The Interferon Gamma Receptor-1 (IFNGR1) −56C/T Gene Polymorphism Is Associated with Increased Risk of Chronic Lymphocytic Leukemia.

Abstract 4617 B-cell chronic lymphocytic leukemia (B-CLL) is the most common type of leukemia in the western world, accounting for approximately 40% of all leukemias in individuals over the age of 65 years. Studies on the racial and geographic distribution have showed that the overall incidence rate of CLL in Europe and North American populations is 20−30 times higher than that in China and Japan. Considering a striking difference existing in the incidence rate of CLL between Chinese and Western populations, we propose that there may be genetic variations controlling predisposition to CLL in separated ethnic groups. Since IFN-γ plays an important role in the occurrence and development of CLL, we further propose that genetic polymorphisms of IFN-γ or its receptors may be associated with the pathogenesis of CLL. This study examined the association between IFN-γ as well as IFN-γR1 gene polymorphisms and CLL among Chinese population. Sixty-five CLL patients and 80 healthy controls were studied. Polymorphisms of the IFN-γ gene (IFNG) at position +874 were determined using the amplification refractory mutation system PCR assay, and the IFN-γR1 gene (IFNGR1) was genotyped at positions −611, −270, −56 and +95 with the matrix-assisted laser desorption/ionization time of flight mass spectrometry. This study showed a positive association between IFNGR1 −56T/T genotype (OR = 2.49; 95% CI = 1.2−5.4) and CLL. Specifically, the frequency of the −56T allele was significantly higher among patients (61.5%) than among controls (46.3%) (OR = 1.86; 95% CI = 1.2−3.0; P = 0.01). There was no significant difference observed between patients and controls with respect to the variant frequencies of IFNG +874, IFNGR1 −611, −270, and +95 polymorphisms. Next, we evaluated the effect of the −56C/T promoter polymorphism in the level of expression of the IFNGR1 gene by a luciferase reporter assay. We observed that the promoter variant with –56T exhibited a higher transcription level than that with –56C in two human B-cell lines (BJAB and Raji) in a cell-type-specific pattern. Furthermore, we did a systematic review of case-control studies which analyzed the allele frequency of –56C/T in two ethnic groups (Caucasian and Asian). We established a database of information extracted from each articles. From 14 studies with a total of 3,229 controls for the –56C/T polymorphism were reviewed. The allele frequencies and 95% CI of IFNGR1 –56C/T polymorphisms among controls were stratified by different ethnicities. The frequency of the –56T allele among Caucasians (Mean% = 61.26; 95% CI = 57.21−65.30) was higher than that among Asians (Mean% = 46.71; 95% CI = 42.68−50.74) ( P < 0.0001). This result lends support to the hypothesis that the higher prevalence of CLL among Caucasians may due to the higher frequency of the IFNGR1 –56T allele. In conclusion, a functional –56C/T polymorphism in IFNGR1 promoter is associated with the occurrence of CLL in Chinese population. However, this study re-emphasizes the need for large cohorts, especially independent data on CLL patients from Caucasian background, before firm conclusions can be reached about genotype-phenotype associations. Disclosures: No relevant conflicts of interest to declare.