The association between common genetic variation in STK11 (LKB1) and colorectal adenomas in the Health Professional's Follow-up Study and the Nurses' Health Study

Abstract

Germline mutations in serine-threonine kinase 11 (<ITALIC>STK11</ITALIC>) are hallmarks in hamartomatous polyps of the rare, hereditary disease, Peutz-Jeghers syndrome (PJS). PJS is associated with colorectal hamartomatous polyps and results in an increased risk of colorectal cancer and other malignancies. However, whether hamartomatous polyps contribute to high rates of neoplasm in carriers, or whether these patients progress through the conventional adenoma-carcinoma pathway is unknown. Single nucleotide polymorphisms (SNPs) in <ITALIC>STK11</ITALIC> are also observed to be polymorphic, so we hypothesized that common genetic variation in the <ITALIC>STK11</ITALIC> gene is positively associated with colorectal adenomas. We evaluated the association between common genetic variation in <ITALIC>STK11</ITALIC> and adenomas using adenoma cases and matched controls from Health Professional's Follow-up Study (HPFS) and Nurses' Health Study (NHS). Lymphocyte DNA was extracted and three tagSNPs in <ITALIC>STK11</ITALIC> (rs2075604, rs3764640, rs8111699) were genotyped using the Illumina HumanOmniExpress platform. Logistic regression models adjusted for age, gender, and race using principal components, were used to compare adenoma cases to controls and estimate odds ratios and 95% confidence intervals for the association between adenomas and <ITALIC>STK11</ITALIC> SNPs. There was no association between colorectal adenomas and any of the SNPs evaluated; rs8111699 (OR=1.05, 95% CI (0.80, 1.37)), rs2075604 (OR=0.72, 95% CI (0.30, 1.75)), rs3764640 (OR=1.05, 95% CI (0.66, 1.66)) Exploratory analyses were conducted to assess effect modification of the association between <ITALIC>STK11</ITALIC> SNPs and adenomas by common risk factors for colorectal neoplasia. Two types of interaction were detected. Evidence was suggested for an interaction between SNP rs2075604 and family history (P=0.03). Also, evidence for another interaction was found with the same SNP and smoking (P=0.05).