Medical Genetics Section, National Institute of Health, Department of Medical Sciences, Ministry of Public Health, Nonthaburi, Thailand.
J Hum Genet. 2012 Jun;57(6):363-7. doi: 10.1038/jhg.2012.35. Epub 2012 May 3.
Tuberculosis (TB) is one of the most devastating chronic infectious diseases, but the role of host genetics in disease development after infection in this disease remains unidentified. Genome-wide association studies (GWASs) in Thais and Japanese were carried out and separately analyzed, attempted replication, then, combined by meta-analysis were not yielding any convincing association evidences; these results suggested that moderate to high effect-size genetic risks are not existed for TB per se. Because of failure in replication attempt of the top 50 single-nucleotide polymorphisms (SNPs) identified form meta-analysis data, we empirically split TB cases into young TB case/control data sets (GWAS-T(young)=137/295 and GWAS-J(young)=60/249) and old TB case/control data sets (GWAS-T(old)=300/295 and GWAS-J(old)=123/685), re-analyzed GWAS based on age-stratified data and replicated the significant findings in two independent replication samples (young TB; Rep-T(young)=155/249, Rep-J(young)=41/462 and old TB; Rep-T(old)=212/187, Rep-J(old)=71/619). GWAS and replication studies conducted in young TB identified at-risk locus in 20q12. Although the locus is located in inter-genic region, the nearest genes (HSPEP1-MAFB) from this locus are promising candidates for TB susceptibility. This locus was also associated with anti-TNF responsiveness, drug with increased susceptibility for TB. Moreover, eight SNPs in an old TB meta-analysis and six SNPs in young TB meta-analysis provided replication evidences but did not survive genome-wide significance.These findings suggest that host genetic risks for TB are affected by age at onset of TB, and this approach may accelerate the identification of the major host factors that affect TB in human populations.
结核病（TB）是最具破坏性的慢性传染病之一，但宿主遗传学在感染后疾病发展中的作用在这种疾病中仍未确定。对泰国人和日本人进行了全基因组关联研究（GWAS），并分别进行了分析，尝试了复制，然后通过荟萃分析进行了组合，但没有产生任何令人信服的关联证据；这些结果表明，TB 本身不存在中等至高效应大小的遗传风险。由于从荟萃分析数据中确定的前 50 个单核苷酸多态性（SNP）的复制尝试失败，我们根据年龄将 TB 病例分为青年 TB 病例/对照数据集（GWAS-T（青年）=137/295 和 GWAS-J（青年）=60/249）和老年 TB 病例/对照数据集（GWAS-T（老年）=300/295 和 GWAS-J（老年）=123/685），基于年龄分层数据重新分析 GWAS，并在两个独立的复制样本中复制了显著发现（青年 TB；Rep-T（青年）=155/249，Rep-J（青年）=41/462 和老年 TB；Rep-T（老年）=212/187，Rep-J（老年）=71/619）。在青年 TB 中进行的 GWAS 和复制研究确定了 20q12 中的风险基因座。虽然该基因座位于基因间区域，但来自该基因座的最近基因（HSPEP1-MAFB）是 TB 易感性的有希望的候选基因。该基因座还与抗 TNF 反应性、增加 TB 易感性的药物相关。此外，在老年 TB 荟萃分析中有 8 个 SNP，在青年 TB 荟萃分析中有 6 个 SNP 提供了复制证据，但没有达到全基因组意义。这些发现表明，TB 的宿主遗传风险受 TB 发病年龄的影响，这种方法可能加速确定影响人类人群中 TB 的主要宿主因素。
