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Objective: Published data concerning associations between 1RS1 variants and type 2 diabetes and related traits have been inconsistent. We examined the relationship between common variants in IRS1, type 2 diabetes, and related traits including insulin resistance, hyperglycemia and DNA damage in the Boston Puerto Rican Health Study. Methods: We genotyped six common 1RS1 variants in an adult Puerto Rican population (n=1132) and tested for association with risk of type 2 diabetes and related traits. Results: SNPs rs934167 and rs 1801123 showed significant association with fasting glucose concentrations (p = 0.005 and p = 0.016, respectively) and rs934167 showed significant association with plasma insulin levels (p = 0.005). Carriers of the rs934167 minor allele had significantly higher HOMA-IR and lower QUICKI (p = 0.001 andp = 0.001, respectively), and a 40% and 58% greater likelihood of being hyperglycaemic or hyperinsulinemic (OR = 1.40 and 1.58; p = 0.013 and 0.002, respectively). However, they exhibited only a marginally significant trend towards having type 2 diabetes (OR=1.27, p = 0.077). Furthermore, carriers of the haplotype C-T of the rs934167 and rsl801123 minor alleles showed consistent patterns of associations after correction for multiple testing. In addition, the G972R (rs 1801278) minor allele was significantly associated with higher urinary 8-OHdG concentrations (p = 0.020) and plasma CRP levels (p = 0.035). Conclusions: Our results support 1RS1 variants associated with type 2 diabetes risk in adult Puerto Ricans. Moreover, we report the novel finding that IRS1 variant G972R (rs 1801278) may contribute to oxidative DNA damage and inflammation. [ABSTRACT FROM AUTHOR]