Background CD28 is one of a number of costimulatory molecules that play crucial roles in immune regulation and homeostasis. Accumulating evidence indicates that immune factors influence breast carcinogenesis. To clarify the relationships between polymorphisms in the CD28 gene and breast carcinogenesis, a case-control study was conducted in women from Heilongjiang Province in northeast of China. Methodology/Principal Findings Our research subjects consisted of 565 female patients with sporadic breast cancer and 605 age- and sex-matched healthy controls. In total, 12 single nucleotide polymorphisms (SNPs) in the CD28 gene were successfully determined using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The relationship between the CD28 variants and clinical features, including histological grade, tumor size, lymph node metastasis, human epidermal growth factor receptor 2 (C-erbB2), estrogen receptor (ER), progesterone receptor (PR), and tumor protein 53 (P53) status were analyzed. A statistically significant association was observed between rs3116496 and breast cancer risk under different genetic models (additive P = 0.0164, dominant P = 0.0042). Different distributions of the rs3116496 ‘T’ allele were found in patients and controls, which remained significant after correcting the P value for multiple testing using Haploview with 10,000 permutations (corrected P = 0.0384). In addition, significant associations were observed between rs3116487/rs3116494 (D’ = 1, r2 = 0.99) and clinicopathological features such as C-erbB2 and ER status, in breast cancer patients. Conclusions/Significance Our findings indicate that CD28 gene polymorphisms contribute to sporadic breast cancer risk and have a significant association with clinicopathological features in a northeast Chinese Han population.
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