Tagging Single Nucleotide Polymorphisms in the IRF1 and IRF8 Genes and Tuberculosis Susceptibility

Abstract

Genes encoding IRF1 and IRF8 protein have been proposed as candidate tuberculosis susceptibility genes. In order to elucidate whether the IRF1 and IRF8 variants were associated with tuberculosis susceptibility, we conducted a case-control study consisting of 495 controls and 452 ethnically matched cases with tuberculosis in a Chinese population. Seven haplotype tagging single-nucleotide polymorphisms (tagSNPs) (rs2057656; rs2706381; rs2070724; rs2070721; rs2549008; rs2549007; rs2706386) from HapMap database were analyzed, which provided an almost complete coverage of the genetic variations in the IRF1 gene. Fifteen tagSNPs (rs12924316; rs182511; rs305080; rs2292980; rs925994; rs424971; rs16939967; rs11117415; rs4843860; rs9926411; rs8064189; rs12929551; rs10514611; rs1044873; rs6638) were observed in the IRF8 gene. All these tagSNPs were genotyped by SNPstream genotyping and SNaPshot typing. None of the seven tagSNPs was individually associated with tuberculosis in the IRF1 gene. In the IRF8 gene, interestingly, we found that three tagSNPs (rs925994 and rs11117415 located in the intron region; rs10514611 located in the 3′UTR) were associated with risk of tuberculosis after Bonferroni correction. Per allele OR was 1.75 (95% CI 1.35∼2.27, P = 0.002), 4.75 (95% CI 2.16∼10.43, P = 0.002) and 3.39 (95% CI 1.60∼7.20, P = 0.015) respectively. Luciferase reporter gene assay showed that the construct that contained the non-risk allele C of rs10514611 showed significantly higher luciferase activity than did the risk T allele (P<0.01), which implied rs10514611 was a potential functional SNP site. Our results indicated that the IRF8 gene might participate in genetic susceptibility to tuberculosis in a Chinese population.

Myeloid Growth Factors Promote Resistance to Mycobacterial Infection by Curtailing Granuloma Necrosis through Macrophage Replenishment

“…At this concentration, we found an infection phenotype similar to that of csf1r deficiency: increased bacterial cording and growth following upon granuloma formation ( Figures 5 D and 5E). These observations extend our findings with csf1r deficiency to those of other myeloid growth factors and suggest a mechanism whereby human IRF8 deficiency causes susceptibility to virulent mycobacteria as well as to the attenuated BCG vaccine strain ( Ding et al., 2012; Hambleton et al., 2011 ).…”

“…Mutations in hematopoietic transcription factors such as PU.1 and IRF8 are also associated with numerical deficits in macrophages ( DeKoter et al., 2007; Terry and Miller, 2014 ). We were particularly interested in IRF8 deficiency, because even a modest reduction in monocytes is associated with human susceptibility to TB as well as to the ESX-1-deficient vaccine strain BCG ( Crosslin et al., 2013; Ding et al., 2012; Hambleton et al., 2011 ).…”

“…Humans with rare variants in the DNA binding domain of IRF8 had fewer monocytes and got disseminated BCG infection as infants soon after vaccination ( Hambleton et al., 2011 ). Additionally, common variants in IRF8 are associated with monocyte abundance and with susceptibility to virulent TB, although different variants were examined in the two studies ( Crosslin et al., 2013; Ding et al., 2012 ). Based on findings in Irf8 - and Csf1 -deficient mice, it has been suggested that these deficiencies may cause susceptibility through poor antigen presentation leading to defective T cell immunity ( Hambleton et al., 2011; Teitelbaum et al., 1999; Turcotte et al., 2005 ).…”

Categorical complexities of Plasmodium falciparum malaria in individuals is associated with genetic variations in ADORA2A and GRK5 genes

“…The absolute values of Lewontin's D 0 and Pearson's correlation (r) were used to measure the LD between SNP pairs. The formula: a = 1 À (1 À a 0 )1/n (corrected for n comparisons, a 0 = un-corrected p, n = 6) was used for performing Bonferroni multiple corrections for all SNPs (Ding et al, 2012). Quanto (version 1.1) was used to calculate the power of the study, with the following parameters: a population risk of 2% for malaria, a dominant model analysis, 8.7% of a minor allele frequency (450 controls) for OR = 0.6 and 1.6 at 2-sided p < 0.05 for 450 samples each from the two groups comprising of all malaria cases and controls, to achieve 74.15% and 80.15% power respectively when the OR of 0.6 and 1.6 were returned (Gauderman, 2002;Gauderman and Morrison, 2006).…”

Five known tagging DLL3 SNPs are not associated with congenital scoliosis

“…[20,21] Different populations may have different genetic associations with CS. To elucidate the role of the DLL3 in CS susceptibility, we determined the association of SNP in the DLL3 gene with CS in the Chinese Han Population.…”