干扰素-γ（IFNG）微卫星重复序列以及与印度人群疟疾易感性增强相关的Ⅰ型干扰素受体（IFNAR1）单核苷酸多态性单倍型。
Interferon-γ (IFNG) microsatellite repeat and single nucleotide polymorphism haplotypes of IFN-α receptor (IFNAR1) associated with enhanced malaria susceptibility in Indian populations.
作者信息
Kanchan Kanika, Jha Pankaj, Pati Sudhanshu S, Mohanty Sanjib, Mishra Saroj K, Sharma Surya K, Awasthi Shally, Venkatesh Vimala, Habib Saman
机构信息
Division of Molecular and Structural Biology, CSIR-Central Drug Research Institute, Lucknow, India.
Genomics and Molecular Medicine, CSIR-Institute of Genomics and Integrative Biology, Delhi, India.
出版信息
Infect Genet Evol. 2015 Jan;29:6-14. doi: 10.1016/j.meegid.2014.10.030. Epub 2014 Nov 7.
Pro-inflammatory cytokines IFNγ and IFNα function through their cellular receptors IFNγR1 and IFNαR1, respectively to mediate immune processes during malaria infection. A total of 21 SNPs, 2 ins/del polymorphisms and a microsatellite repeat, selected on the basis of their reported association with infectious diseases including malaria in world populations, were analysed for association with Plasmodium falciparum malaria susceptibility in a case-control study with adult patients and ethnically-matched controls drawn from a disease meso- to hyperendemic and a nonendemic region of India. Among the five IFNG SNPs tested, an intron 3 and a 3'UTR SNP associated with disease in the endemic region. In addition, large (CA)n repeats of IFNG intron 1 associated with protection from severe malaria in the endemic region (severe vs. control, odds ratio=0.21, 95% CI=0.08-0.52, P=1.3 × 10(-4)). The TA11CAG haplotype (rs2069705 T/C, rs2430561 A/T, rs3138557 (CA)n, rs2069718 T/C, rs2069727 A/G, rs2069728 G/A) carrying a short CA11 repeat also exhibited very strong association with severe malaria, particularly in the endemic region (severe vs. control, OR=14.56, 95% CI=3.39-85.81, P=3 × 10(-5)). One SNP each from the IFNA8 and IFNA17 of IFNA gene cluster had a protective effect in the non-endemic region but not in the endemic region. A promoter and an intron 2 SNP of IFNAR1 were risk factors for disease and the IFNAR1 haplotype GCCAGG (rs2843710 C/G, rs2850015 C/T, +6993 C/T, rs2243594 A/G, rs1012335 G/C, rs2257167 G/C) carrying both the risk alleles strikingly associated with disease manifestation in the endemic region (severe vs. control, OR=27.14, 95% CI=3.12-1254, P=2 × 10(-5); non-severe vs. control, OR=61.87, 95% CI=10.08-2521, P=1 × 10(-8)). The data indicates dissimilar contribution of cytokine and cytokine receptor variants to disease in populations residing in areas of differential malaria endemicity.
促炎细胞因子IFNγ和IFNα分别通过其细胞受体IFNγR1和IFNαR1发挥作用，以介导疟疾感染期间的免疫过程。在一项病例对照研究中，从印度疾病中高度流行地区和非流行地区选取成年患者及种族匹配的对照，分析了总共21个单核苷酸多态性（SNP）、2个插入/缺失多态性以及1个微卫星重复序列，这些是根据它们在世界人群中与包括疟疾在内的传染病的报道关联而选择的，用于研究其与恶性疟原虫疟疾易感性的关联。在所检测的5个IFNG SNP中，1个内含子3和1个3'非翻译区SNP与流行地区的疾病相关。此外，IFNG内含子1的大（CA）n重复序列与流行地区预防重症疟疾相关（重症与对照相比，比值比=0.21，95%置信区间=0.08 - 0.52，P = 1.3×10⁻⁴）。携带短CA11重复序列的TA11CAG单倍型（rs2069705 T/C、rs2430561 A/T、rs3138557（CA）n、rs2069718 T/C、rs2069727 A/G、rs2069728 G/A）也与重症疟疾表现出非常强的关联，特别是在流行地区（重症与对照相比，OR = 14.56，95%置信区间=3.39 - 85.81，P = 3×10⁻⁵）。IFNA基因簇的IFNA8和IFNA17各有1个SNP在非流行地区有保护作用，但在流行地区则不然。IFNAR1的1个启动子和1个内含子2 SNP是疾病的危险因素，携带两个风险等位基因的IFNAR1单倍型GCCAGG（rs2843710 C/G、rs2850015 C/T、+6993 C/T、rs2243594 A/G、rs1012335 G/C、rs2257167 G/C）与流行地区的疾病表现显著相关（重症与对照相比，OR = 27.14，95%置信区间=3.12 - 1254，P = 2×10⁻⁵；非重症与对照相比，OR = 61.87，95%置信区间=10.08 - 2521，P = 1×10⁻⁸）。数据表明，细胞因子和细胞因子受体变体对不同疟疾流行程度地区人群疾病的贡献不同。
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