Edenberg Howard J, Xuei Xiaoling, Wetherill Leah Flury, Bierut Laura, Bucholz Kathleen, Dick Danielle M, Hesselbrock Victor, Kuperman Sam, Porjesz Bernice, Schuckit Marc A, Tischfield Jay A, Almasy Laura A, Nurnberger J I, Foroud Tatiana
Indiana University School of Medicine, Indianapolis, IN, USA.
Hum Mol Genet. 2008 Apr 1;17(7):963-70. doi: 10.1093/hmg/ddm368. Epub 2007 Dec 12.
A broad region on chromosome 4q has been linked to alcohol dependence (alcoholism). We hypothesized that such broad linkage regions represent the combined action of multiple genes. Seeking to identify genes within that region that are associated with alcoholism, we have tested the association of NFKB1, located at 4q24, with alcoholism. NFKB1 encodes a 105 kDa transcription inhibitor that is cleaved to the 50 kDa DNA-binding subunit of the ubiquitous transcription factor NF-kappaB. NF-kappaB regulates many genes relevant to brain function, and its actions can be potentiated by ethanol; thus, NFKB1 is an excellent candidate gene for alcoholism. Nineteen SNPs in and near NFKB1 were analyzed in a sample of 219 multiplex alcoholic families of European American descent. Family-based association analyses detected significant evidence of association with eight SNPs and marginal evidence for five more. The association was driven by the affected individuals with earlier onset of alcoholism (55% of the sample with onset < or =21 years). Further analysis of the age of onset as a quantitative variable provided evidence for the association of 12 SNPs in this gene. Thus, variations in NFKB1 appear to affect the risk for alcoholism, particularly contributing to an earlier onset of the disease.
4号染色体长臂上的一个广泛区域已被证实与酒精依赖（酗酒）有关。我们推测，如此广泛的连锁区域代表了多个基因的联合作用。为了确定该区域内与酗酒相关的基因，我们检测了位于4q24的NFKB1与酗酒之间的关联。NFKB1编码一种105 kDa的转录抑制剂，该抑制剂可被切割成普遍存在的转录因子NF-κB的50 kDa DNA结合亚基。NF-κB调节许多与脑功能相关的基因，其作用可被乙醇增强；因此，NFKB1是酗酒的一个极佳候选基因。在一个由219个欧美裔多重酗酒家庭组成的样本中，对NFKB1内部及其附近的19个单核苷酸多态性（SNP）进行了分析。基于家系的关联分析发现，有显著证据表明8个SNP与之相关，另外5个SNP有边缘证据与之相关。这种关联是由酗酒发病较早的受影响个体驱动的（样本中55%的个体发病年龄≤21岁）。将发病年龄作为一个定量变量进行进一步分析，为该基因中12个SNP的关联提供了证据。因此，NFKB1的变异似乎会影响酗酒风险，尤其会导致该病更早发病。
