| BackgroundsHepatitis B virus (HBV) infection is a serious global health problem, especially in China, and there are about 120 million chronic HBV carriers. It has been shown that several factors contribute to the various clinical outcomes. Recently, genetic epidemiological studies provide robust evidence that genetic variation in human populations contributes to susceptibility to hepatitis B. In this present study, the host genetic factors that can affect the outcomes of HBV infection will be disclosed by population based case control design, with human leukocyte antigen (HLA) classⅡgene and tumor necrosis factorα(TNFα) gene as candidate genes.MethodsIn 196 chronic hepatitis B patients (CHB), 184 chronic HBV carriers (CC) and 143 spontaneously cleared subjects (SC), polymorphisms of TNF-αpromoter region were detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and polymerase chain reaction-sequence specific primer (PCR-SSP), and analyzed its relationship with the outcomes of HBV infection.Association of polymorphisms of HLA-DQB1 and DRB1 with outcomes of HBV infection was explored in 389 CHB, 246 CC and 198 SC with PCR-SSP detection method.Results1. Association of polymorphisms in TNF-αpromoter region with outcomes of HBV infectionCase control study was performed with SC as the control group, after adjustment by multiple logistic regression analysis, frequency of TNF-α-857TT genotype in CHB group was significantly lower than that in SC group (9.18%vs17.48%, P=0.03, OR=0.48, 95%CI=0.24-0.94). Frequency of haplotype GGCAC constructed by TNF-α-238/-308/-857/-863/-1031 in CHB group was clearly lower than that in SC group (8.16%vs 13.29%, P=0.03, OR=0.58, 95%CI=0.34-0.98).When CC was regarded as the control group, after adjustment by multiple logistic regression analysis it showed frequency of TNF-α-863CC genotype in CHB group was significantly higher than that in CC group (62.24%vs 45.11%; P=0.01, OR=1.85, 95%CI=1.15-2.98). Frequencies of haplotypes GGCCT, GGCCC, GGTCT constructed by TNF-α-238/-308/-857/-863/-1031 in CHB group were clearly higher than those in CC group (45.66%vs36.14%, P=0.008, OR=1.48, 95%CI=1.10-2.01; 13.27%vs7.61%, P=0.01, OR=1.86, 95%CI=1.12-3.10; 10.71%vs6.25%, P=0.04, OR=1.80, 95%CI=1.03-3.16).2. Association of polymorphisms in HLA-DQB1 and DRB1 with outcomes of HBV infection(1) Case control study performed in CHB group and SC group After adjustment by multiple logistic regression analysis, frequencies of DQB1~*0301/4, DQB1~*0303, DRB1~*11 and DRB1~*12 in CHB group were statistically higher than those in SC group (26.61%vs16.67%, P=0.0002, OR=1.86, 95%CI=1.35-2.57; 16.58%vs11.36%, P=0.007, OR=1.70, 95%CI=1.16-2.49; 5.91%vs2.27%, P=0.003, OR=3.09, 95%CI=1.47-6.51; 16.58%vs8.84%, P=0.0008, OR=2.01, 95%CI=1.34-3.03); frequencies of DQB1~*0602, DQB1~*0604, DRB1~*01 and DRB1~*13 in CHB group were clearly lower than those in SC group (14.01%vs20.96%, P=0.005, OR=0.72, 95%CI=0.48-0.86; 1.16%vs3.79%, P=0.01, OR=0.34, 95%CI=0.14-0.80; 1.67%vs4.29%, P=0.02, OR=0.42, 95%CI=0.19-0.89; 2.44%vs5.81%, P=0.003, OR=0.38, 95%CI=0.20-0.72).Individuals carrying haplotype ~*11-~*0501-~*0301/4 (HLA-DRB1-DQA1-DQB1) in CHB group were significantly more than those in SC group (3.21%vs0.52%, P=0.004, OR=6.37, 95%CI=1.46-39.13); and number of individuals with haplotype ~*09-~*0302-~*0602 was clearly less than in SC group (1.54%vs4.40%, P=0.003, OR=0.34, 95%CI=0.15-0.76)。(2) Case control study performed in CHB group and CC groupFrequencies of DQB1~*0301/4, DQB1~*0303 in CHB group were higher than those in CC group after adjusted by logistic regression analysis (26.61%vs21.75%, P=0.04, OR=1.35, 95%CI=1.02-1.80; 16.58%vs9.55%, P=0.001, OR=1.87, 95%CI=1.29-2.72); frequencies of DQB1~*0601, DRB1~*04, DRB1~* 13 in CHB group were lower than those in CC group (4.88%vs9.96%, P=0.006, OR=0.52, 95%CI=0.33-0.83; 10.03%vs14.84%, P=0.002, OR=0.58, 95%CI=0.41-0.82; 2.44%vs5.28%, P=0.003, OR=0.40, 95%CI=0.21-0.73).Haplotypes of HLA-DRB1-DQA1-DQB1 ~*03-~*0501-~*0201, ~*11-~*0501-~*0301/4, ~*12-~*0601-~*0301/4 and ~*09-~*0302-~*0303, in CHB group were more than in CC group (2.31%vs0%, P=0.0007, OR=1.65, 95%CI=1.58-1.72; 3.21%vs0.41%, P=0.0007, OR=8.13, 95%CI=1.86-49.89; 3.98%vs0.81%, P=0.0008, OR=5.06, 95%CI=1.69-17.00; 6.43%vs0.20%, P＜0.0001, OR=33.72, 95%CI=5.02-659.55); haplotypes of ~*08-~*0301-~*0601,~*09-~*0301-~*0303 in CHB group were less than in CC group (2.31%vs4.47%, P=0.03, OR=0.51, 95%CI=0.26-0.99; 2.44%vs5.08%, P=0.01, OR=0.47, 95%CI=0.24-0.89).ConclusionsWe can conclude from case control studies performed in CHBvsSC and CHBvsCC: TNF-α-863CC genotype, DQB1~*03 alleles (DQB1~*0301/4, ~*0303) and haplotype DRB1~*ll-DQA1~*0501-DQB1~*0301/4 are the susceptible factors to persistence of hepatitis B; and individuals carrying TNF-α-857TT, DQB1~*06 alleles (DQB1~*0601, ~*0602, ~*0604) and DRB1~*13 are resistant to chronic hepatitis B. BackgroundsChronic hepatitis B is the heavy burden of economic, society and health in China, and the annual medical cost related to hepatitis B reaches 30 billion RMB. Interferonα(IFNα) is one of the first line drugs against Hepatitis B Virus (HBV), however, variation of response to IFNαbetween individuals is the main problem that interfere with the clinical treatment. In this present study, nested case control study was used to perform the pharmocogenomics study of IFNαagainst HBV, with human leukocyte antigen (HLA) classⅡgenens, interferonαreceptor 2 (IFNAR2) and myxovirus-resistance A (MxA) as the candidate genes.MethodsIn 252 chronic hepatitis B patients treated by IFNα, HLA-DQB1 and DRB1 polymorphisms were identified by PCR-SSP, and polymorphisms in IFNAR2 rs2284551 G/A, rs2248202 C/A, rs4986956 T/C and MxA-88 G/T, -123 C/A, 20 C/A, rs467558 C/T, rs469390 G/A were detected by PCR-RFLP.Results1. After 3-6 months therapy, the total response rate is 69.1%, in which complete resonse (CR) rate is 16.3 % (41/252), and partial response (PR) rate is 52.8 % (133/252).2. ALT values of baseline in CR group and PP group are significantly higher than that in non-response (NR) group (189.0 IU/L & 156.5IU/L vs 101.0IU/L, P=0.001). There was no significant difference in gender, age and viral genotype among CR group, PR group and NR group (P＞0.05).3. After adjustment for age and gender by non-conditional logistic regression, frequencies of DQB1~*0501 and DQB1~*0303 in response group were clearly lower than those in NR group (1.50%vs4.73%, P=0.03, OR=0.27. 95%CI=0.08-0.86; 17.07%vs26.35%, P=0.01, OR=0.55, 95%CI=0.34-0.87): the frequency of DRB1~*14 in response group was clearly higher than that in NR group (5.99%vsl.35%, P=0.04, OR=4.65, 95%CI=1.07-20.16).4. Frequency of haptotype DRB1~*09-DQA1~*0302-DQB1~*0303 in response group was significantly lower than that in NR group (6.89%vs14.86%, P=0.005, OR=0.42, 95%CI=0.22-0.82).5. After adjustment for age and gender by non-conditional logistic regression analysis, frequency of MxA20AA genotype in response group was significantly lower than that in NR group (10.92%vs21.79%. P=0.03, OR=0.45, 95%CI=0.22-0.94). There was no clear difference in the frequencies of other four MxA polymorphisms and three IFNAR2 polymorphims between response group and NR group.ConclusionsHigh baseline ALT level is related to response to IFNα. Individuals carrying MxA20AA genotype, HLA-DQB1~*0501 allele, DQB1~*0303 allele and haplotype DRB1~*09-DQA1~*0302-DQB1~*0303 are probably susceptible to non-response to IFNα, and those carrying DRB1~* 14 are more probably respond to IFNα. There is no evidence which indicates that IFNAR2 gene polymorphisms are related to short-term efficacy of IFNα. Paroxysmal kinesigenic choreoathetosis (PKC) is an autosomal-dominant movement disorder characterized by attacks of paroxysmal involuntary movements. To date, the causative gene has not been discovered. This study is aimed to localize the causative region and detect the causative mutation.MethodsA PKC family including 16 subjects (5 cases and 11 controls) in Zhcjiang Province was recruited. Nine microsatellite markers on chromosome 16 were selected and genotyped. Two-point LOD scores were calculated by linkage software. Candidate genes were screened in the preliminarily localized region, by PCR-sequencing or PCR-denaturing high performance liquid chromatography (PCR-DHPLC).ResultsThe maximal two-point LOD score was obtained in D16S3081 as 1.21, and haplotype analysis revealed almost all of individuals carrying 5-3-8-3-4-2-5-5-6 in D16S3093/D16S685/D16S690/D16S3081/D16S3080 D16S411/D16S3136/D16S3112/D16S3057 were affected by PKC. There was no causative mutation in ten candidate genes, including CACNG3 (calcium channel voltage-dependent gamma-3 subunit) gene, IL4R (interleukin 4 receptor) gene, ADCY7 (adenylate cyclase-7) gene, STM (monoamine-preferring sulfotransferase) gene, PPP4C (protein phosphatase-4 catalytic subunit) gene, ABCC11 gene and ABCC12 (ATP-binding cassette transporter superfamily) gene, GRIN2A (glutamate receptor ionotropic N-methyl-D-aspartate, subunit 2A), SLC5A2 (solute carrier family 6, member 2), and SLC6A2 (solute carrier family 6, member 2) genes. ConclusionsThe culprit gene for PKC was located in～19.34cM region between 16p12.1-q13, and CACNG3, IL4R, ADCY7, STM, PPP4C, ABCC11, ABCC12, GRIN2A, SLC5A2, SLC6A2 were all ruled out as the cause.
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