Functional Variants in the Promoter Region of Chitinase 3–Like 1 (CHI3L1) and Susceptibility to Schizophrenia

Abstract

The chitinase 3-like 1 gene (CHI3L1) is abnormally expressed in the hippocampus of subjects with schizophrenia and may be involved in the cellular response to various environmental events that are reported to increase the risk of schizophrenia. Here, we provide evidence that the functional variants at the CHI3L1 locus influence the genetic risk of schizophrenia. First, using case-control and transmission/disequilibrium-test (TDT) methodologies, we detected a significant association between schizophrenia and haplotypes within the promoter region of CHI3L1 in two independent cohorts of Chinese individuals. Second, the at-risk CCC haplotype (P=.00058 and .0018 in case-control and TDT studies, respectively) revealed lower transcriptional activity (P=2.2 x 10(-7)) and was associated with lower expression (P=3.1 x 10(-5)) compared with neutral and protective haplotypes. Third, we found that an allele of SNP4 (rs4950928), the tagging SNP of CCC, impaired the MYC/MAX-regulated transcriptional activation of CHI3L1 by altering the transcriptional-factor consensus sequences, and this may be responsible for the decreased expression of the CCC haplotype. In contrast, the protective TTG haplotype was associated with a high level of CHI3L1 expression. Our findings identify CHI3L1 as a potential schizophrenia-susceptibility gene and suggest that the genes involved in the biological response to adverse environmental conditions are likely to play roles in the predisposition to schizophrenia.

YKL-40 and Alcoholic Liver and Pancreas Damage and Disease in 86258 Individuals from the General Population: Cohort and Mendelian Randomization Studies

“…Indeed, plasma concentrations of YKL-40 are partly heritable (10 ) and the rs4950928, a single nucleotide polymorphism in the proximal promoter of CHI3L1, accounts for 9% of its variance (10 ). Mechanistically, MYC/ MAX transcriptional factors do not bind well to the minor allele of rs4950928 (11 ), which decreases CHI3L1 transcription (12 ) and consequently plasma YKL-40 concentrations (13)(14)(15).…”

Association of the Polymorphisms and Plasma Level of CHI3L1 with Alzheimer’s Disease in the Chinese Han Population: A Case-Control Study

“…At the same time, many different genome-wide association studies have demonstrated that the different SNPs in the promoter region of the CHI3L1 gene are linked to the circulating CHI3L1 levels [40,41], but it was unclear whether the CHI3L1 SNPs could affect its expression levels. With this question, we determined the plasma CHI3L1 levels in AD patients and healthy controls with different genotypes of these three SNPs and found that the carriers with the variant genotype CG+GG of rs4950928 had lower plasma CHI3L1 levels, whereas the presence of the rs10399931 CT+TT genotype enhanced apparently plasma CHI3L1 when compared with the corresponding CC genotype carriers, and no significant differences were discovered between rs6691378 genotypes and CHI3L1 expressions.…”

Positive selection of three chitinase genes of the family 18 of glycoside hydrolases in mammals

“…Unlike AMCase and chitotriosidase, HC-gp39 lost its chitin-binding domain and distributed the binding sites in the carbohydrate-binding groove, so we suggested that the other 10 sites we identified are related to the function of binding carbohydrate. Recent research has also implicated the CHI3L1 gene in susceptibility to schizophrenia (Zhao et al 2007). …”