Association between organophosphate esters and incident type 2 diabetes risk: modification by genetic risk and lifestyle.

People are widely exposed to organophosphate esters (OPEs) as flame retardants and plasticizers. OPEs may affect type 2 diabetes (T2D) risk, but prospective evidence is limited and inconsistent, and the modifying effects of genetic and lifestyle factors remain unclear. The present nested case-control study within the Dongfeng-Tongji cohort of retired adults (median age: 62 years; mean follow-up: 4.6 years) included 981 pairs of incident T2D cases and controls matched by age and sex. We measured 10 plasma OPEs in baseline blood samples and used conditional logistic regression, restricted cubic splines, quantile g-computation, and Bayesian kernel machine regression to examine their association with T2D risk. We examined effect modification by lifestyle and polygenic risk score. Each twofold increase in plasma triphenyl phosphate (TPHP) was associated with 6% higher odds of T2D (odds ratio, OR=1.06; 95% confidence interval, CI: 1.01-1.11). The odds were 49% higher in the highest tertile versus the lowest (OR = 1.49, 95% CI: 1.04-2.14). Tri-isobutyl phosphate and tri-n-butyl phosphate (TiBP+TnBP) in the highest tertile showed an inverse association versus the lowest (OR = 0.75, 95% CI: 0.58-0.99). Detectable tri(1-chloro-2-propyl) phosphate (TCPP) was associated with 75% higher odds of T2D versus undetectable levels (OR = 1.75, 95% CI: 1.30-2.36). The overall mixture effect was not significant, with TPHP positive and TiBP+TnBP negative as main contributors. Interaction analysis using relative excess risk (RERI showed additive synergy for high TPHP combined with an unhealthy lifestyle (RERI = 0.88, 95% CI: 0.09-1.52), low TiBP+TnBP combined with an unhealthy lifestyle (RERI = 0.67, 95% CI: 0.02-1.32), and low TiBP + TnBP combined with high genetic risk (RERI = 0.88, 95% CI: 0.03-1.74). The highest odds of T2D were for high PRS, unhealthy lifestyle, and high TPHP (OR=7.16, 95%CI: 4.06-12.62) or low TiBP+TnBP (OR=6.63, 95%CI: 3.83-11.47). Healthy lifestyle may offset OPEs and genetic effects.