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Genetic Fine Mapping and Genomic Annotation Defines Causal Mechanisms at A Novel Colorectal Cancer Susceptibility Locus in Han Chinese.

ABSTRACT: Genome-wide association studies of colorectal cancer (CRC) have identified two risk SNPs. The characterization of these risk regions in diverse racial groups with different linkage disequilibrium structure would aid in localizing the causal variants. Herein, fine mapping of the established CRC loci was carried out in 1,508 cases and 1,482 controls obtained from the Han Chinese population. One distinct association signal was identified at these loci, where fine mapping implicated rs1010208 as a functional locus. Next, the candidate target genes of functional SNP rs1010208 were analyzed using data from TCGA databases by expression quantitative trait loci analysis method; the data from Peking University People's Hospital were utilized for verification. The dual-luciferase reporter system analysis confirmed that rs1010208 is a regulatory region that can be mutated to decrease the expression of HINT1, resulting in proliferation and invasiveness of CRC.

SUBMITTER: Jiang K

PROVIDER: S-EPMC7592009 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Genetic Fine Mapping and Genomic Annotation Defines Causal Mechanisms at A Novel Colorectal Cancer Susceptibility Locus in Han Chinese.

Jiang Kewei K Du Fengying F Lv Liang L Zhuo Hongqing H Xu Tao T Peng Lipan L Chen Yuezhi Y Li Leping L Zhang Jizhun J

Journal of Cancer 20200930 23

Genome-wide association studies of colorectal cancer (CRC) have identified two risk SNPs. The characterization of these risk regions in diverse racial groups with different linkage disequilibrium structure would aid in localizing the causal variants. Herein, fine mapping of the established CRC loci was carried out in 1,508 cases and 1,482 controls obtained from the Han Chinese population. One distinct association signal was identified at these loci, where fine mapping implicated rs1010208 as a f ...[more]

PMID: 33123275

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Project description:PSORS1 (psoriasis susceptibility gene 1) is a major susceptibility locus for psoriasis. Several fine-mapping studies have highlighted a 300-kb candidate region of PSORS1 where multiple biologically plausible candidate genes were suggested. The most recent study has indicated HLA-Cw6 as the primary PSORS1 risk allele within the candidate region in a Caucasian population. In this study, a family-based association analysis of the PSORS1 locus was performed by analyzing 10 polymorphic microsatellite markers from the PSORS1 region as well as HLA-B, HLA-C and CDSN loci in 163 Chinese families of psoriasis. Five marker loci show strong evidence (P<10(-3)), and one marker locus shows weak evidence (P = 0.04) for association. The haplotype cluster analysis showed that all the risk haplotypes are Cw6 positive and share a 369-kb region of homologous marker alleles which carries all the risk alleles, including HLA-Cw6 and CDSN*TTC, identified in this study. The recombinant haplotype analysis of the HLA-Cw6 and CDSN*TTC alleles in 228 Chinese families showed that the HLA-Cw6(-)/CDSN*TTC(+) recombinant haplotype is clearly not associated with risk for psoriasis (TratioNT = 29:57, p = 0.0025) in a Chinese population, suggesting that the CDSN*TTC allele itself does not confer risk without the presence of the HLA-Cw6 allele. The further exclusion analysis of the non-risk HLA-Cw6(-)/CDSN*TTC(+) recombinant haplotypes with common recombination breakpoints has allowed us to refine the location of PSORS1 to a small candidate region. Finally, we performed a conditional linkage analysis and showed that the HLA-Cw6 is a major risk allele but does not explain the full linkage evidence of the PSORS1 locus in a Chinese population. By performing a series of family-based association analyses of haplotypes as well as an exclusion analysis of recombinant haplotypes, we were able to refine the PSORS1 gene to a small critical region where HLA-C is a strong candidate to be the PSORS1 susceptibility gene.

Dataset Information

Genetic Fine Mapping and Genomic Annotation Defines Causal Mechanisms at A Novel Colorectal Cancer Susceptibility Locus in Han Chinese.

Publications

Genetic Fine Mapping and Genomic Annotation Defines Causal Mechanisms at A Novel Colorectal Cancer Susceptibility Locus in Han Chinese.

Similar Datasets

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