Authors' Affiliations: University of Hawaii Cancer Center, Honolulu, Hawaii; Translational Genomics Research Institute, Phoenix, Arizona; Department of Preventive Medicine, Keck School of Medicine and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles; Cancer Prevention Institute of California, Fremont, California; Fred Hutchinson Cancer Research Center, Seattle, Washington; Mayo Clinic, Rochester, Minnesota; University of Melbourne, Carlton, Victoria, Australia; Cancer Care Ontario, Toronto, Ontario, Canada; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina; Stanford Cancer Institute, Stanford, California; and National Center for Tumor Diseases and German Cancer Research Center, Heidelberg, Germany.
Cancer Epidemiol Biomarkers Prev. 2013 Nov;22(11):2094-101. doi: 10.1158/1055-9965.EPI-13-0694. Epub 2013 Sep 17.
It is widely accepted that chronic inflammation plays a role in the etiology of colorectal cancer. Using a two-stage design, we examined the associations between colorectal cancer and common variation in 37 key genes in the inflammation and innate immunity pathways.
In the discovery stage, 2,322 discordant sibships (2,535 cases, 3,915 sibling controls) from the Colorectal Cancer Family Registry were genotyped for more than 600 tagSNPs and 99 single-nucleotide polymorphisms (SNP) were selected for further examination based on strength of association. In the second stage, 351 SNPs tagging gene regions covered by the 99 SNPs were tested in 4,783 Multiethnic Cohort subjects (2,153 cases, 2,630 controls).
The association between rs9858822 in the PPARG gene and colorectal cancer was statistically significant at the end of the second stage (OR per allele = 1.36, Bonferroni-adjusted P = 0.045), based on the "effective" number of markers in stage II (n = 306). The risk allele C was common (frequency 0.3) in African Americans but rare (frequency < 0.03) in whites, Japanese Americans, Latinos, and Native Hawaiians. No statistically significant heterogeneity of effects across race/ethnicity, body mass index (BMI) levels, regular aspirin use, or pack-years of smoking was detected for this SNP. Suggestive associations were also observed for several SNPs in close vicinity to rs9858822.
Our results provide new evidence of association between PPARG variants and colorectal cancer risk.
Further replication in independent samples is warranted.
慢性炎症在结直肠癌的病因学中起作用，这一观点已被广泛接受。我们采用两阶段设计，研究了炎症和先天免疫途径中 37 个关键基因的常见变异与结直肠癌之间的关联。
在发现阶段，对来自结直肠癌家族登记处的 2322 对不一致的同胞（2535 例病例，3915 名同胞对照）进行了超过 600 个标签 SNP 的基因分型，并根据关联强度选择了 99 个单核苷酸多态性（SNP）进行进一步研究。在第二阶段，对多民族队列中 4783 名受试者（2153 例病例，2630 名对照）中由 99 个 SNP 标记的基因区域的 351 个 SNP 进行了检测。
在第二阶段结束时，PPARG 基因中的 rs9858822 与结直肠癌的关联具有统计学意义（每个等位基因的 OR = 1.36，Bonferroni 调整后的 P = 0.045），这是基于第二阶段的“有效”标记数量（n = 306）。风险等位基因 C 在非裔美国人中较为常见（频率为 0.3），但在白种人、日裔美国人、拉丁裔和夏威夷原住民中则很少见（频率<0.03）。未发现该 SNP 在种族/族裔、体重指数（BMI）水平、定期使用阿司匹林或吸烟包年数方面存在明显的跨种族/族裔效应异质性。在 rs9858822 附近的几个 SNP 也观察到了提示性关联。
我们的结果提供了 PPARG 变异与结直肠癌风险之间关联的新证据。
需要在独立样本中进一步复制。
