Molecular Biology and Human Genetics, MRC Centre for Molecular and Cellular Biology and the DST/NRF Centre of Excellence for Biomedical TB Research, Faculty of Health Sciences, P.O. Box 19063, Stellenbosch University, Tygerberg 7505, South Africa.
Tuberculosis (Edinb). 2010 Mar;90(2):71-83. doi: 10.1016/j.tube.2010.02.002. Epub 2010 Mar 4.
The evidence for a human genetic component in susceptibility to tuberculosis (TB) is incontrovertible. Quite apart from studies of rare disease events illustrating the importance of key genes in humans and animals, TB at the population level is also influenced by the genetics of the host. Heritability of disease concordance and immune responses to mycobacterial antigens has been clearly shown, and ranges up to 71%. Linkage studies, designed to identify major susceptibility genes in a disease, have produced a number of candidate loci but few, except for regions on chromosome 5p15, 20p and 20q, have been replicated. The region on 5p15 regulates the intensity of the response to the tuberculin skin test, and another locus on 11p14 appears to control resistance to the bacterium. In addition, numerous genes and pathways have been implicated in candidate gene association studies, with validation of polymorphisms in IFNG, NRAMP1, and NOS2A and equivocal results for IL10, CCL2, DC-SIGN, P2RX7, VDR, TLR2, TLR9 and SP110. Other more recently researched candidate genes such as TNFRSF1B remain to be validated, preferably in meta-analyses. New approaches have provided early evidence for the importance of gene-gene interactions in regulating resistance to disease, and also the prospect that applying host genetics in the field of vaccinomics could lead to a more targeted approach in designing interventions to aid the human immune system in combating mycobacteria. Genome-wide association studies and admixture mapping are approaches that remain to be applied to TB, and it is not clear, as is the case with other complex diseases, how much of the heritability of the TB susceptibility phenotype will be determined by multiple genes of small effect versus rare variants with disproportionately large effects.
结核病易感性的人类遗传因素的证据是无可争议的。除了研究罕见疾病事件阐明了人类和动物关键基因的重要性外，人群水平的结核病也受到宿主遗传学的影响。疾病一致性和对分枝杆菌抗原的免疫反应的遗传性已得到明确证明，范围高达 71%。为了在疾病中识别主要易感性基因而设计的连锁研究已经产生了一些候选基因座，但很少有基因座（除了染色体 5p15、20p 和 20q 上的区域外）得到复制。5p15 上的区域调节对结核菌素皮肤试验反应的强度，11p14 上的另一个位点似乎控制对细菌的抵抗力。此外，在候选基因关联研究中，许多基因和途径都被牵连，IFNG、NRAMP1 和 NOS2A 中的多态性得到了验证，而 IL10、CCL2、DC-SIGN、P2RX7、VDR、TLR2、TLR9 和 SP110 的结果则存在争议。其他最近研究的候选基因，如 TNFRSF1B，仍有待验证，最好在荟萃分析中进行。新方法为基因-基因相互作用在调节疾病抵抗力方面的重要性提供了早期证据，并且有望在疫苗组学领域应用宿主遗传学，从而为设计干预措施提供更有针对性的方法，以帮助人体免疫系统对抗分枝杆菌。全基因组关联研究和混合映射仍然适用于结核病，并且与其他复杂疾病一样，结核病易感性表型的遗传力有多少将由多个具有较小效应的基因决定，还是由具有不成比例大效应的罕见变异决定，这一点尚不清楚。
