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《Journal of Sun Yat-sen University(Medical Sciences)》 2016-06
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p.Asn1322Ser in ABCA6 and p.Cys1988Phe in ABCA7 Genes Are Associated with Resistance to Chronic Hepatitis B Virus Infection

JIANG Dan-hua;XU Ting-ting;LI Fu-cheng;LIAO Qi-jun;ZHAO Qiang;LIU Rui-hong;LIU Jin-song;WANG Yi-ming;Department of Medical Genetics//Center for Genome Research,Zhongshan School of Medicine,Sun Yat-sen University;School of Life Sciences,University of Science and Technology of China;Beijing Genomics Institute (BGI)-Shenzhen;Reproductive Medicine Center,First Affiliated Hospital, Sun Yat-sen University;Department of Pharmacy,Xinhua College, Sun Yat-Sen University;  
【Objective】By screening exome sequencing data in 99 "hepatitis B susceptible individuals " and 90 "hepatitis Bresistant individuals", we have previously identified p.Ser267 Phe in the hepatitis B virus(HBV) receptor SLC10A1 that renders the carrier a higher resistance to chronic HBV infection than the wild-type carrier. We aimed to identify more HBV resistant genes and their variants by further mining the exome sequencing data. 【Methods】All single nucleotide variations and small insertions, deletions were retrieved from the exome sequencing data. We selected alleles present in the hepatitis B resistant group significantly higher than the susceptible group and Fisher exact test was performed to test the difference of the alleles in the two groups. Selected genes and their variations(P 0.05) were further analyzed by means of bioinformatics and structural analyses of the wild and mutant proteins.【Results】We found that p.Asn1322 Ser in ABCA6 and p.Cys1988 Phe in ABCA7 are significantly associated with the resistance to chronic hepatitis B with the P values of 0.0187 and 0.0099 respectively. Bioinformatics analyses showed that the two mutations may affect the function of the wild-type proteins encoded. They occurred on the across-species conserved amino acids on the ABC transporter domain on each of the wild-type proteins. Our structural analyses showed that the Asn1322 in ABCA6 may affect ATP-binding function of the wild-type protein; p.Cys1988 Phe in ABCA7 affect the S-S bound and therefore interfere with the beta folding of the wild-type protein. 【Conclusions】We have identified two previously unknown genes and their variations p.Asn1322 Ser in ABCA6 and p.Cys1988 Phe in ABCA7 are associated with resistance to chronic hepatitis B virus infection. These results shed more light in the pathogenesis of HBV infection. Our study also demonstrated that exome sequencing of individuals with extreme phenotype is a powerful way to unravel genetic elements that underlie complex traits.
【Fund】: 国家自然科学基金资助项目(31471193 31271342)
【CateGory Index】: R512.62
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