Identification of Susceptibility Loci and Genes for Colorectal Cancer Risk

Zeng, Chenjie; Matsuda, Koichi; Jia, Wei‐Hua; Chang, Jiang; Kweon, Sun‐Seog; Xiang, Yong‐Bing; Shin, Aesun; Jee, Sun Ha; Kim, Dong-Hyun; Zhang, Ben; Cai, Qiuyin; Guo, Xingyi; Long, Jirong; Wang, Nan; Courtney, Regina; Pan, Zhizhong; Wu, Chen; Takahashi, Atsushi; Shin, Min Ho; Matsuo, Keitaro; Matsuda, Fumihiko; Gao, Yu‐Tang; Oh, Jae Hwan; Kim, Soriul; Jung, Keum Ji; Ahn, Yoon‐Ok; Ren, Ze-Fang; Li, Honglan; Wu, Jie; Shi, Jiajun; Wen, Wanqing; Yang, Gong; Li, Bingshan; Ji, Bu‐Tian; Kim, Hyeong–Rok; Jeong, Jinyoung; Park, Ji Won; Tajima, Kazuo; Cho, Sang‐Hee; Kubo, Michiaki; Shu, Xiao‐Ou; Lin, Dong; Zeng, Yi‐Xin; Wang, Zheng; Baron, John A.; Berndt, Sonja I.; Bézieau, Stéphane; Brenner, Hermann; Caan, Bette J.; Carlson, Christopher S.; Chan, Andrew T.; Chang‐Claude, Jenny; Chanock, Stephen J.; Curtis, Keith R.; Duggan, David; Fuchs, Charles S.; Gallinger, Steven; Giovannucci, Edward; Haile, Robert W.; Hayes, Richard B.; Hoffmeister, Michael; Hopper, John L.; Hsu, Li; Hudson, Thomas J.; Hunter, David J.; Hutter, Carolyn M.; Jackson, Rebecca D.; Küry, Sébastien; Marchand, Loı̈c Le; Lemire, Mathieu; Lindor, Noralane M.; Ma, Jing; Newcomb, Polly A.; Potter, John D.; Qu, Conghui; Schoen, Robert E.; Slattery, Martha L.; Thibodeau, Stephen N.; White, Emily; Zanke, Brent W.; Blalock, Kendra L.; Campbell, Peter T.; Casey, Graham; Conti, David V.; Edlund, Christopher K.; Figueiredo, Jane C.; Gauderman, W. James; Gong, Jian; Green, Roger C.; Gruber, Stephen B.; Harju, John F.; Harrison, Tabitha A.; Jacobs, Eric J.; Jenkins, Mark A.; Jiao, Shuo; Li, Li; Lin, Yi; Manion, Frank J.; Moreno, Vı́ctor; Mukherjee, Bhramar; Peters, Ulrike; Raskin, Leon; Schumacher, Fredrick; Seminara, Daniela; Severi, Gianluca; Stenzel, Stephanie L.; Thomas, Duncan C.

doi:10.1053/j.gastro.2016.02.076

Cited by 103 publications

(106 citation statements)

References 59 publications

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“…Details of the GWAS methodology, including genotyping protocol, filtering, and data cleaning procedures have been previously described. 9,11,12 Included in this study were 3,608 participants from the SBCS (N=1,875) and SWHS (N=1,733) whose lipid and genetic data were generated in previous studies. Among the 3,608 subjects, we have fasting information for 2,433 participants, with 44.55% samples being fasting and 55.45% non-fasting.…”

Section: Methodsmentioning

confidence: 99%

A common deletion in the haptoglobin gene associated with blood cholesterol levels among Chinese women

Zheng

Bastarache

et al. 2017

J Hum Genet

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Haptoglobin (HP) protein plays a critical role in binding and removing free hemoglobin from blood. A deletion in the HP gene affects the protein structure and function. A recent study developed a novel method to impute this variant and discovered significant association of this variant with low-density lipoprotein (LDL) and total cholesterol levels among European descendants. In the present study, we investigated this variant among 3,608 Chinese women. Consistent with findings from Europeans, we found significant associations between the deletion with lower cholesterol levels; women homozygous for the deletion allele (HP1-HP1), had a lower level of total cholesterol (−4.24 mg/dL, P = 0.02) and LDL cholesterol (−3.43 mg/dL, P = 0.03) than those not carrying the deletion allele (HP2-HP2). Especially, women carrying the HP1S-HP1S, had an even lower level of total cholesterol (−5.59 mg/dL, P = 7.0 × 10−3) and LDL cholesterol (−4.68 mg/dL, P = 8.0 × 10−3) compared to those carrying HP2-HP2. These associations remained significant after an adjustment for an established cholesterol level-related variant, rs2000999. Our study extends the previous findings regarding the association of HP structure variant with blood cholesterol levels to East Asians and affirms the validity of the new methodology for assessing HP structure variation.

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Section: Methodsmentioning

confidence: 99%

A common deletion in the haptoglobin gene associated with blood cholesterol levels among Chinese women

Zheng

Bastarache

et al. 2017

J Hum Genet

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“…Data used for the current project came from studies conducted in Shanghai. Details of the study design are described elsewhere . Briefly, the project includes 3,303 CRC cases from three resources: the Shanghai Women's Health Study (SWHS) ( N = 489), the Shanghai Men's Health Study (SMHS) ( N = 239) and the Shanghai Cancer Registry ( N = 2,575).…”

Section: Methodsmentioning

confidence: 99%

“…Genomic DNA was extracted from blood samples or buccal cells using conventional methods. The details of genotyping and quality control for samples from the SWHS and SMHS were reported previously . The samples from the Shanghai Cancer Registry were genotyped with Infinium OncoArray‐500 K Bead Chip (Illumina, San Diego, CA) in accordance with the manufacturer's protocol.…”

Section: Methodsmentioning

confidence: 99%

“…Colorectal cancer (CRC) is the third most common cancer and the fourth leading cause of cancer‐related mortality worldwide, resulting in over 1.6 million new cases and 771,000 deaths each year . Recently, genome‐wide association studies (GWAS) have identified multiple single nucleotide polymorphisms (SNPs) at approximately 40 loci associated with CRC susceptibility . Of these, 18 loci were identified in previous studies conducted in the Asia CRC Consortium .…”

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Evaluation of genetic variants in association with colorectal cancer risk and survival in Asians

Wang

Khankari

et al. 2017

Int. J. Cancer

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Genome-wide association studies (GWAS) have identified over 40 genetic loci associated with colorectal cancer (CRC) risk. The association of single nucleotide polymorphisms (SNPs) at these loci with CRC risk and survival has not been adequately evaluated in East Asians. GWAS-identified CRC risk variants were used to construct weighted genetic risk scores (GRSs). We evaluated these GRSs in association with CRC risk in 3,303 CRC cases and 3,553 controls using logistic regression models. Associations with overall and CRC-specific survival were assessed in 731 CRC patients using Cox regression models. The association between the GRSs (overall and Asian-specific) and CRC risk was approximately 2-fold (highest versus lowest quintile), and the shape of the dose-response was linear (Ptrend =1.24×10−13 and 3.02×10−14 for overall GRS and Asian-specific GRS, respectively). The association of the GRS with CRC risk was stronger among those with a family history of CRC (Pinteraction =0.007). Asian-specific GRS using previously reported survival SNPs increased risk for mortality and the shape of the dose-response was linear for CRC-specific and all-cause mortality (Ptrend =0.01 and 0.006, respectively). Furthermore, the minor alleles of rs6983267 and rs1957636 were associated with worse CRC-specific and overall survival. We show that GRSs constructed using GWAS-identified common variants are strongly associated with CRC risk in Asians. We confirm previous findings for the possible association between some SNPs with survival, and provide evidence for two additional CRC risk variants that may be related to CRC survival.

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“…Meta-analyses of thousands of cases and controls have been necessary to confidently estimate the 1.4 to 3 fold colon cancer risk associated with several relatively common APC and CHEK2 variants (Liang et al, 2013, Xiang et al, 2011). In genome-wide association studies (GWAS), tens of thousands of individuals have been tested to find common genetic variants responsible for 1.5 fold risk while leaving substantial uncertainty about lower levels of risk despite the enormity of these studies (Kar et al, 2016, Zeng et al, 2016). The scale of these studies illustrates the statistical impossibility of independently distinguishing low risk from no risk with any confidence for family-specific variants (Shirts et al, 2013).…”

Section: Family-specific Variants and The Charge Towards Precision Mementioning

confidence: 99%

Family-Specific Variants and the Limits of Human Genetics

Shirts

Pritchard

Walsh

2016

Trends in Molecular Medicine

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Every single nucleotide change compatible with life is present in the human population today. Understanding these rare human variants defines an extraordinary challenge for genetics and medicine. The new clinical practice of sequencing many genes for hereditary cancer risk has illustrated the utility of clinical next-generation sequencing in adults, identifying more medically actionable variants than single gene testing. However, it has also revealed a linear relationship between length of DNA evaluated and number of rare “variants of uncertain significance” reported. We propose that careful approaches to phenotype-genotype inference, distinguishing between diagnostic and screening intent, and expanded use of family-scale genetics studies as a source of information on family-specific variants will reduce variants of uncertain significance reported to patients.

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Identification of Susceptibility Loci and Genes for Colorectal Cancer Risk

Cited by 103 publications

References 59 publications

A common deletion in the haptoglobin gene associated with blood cholesterol levels among Chinese women

A common deletion in the haptoglobin gene associated with blood cholesterol levels among Chinese women

Evaluation of genetic variants in association with colorectal cancer risk and survival in Asians

Family-Specific Variants and the Limits of Human Genetics

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