Genome-wide association study identifies high-impact susceptibility loci for HCC in North America.
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Hassan Manal M, Li Donghui, Han Younghun, Byun Jinyoung, Hatia Rikita I, Long Erping, Choi Jiyeon, Kelley Robin Kate, Cleary Sean P, Lok Anna S, Bracci Paige, Permuth Jennifer B, Bucur Roxana, Yuan Jian-Min, Singal Amit G, Jalal Prasun K, Ghobrial R Mark, Santella Regina M, Kono Yuko, Shah Dimpy P, Nguyen Mindie H, Liu Geoffrey, Parikh Neehar D, Kim Richard, Wu Hui-Chen, El-Serag Hashem, Chang Ping, Li Yanan, Chun Yun Shin, Lee Sunyoung S, Gu Jian, Hawk Ernest, Sun Ryan, Huff Chad, Rashid Asif, Amin Hesham M, Beretta Laura, Wolff Robert A, Antwi Samuel O, Patt Yehuda, Hwang Lu-Yu, Klein Alison P, Zhang Karen, Schmidt Mikayla A, White Donna L, Goss John A, Khaderi Saira A, Marrero Jorge A, Cigarroa Francisco G, Shah Pankil K, Kaseb Ahmed O, Roberts Lewis R, Amos Christopher I
Аннотация
APPROACH AND RESULTS: We conducted a 2-stage genome-wide association study (GWAS) on HCC not affected by HBV infections. A total of 1872 HCC cases and 2907 controls were included in the discovery stage, and 1200 HCC cases and 1832 controls in the validation. We analyzed the discovery and validation samples separately and then conducted a meta-analysis. All analyses were conducted in the presence and absence of HCV. The liability-scale heritability was 24.4% for overall HCC. Five regions with significant ORs (95% CI) were identified for nonviral HCC: 3p22.1, MOBP , rs9842969, (0.51, [0.40-0.65]); 5p15.33, TERT , rs2242652, (0.70, (0.62-0.79]); 19q13.11, TM6SF2 , rs58542926, (1.49, [1.29-1.72]); 19p13.11 MAU2 , rs58489806, (1.53, (1.33-1.75]); and 22q13.31, PNPLA3 , rs738409, (1.66, [1.51-1.83]). One region was identified for HCV-induced HCC: 6p21.31, human leukocyte antigen DQ beta 1, rs9275224, (0.79, [0.74-0.84]). A combination of homozygous variants of PNPLA3 and TERT showing a 6.5-fold higher risk for nonviral-related HCC compared to individuals lacking these genotypes. This observation suggests that gene-gene interactions may identify individuals at elevated risk for developing HCC.
CONCLUSIONS: Our GWAS highlights novel genetic susceptibility of nonviral HCC among European descent populations from North America with substantial heritability. Selected genetic influences were observed for HCV-positive HCC. Our findings indicate the importance of genetic susceptibility to HCC development.