Chronic hepatitis B(CHB)is a major global health issue.The role of rare genetic variants in CHB has not been elucidated.We aimed to identify rare allelic variants predisposing to CHB.We performed exome sequencing in 50 CHB patients who had no identifiable risk factors to CHB and 40 controls who were healthy and hepatitis B surface antibody positive,but had never received hepatitis B vaccination.We selected six rare variant alleles and followed up their association with disease status by Sanger sequencing in a case-control study comprising 1728 CHB patients and 1636 healthy controls.The latter had either not been immunized with hepatitis B vaccine or had uncertain vaccination status.Our results showed that transmembrane protein 2 p.Ser1254Asn,interferon alpha 2 p.Ala120Thr,its regulator NLR family member X1 p.Arg707Cys and complement component 2 p.Glu318Asp were associated with CHB,with P values of <1.0×10-7,2.76×105,5.08×10-5,2.78×10-4 and ORs of 2.45,4.08,2.34 and 1.97 respectively.The combined P value was<2.0×10-16.As there has been no indication of immunological functions for the associated gene,transmembrane protein 2,we further studied its expression by immunohistochemistry,real time PCR and western blotting.Our results showed that it was strongly expressed by healthy hepatocytes,but its expression was reduced in liver tissues with CHB,hepatitis B viral(HBV)genome-containing HepG2.2.15 cells,as compared with healthy liver tissues and non-HBV genome-containing HepG2 cells(P=0.022 and 0.0036 respectively).