摘要
研究目的
酒精依赖综合征是一种复杂的疾病,它受生理、心理、环境、遗传等诸多因素的影响,其中遗传因素占主要地位,其遗传方式属于多基因遗传。本研究通过对酒精依赖综合征患者组及健康对照组儿茶酚胺氧位甲基转移酶基因外显子、内含子、3’、5’非编码区4个候选基因的检测,探讨儿茶酚胺氧位甲基转移酶(catechol-O-methyltransferase.COMT)基因在酒精依赖综合征患者组及健康对照组的遗传特征,以期揭示酒精依赖综合征与上述4个侯选基因的关联性,为探索酒精依赖综合征的发病机理及其基因诊断和治疗提供科学的依据。
研究方法
按照《精神疾病诊断及统计手册第4版》(Diagnostic & Statistic Manuel of Mental DisordersⅣ,DSM-Ⅳ)诊断标准选择2006-2009年四年来云南省精神病医院酒与药物依赖治疗科酒精依赖综合征住院患者107例,健康对照组214例。各样本静脉血200μl,通过饱和酚／氯仿法提取DNA,采用聚合酶链式反应-限制性片断长度多态性(PCR-RFLP)分析技术检测酒精依赖综合征组和健康对照组在4个候选基因中的基因型和等位基因频率。应用SPSS11.5、Arlequin、HWSIM和SHEsis等软件进行统计学分析。
研究结果
COMT基因rs2075507位点在酒依赖组和对照组中共检出两种等位基因：等位基因G、等位基因A和三种基因型：G/G型、G/A型和A/A型。其中,酒依赖组中G/G型有7例,占6.5%,G/A型有46例,占43.0%,A/A型有54例,占50.5%；等位基因G的频率为28.0%,等位基因A的频率为72.0%。健康对照组中G/G型有21例,占9.8%,G/A型有84例,占39.3%,A/A型有109例,占50.9%；等位基因G的频率为29.4%,等位基因A的频率为70.6%。COMT基因rs737865位点在两组中共检出两种等位基因：等位基因T、等位基因C和三种基因型：T/T型、T/C型和C/C型。其中,酒依赖组中T/T型有45例,占42.1%,T/C型有58例,占54.2%,C/C型有4例,占3.7%；等位基因T的频率为69.2%,等位基因A的频率为30.8%。健康对照组中T/T型有120例,占56.1%,T/C型有73例,占34.1%,C/C型有21例,占9.8%；等位基因T的频率为73.1%,等位基因A的频率为26.9%。COMT基因rs4680位点在两组中共检出两种等位基因：等位基因G、等位基因A和三种基因型：G/G型、G/A型和A/A型。其中,酒依赖组中G/G型有61例,占57.0%,G/A型有40例,占37.4%,A/A型有6例,占5.6%；等位基因G的频率为75.7%,等位基因A的频率为24.3%。健康对照组中G/G型有106例,占49.5%,G/A型有96例,占44.9%,A/A型有12例,占5.6%；等位基因G的频率为72%,等位基因A的频率为28%。COMT基因rs165599位点在两组中共检出两种等位基因：等位基因G、等位基因A和三种基因型：G/G型、G/A型和A/A型。其中,酒依赖组中G/G型有23例,占21.5%,G/A型有52例,占48.6%,A/A型有32例,占29.9%：等位基因G的频率为45.8%,等位基因A的频率为54.2%。健康对照组中G／G型有34例,占15.9%,G/A型有112例,占52.3%,A/A型有68例,占31.8%;等位基因G的频率为42.1%,等位基因A的频率为57.9%。
上述4个候选基因中,酒依赖组和健康对照组相比较,COMT基因rs737865位点多态性的基因型在两组中有差异,差异有统计学意义(P<0.05)。C/C基因型频率在健康对照组较酒依赖组高。其余3个位点统计学分析均无显著性差异(P＞0.05)。进一步对rs737865位点进行logistic回归分析时,结果显示携带C/C基因型可能降低其嗜酒的发生率(OR：0.822),但由于P值大于0.05,所以无统计学意义。对COMT基因rs2075507、rs737865、rs4680、rs1655994个基因位点进行单倍型分析,云南汉族人群中构建出12种主要单倍型(每种单倍型在对照组和酒依赖组中的频率至少有一个大于1%),单倍型A-C-A-A有可能是云南汉族酒精依赖发生的一种危险因子(P=0.003347、OR=2.865)。四个位点的连锁不平衡分析显示：云南汉族人群中,COMT基因的rs2075507和rs737865之间存在着强连锁(D>0.8)。
研究结论
在云南汉族人群中,COMT基因rs2075507、rs4680和rs165599位点与酒依赖无关联性,而COMT基因rs737865多态性与酒依赖存在相关性,三种基因型在两组中的差异有统计学意义(P<0.05),C/C基因型频率在健康对照组较酒依赖组高,提示C/C基因型可能是酒精依赖的保护因子,C/C基因型可能降低嗜酒的发生率。
单倍型A-C-A-A有可能是云南汉族酒精依赖发生的一种危险因子(P=0.003347、OR=2.865)。
云南汉族人群中,COMT基因的rs2075507和rs737865之间存在着强连锁(D’>0.8)。
Objective:Alcohol dependence syndrome is a complex disorder which is influenced by physiological, psychological, environmental factors, individual inheritance and so on. Study indicates that hereditary factor plays a dominating role in the process of alcohol dependence pathogenesis which is one of the processes of polygenes heredity. In the study, we discuss the hereditary features of COMT (catechol-O-methyltransferse) gene in both alcoholic dependent group and healthy control group by detecting its exon, intron and another 2 candidate genes in 3',5'noncoding regions. We hope to reveal the genetic relevance between alcohol dependence syndrome and the four candidate genes in order to find out the etiopathogenesis of alcohol dependence syndrome and, so to provide scientific evidence to enhance genetic diagnosis and clinical therapy accordingly.
Methods:According to the《Diagnostic and Statistic Manuel of Mental DisordersⅣ》(DSM-Ⅳ) diagnostic criteria, we select 107 alcoholic dependent patients of Mental Health Center of Yunnan Province and 214 normal persons as control group in the period during 2006-2009.200ul venous blood samples from each person of the alcoholic dependent group and healthy control group were obtained, DNA was extracted by phenol-chloroform method and polymorphism of the 4 candidate genes was assessed by detecting genotypes and allele frequencies by polymerase chain reaction and restriction fragment length technique (PCR-RFLP) in both groups. All data were analyzed by statistical software:SPSS 11.5, Arlequin, HWSIM and SHEsis.
Results:There are two alleles(G、A) at gene locus rs2075507 and three genotypes (G/G、G/A、A/A) of COMT gene. Genotype G/G is found in 7 cases among alcoholic dependent group, which take up 6.5%. There are 46 cases with genotype G/A. 43%. A/A genotype is found in 54 patients that account for 50.5%. The frequency of allele G is 28.0% and the frequency of allele A is 72.0%. By the contrast, genotype G/G is found in 21 cases (9.8%), genotype G/A is found in 84 cases (39.3%), genotype A/A is found in 109 cases (50.9%) in control group. The frequency of G allele is 29.4%, the frequency of A allele is 70.6%.We discover two alleles(T、C) at gene locus rs73786 of COMT gene and three genotypes (T/T、T/C、C/C). In patients with alcoholic dependent syndrome, genotype T/T are found in 45 cases(42.1%), genotype T/C are found in 58 cases(54.2%), genotype C/C are found in 4 cases(3.7%), The frequency of T allele is 69.2% and the frequency of C allele is 30.8%. In healthy control group, genotype T/T are found in 120 cases(56.1%), genotype T/C are found in 73 cases(34.1%), genotype C/C are found in 21 cases(9.8%). The frequency of T allele is 73.1% and the frequency of C allele is 26.9%. There are two alleles(G、A) at gene locus rs4680 and three genotypes (G/G、G/A、A/A) of COMT gene. In patients with alcohol dependence syndrome, genotype G/G is found in 61 cases (57.0%), genotype G/A is found in 40 cases (37.4%), genotype A/A is found in 6 cases (5.6%). The frequency of G allele is 75.7%, the frequency of A allele is 24.3%. In control group, genotype G/G is found in 106 cases (49.5%), genotype G/A is found in 96 cases (44.9%), genotype A/A is found in 12 cases (5.6%). The frequency of G allele is 72% and the frequency of A allele is 28%. There are two alleles(G、A) at gene locus rs 16559 and three genotypes (G/G、G/A、A/A) of COMT gene. In patients with alcohol dependence syndrome, genotype G/G is found in 23 cases (21.5%), genotype G/A is found in 52 cases(48.6%), genotype A/A is found in 32 cases(29.9%). The frequency of G allele is 45.8% and the frequency of A allele is 54.2%.Compared with control group, genotype G/G is found in 34 cases(15.9%), genotype G/A is found in 112 cases(52.3%), genotype A/A is found in 68 cases(31.8%). The frequency of G allele is 42.1% and the frequency of allele A is 57.9%.
The genotype frequencies of COMT gene at gene locus rs737865 differed significantly between alcoholic dependent group and control group(P＜0.05).The frequency of C/C genotype in control group is higher than alcoholic dependent group. Frequencies of rest genotypes and alleles in both alcoholic dependent group and control group have no statistical significant differences (P＞0.05). Logistic regression analysis indicates that C/C genotype was associated positively with alcoholic dependence syndrome(OR:0.822). but it has no statistical meaning (P＞0.05).The results of haplotype analysis for gene loci rs2075507, rs737865, rs4680, rs165599 reveal that there are 12 kinds of major haplotypes in Han majority of Yunnan province (frequency of each haplotype is greater than 1% at least in one group), A-C-A-A haplotype might be a factor leading to alcoholic dependence syndrome(P=0.003347、OR=2.865). Lingkage disequilibrium analysis shows that there is a strong linkage between rs2075507 and rs737865 in Han majority of Yunnan province (D＞0.8).
Conclusion:There is no significant association of gene loci rs2075507, rs4680 and rs165599 between alcoholic dependent group and control group in Han majority of Yunnan province. However, rs737865 gene polymorphism is related to alcoholic dependence. The frequency of three genotypes at this gene locus has statistical significant difference (P＜0.05) in both alcoholic dependent group and control group. The frequency of genotype C/C in control group is higher than alcoholic dependent group, C/C genotype is associated positively with alcohol dependence. A-C-A-A haplotype might be a dangerous factor leading to alcohol dependence syndrome(P=0.003347、OR=2.865).There are strong linkage between rs2075507 and rs737865 in Han majority of Yunnan province (D＞0.8).
引文
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