circumstantial evidence suggests that schizophrenia is a neurodevelopmental disorder. Genes contributing to neurodevelopment may be potential candidates for schizophrenia. The human SOX11 gene is a member of the developmentally essential SOX (Sry-related HMG box) transcription factor gene family and mapped to chromosome 2p, a potential candidate region for schizophrenia. METHODS: Our previous genome-wide association study (GWAS) implicated an involvement of SOX11 with schizophrenia in a Chinese Han population. To further investigate the association between SOX11 polymorphisms and schizophrenia, we performed an independent replication case-control association study in a sample including 768 cases and 1348 controls. RESULTS: After Bonferroni correction, four SNPs in SOX11 distal 3'UTR significantly associated with schizophrenia in the allele frequencies: rs16864067 (allelic P = .0022), rs12478711 (allelic P = .0009), rs2564045 (allelic P = .0027), and rs2252087 (allelic P = .0025). The haplotype analysis of the selected SNPs showed different haplotype frequencies for two blocks (rs4371338-rs7596062-rs16864067-rs12478711 and rs2564045-rs2252087-rs2564055-rs1366733) between cases and controls. Further luciferase assay and electrophoretic mobility shift assay (EMSA) revealed the schizophrenia-associated SOX11 SNPs may influence SOX11 gene expression, and the risk and non-risk alleles may have different affinity to certain transcription factors and can recruit divergent factors. CONCLUSIONS: Our results suggest SOX11 as a susceptibility gene for schizophrenia, and SOX11 polymorphisms and haplotypes in the distal 3'UTR of the gene might modulate transcriptional activity by serving as cis-regulatory elements and recruiting transcriptional activators or repressors. Also, these SNPs may potentiate as diagnostic markers for the disease.

[Role of pregnane X receptor (PXR) in endobiotic metabolism].

As a member of the nuclear receptor superfamily, the pregnane X receptor (PXR) is a ligand-activated transcription factor. PXR is highly expressed in liver and intestinal tissues, and also found in other tissues and organs, such as stomach and kidney. After heterodimerization with retinoid X receptor (RXR), PXR recruits numerous co-activating factors, and binds to specific DNA response elements to perform transcriptional regulation of the downstream target genes. As an acknowledged receptor for xenobiotics, PXR was initially considered as a nuclear receptor regulating drug metabolizing enzymes and transporters. However, nowadays, PXR has also been recognized as an important endobiotic receptor. Recent studies have shown that PXR activation can regulate glucose metabolism, lipid metabolism, steroid endocrine homeostasis, detoxification of cholic acid and bilirubin, bone mineral balance, and immune inflammation in vivo. This review focuses on the role of PXR in metabolism of endogenous substances.