Hsu Ling-I, Chokkalingam Anand P, Briggs Farren B S, Walsh Kyle, Crouse Vonda, Fu Cecilia, Metayer Catherine, Wiemels Joseph L, Barcellos Lisa F, Buffler Patricia A
School of Public Health, University of California, Berkeley, Berkeley, CA, 94720, USA,
Cancer Causes Control. 2015 Apr;26(4):609-19. doi: 10.1007/s10552-015-0550-3. Epub 2015 Mar 12.
Genome-wide association studies focusing on European-ancestry populations have identified ALL risk loci on IKZF1, ARID5B, and CEBPE. To capture the impacts of these genes on ALL risk in the California Hispanic population, we comprehensively assessed the variation within the genes and further assessed the joint effects between the genetic variation and surrogates for early-life infections (the presence of older siblings, daycare attendance, and ear infections).
Genotypic data for 323 Hispanic ALL cases and 454 controls from the California Childhood Leukemia Study were generated using Illumina OmniExpress v1 platform. Logistic regression assuming a log-additive model estimated odds ratios (OR) associated with each SNP, adjusted for age, sex, and the first five principal components. In addition, we examined potential interactions between six ALL risk alleles and surrogates for early-life infections using logistic regression models that included an interaction term.
Significant associations between genotypes at IKZF1, ARID5B, and CEBPE and ALL risk were identified: rs7780012, OR 0.50, 95% confidence interval (CI) 0.35-0.71 (p = 0.004); rs7089424, OR 2.12, 95% CI 1.70-2.65 (p = 1.16 × 10(-9)); rs4982731, OR 1.69, 95% CI 1.37-2.08 (p = 2.35 × 10(-6)), respectively. Evidence for multiplicative interactions between genetic variants and surrogates for early-life infections with ALL risk was not observed.
Consistent with findings in non-Hispanic White population, our study showed that variants within IKZF1, ARID5B, and CEBPE were associated with increased ALL risk, and the effects for ARID5B and CEBPE were most prominent in the high-hyperdiploid ALL subtype in the California Hispanic population. Results implicate the ARID5B, CEBPE, and IKZF1 genes in the pathogenesis of childhood ALL.
针对欧洲裔人群的全基因组关联研究已确定IKZF1、ARID5B和CEBPE上的所有风险位点。为了解这些基因对加利福尼亚西班牙裔人群患急性淋巴细胞白血病（ALL）风险的影响，我们全面评估了这些基因内部的变异，并进一步评估了基因变异与早期感染替代指标（年长兄弟姐妹的存在、日托出勤情况和耳部感染）之间的联合效应。
使用Illumina OmniExpress v1平台生成了来自加利福尼亚儿童白血病研究的323例西班牙裔ALL病例和454例对照的基因分型数据。采用对数相加模型的逻辑回归估计与每个单核苷酸多态性（SNP）相关的比值比（OR），并对年龄、性别和前五个主成分进行了校正。此外，我们使用包含交互项的逻辑回归模型，研究了六个ALL风险等位基因与早期感染替代指标之间的潜在相互作用。
确定了IKZF1、ARID5B和CEBPE基因座的基因型与ALL风险之间存在显著关联：rs7780012，OR为0.50，95%置信区间（CI）为0.35 - 0.71（p = 0.004）；rs7089424，OR为2.12，95%CI为1.70 - 2.65（p = 1.16×10⁻⁹）；rs4982731，OR为1.69，95%CI为1.37 - 2.08（p = 2.35×10⁻⁶）。未观察到基因变异与早期感染替代指标之间存在增加ALL风险的相乘交互作用的证据。
与非西班牙裔白人人群的研究结果一致，我们的研究表明IKZF1、ARID5B和CEBPE内部的变异与ALL风险增加相关，并且在加利福尼亚西班牙裔人群的高超二倍体ALL亚型中，ARID5B和CEBPE的影响最为显著。结果表明ARID5B、CEBPE和IKZF1基因与儿童ALL的发病机制有关。
