DST/NRF Centre of Excellence for Biomedical Tuberculosis Research/MRC Centre of Molecular and Cellular Biology, Division of Molecular Biology and Human Genetics, Faculty of Health Sciences, Stellenbosch University, Tygerberg, South Africa.
Eur J Hum Genet. 2011 Jun;19(6):676-81. doi: 10.1038/ejhg.2011.1. Epub 2011 Feb 2.
We have validated the association of two genes on chromosome 20q13.31-33 with tuberculosis susceptibility. A previous genome-wide linkage study performed by Cooke et al identified the genes melanocortin-3-receptor (MC3R) and cathepsin Z (CTSZ) as possible candidates in tuberculosis susceptibility. MC3R has been implicated in obesity studies and is known to play a role in many biological systems including the regulation of energy homeostasis and fat metabolism. CTSZ has been detected in immune cells, such as macrophages and monocytes, and it is hypothesized that the protein may play a role in the immune response. In our South African population a case-control study confirmed the previously reported association with a single-nucleotide polymorphism (SNP) in CTSZ and found an association in MC3R with a SNP not previously implicated in tuberculosis susceptibility. Six SNPs in MC3R and eight in CTSZ were genotyped and haplotypes were inferred. SNP rs6127698 in the promoter region of MC3R (cases = 498; controls = 506) and rs34069356 in the 3'UTR of CTSZ (cases = 396; controls = 298) both showed significant association with tuberculosis susceptibility (P = 0.0004 and < 0.0001, respectively), indicating that pathways involving these proteins, not previously researched in this disease, could yield novel therapies for tuberculosis.
我们已经验证了位于染色体 20q13.31-33 上的两个基因与结核病易感性的关联。Cooke 等人进行的先前全基因组连锁研究确定了黑素皮质素-3 受体 (MC3R) 和组织蛋白酶 Z (CTSZ) 基因作为结核病易感性的可能候选基因。MC3R 已被牵连到肥胖研究中，并且已知在许多生物系统中发挥作用，包括能量稳态和脂肪代谢的调节。CTSZ 已在免疫细胞（如巨噬细胞和单核细胞）中被检测到，据推测该蛋白可能在免疫反应中发挥作用。在我们的南非人群中，一项病例对照研究证实了先前在 CTSZ 中发现的与单核苷酸多态性 (SNP) 的关联，并在 MC3R 中发现了与先前未被牵连到结核病易感性的 SNP 的关联。对 MC3R 中的 6 个 SNP 和 CTSZ 中的 8 个 SNP 进行了基因分型，并推断了单倍型。MC3R 启动子区域中的 SNP rs6127698（病例=498；对照=506）和 CTSZ 3'UTR 中的 SNP rs34069356（病例=396；对照=298）均与结核病易感性显著相关（P=0.0004 和 <0.0001，分别），表明涉及这些蛋白的途径，在这种疾病中尚未被研究，可能为结核病提供新的治疗方法。
