Bilirubin was shown to be related to the generation and functional exertion of endothelial nitric oxide synthase (eNOS) whilst the genetic effect of NOS3 on bilirubin variability was rarely reported. Herein we assessed the associations of three single nucleotide polymorphisms (SNPs) of NOS3 (rs4496877, rs1808593, and rs3918186) with bilirubin elevation in 2077 adults. The results showed that rs1808593 was significantly associated with bilirubin elevation, and odds ratios (ORs) of dominant model for the elevation of total bilirubin (TBIL), direct bilirubin (DBIL), and indirect bilirubin (IDBIL) were 0.837, 0.821 and 0.754, respectively (P 0.05 for all). Stratification analysis indicated that rs3918186 was significantly associated with the elevation of TBIL and IDBIL in the males, and ORs of dominant model were 1.505 and 1.440 with P 0.05 for all. In the smoking group, significant associations of rs4496877, rs1808593, and rs3918186 with TBIL elevation were observed, and ORs of dominant model were 1.739, 0.758 and 1.626 (P 0.05 for all). rs4496877 and rs3918186 were both associated with TBIL elevation in the drinking group, and ORs were 1.557 and 1.769 with P 0.05 for all. In the ≥55 year-old group, rs4496877 and rs1808593 were significantly associated with DBIL and IDBIL elevations, and ORs were 1.340 and 0.790 (P 0.05). Meanwhile, rs4496877, rs1808593, rs3918186, smoking, and drinking were shown to have a notable interaction effects on the TBIL elevation. Our findings supported that NOS3 harbors the genetic susceptibility to the bilirubin elevation. Age, gender, smoking, and drinking could be involved in the genetic modification of NOS3 on the bilirubin variability.
