Division of Health Analytics, Department of Computational and Quantitative Medicine, Beckman Research Institute of the City of Hope, Monrovia, California.
Centre for Big Data Research in Health, The University of New South Wales, Sydney, New South Wales, Australia.
Cancer Epidemiol Biomarkers Prev. 2022 May 4;31(5):1103-1110. doi: 10.1158/1055-9965.EPI-21-0875.
A previous International Lymphoma Epidemiology (InterLymph) Consortium evaluation of joint associations between five immune gene variants and autoimmune conditions reported interactions between B-cell response-mediated autoimmune conditions and the rs1800629 genotype on risk of B-cell non-Hodgkin lymphoma (NHL) subtypes. Here, we extend that evaluation using NHL subtype-specific polygenic risk scores (PRS) constructed from loci identified in genome-wide association studies of three common B-cell NHL subtypes.
In a pooled analysis of NHL cases and controls of Caucasian descent from 14 participating InterLymph studies, we evaluated joint associations between B-cell-mediated autoimmune conditions and tertile (T) of PRS for risk of diffuse large B-cell lymphoma (DLBCL; n = 1,914), follicular lymphoma (n = 1,733), and marginal zone lymphoma (MZL; n = 407), using unconditional logistic regression.
We demonstrated a positive association of DLBCL PRS with DLBCL risk [T2 vs. T1: OR = 1.24; 95% confidence interval (CI), 1.08-1.43; T3 vs. T1: OR = 1.81; 95% CI, 1.59-2.07; P-trend (Ptrend) < 0.0001]. DLBCL risk also increased with increasing PRS tertile among those with an autoimmune condition, being highest for those with a B-cell-mediated autoimmune condition and a T3 PRS [OR = 6.46 vs. no autoimmune condition and a T1 PRS, Ptrend < 0.0001, P-interaction (Pinteraction) = 0.49]. Follicular lymphoma and MZL risk demonstrated no evidence of joint associations or significant Pinteraction.
Our results suggest that PRS constructed from currently known subtype-specific loci may not necessarily capture biological pathways shared with autoimmune conditions.
Targeted genetic (PRS) screening among population subsets with autoimmune conditions may offer opportunities for identifying those at highest risk for (and early detection from) DLBCL.
国际淋巴瘤流行病学（InterLymph）联盟之前对五种免疫基因变异体与自身免疫性疾病之间的联合关联进行了评估，报告称 B 细胞反应介导的自身免疫性疾病与 rs1800629 基因型之间存在相互作用，而后者与 B 细胞非霍奇金淋巴瘤（NHL）亚型的风险有关。在此，我们使用从三种常见 B 细胞 NHL 亚型的全基因组关联研究中确定的位点构建的 NHL 亚型特异性多基因风险评分（PRS）来扩展该评估。
在 14 项参与 InterLymph 研究的白种人 NHL 病例和对照的汇总分析中，我们使用非条件逻辑回归评估了 B 细胞介导的自身免疫性疾病与弥漫性大 B 细胞淋巴瘤（DLBCL；n=1914）、滤泡性淋巴瘤（n=1733）和边缘区淋巴瘤（MZL；n=407）PRS 三分位数（T）之间的联合关联。
我们证明了 DLBCL PRS 与 DLBCL 风险之间存在正相关 [T2 与 T1：OR=1.24；95%置信区间（CI），1.08-1.43；T3 与 T1：OR=1.81；95%CI，1.59-2.07；Ptrend（Ptrend）<0.0001]。在自身免疫性疾病患者中，随着 PRS 三分位数的增加，DLBCL 风险也随之增加，在具有 B 细胞介导的自身免疫性疾病和 T3 PRS 的患者中最高[OR=6.46 与无自身免疫性疾病和 T1 PRS，Ptrend<0.0001，P 交互（Pinteraction）=0.49]。滤泡性淋巴瘤和 MZL 风险没有联合关联或显著的 Pinteraction 的证据。
我们的结果表明，从目前已知的亚型特异性基因座构建的 PRS 不一定能捕捉到与自身免疫性疾病共享的生物学途径。
在具有自身免疫性疾病的人群亚组中进行有针对性的遗传（PRS）筛查可能为识别那些患有 DLBCL 风险最高的人群（并从早期检测到）提供机会。
