Polymorphisms in Regulators of Xenobiotic Transport and Metabolism Genes NR1I2 and NR1I3 and Multiple Myeloma Risk: A Case-Control Study in the Context of IMMEnSE Consortium

Abstract

Abstract 5014Exposure to toxic compounds and pesticides leads to an increased risk to develop Multiple Myeloma (MM). The metabolism and the excretion of xenobiotics are mediated by the enzymes and transporters acting in the detoxifying/elimination process. The nuclear receptors NR1I2 (or PXR) and NR1I3 (or CAR) act as xenosensor activating the detoxifying/elimination process in response to the intracellular levels of xenobiotics. It has been hypothesized that part of the individual variability in drug metabolism efficiency could be due to the genetic variations within these regulator genes affecting their expression and/or function. To investigate the impact of genetic variation within these genes on MM susceptibility, we selected and genotyped 10 tag Single Nucleotide Polymorphisms (SNPs) in the PXR gene and 7 tag SNPs in the CAR gene in 627 MM cases (320 males and 307 females) and 883 (459 males and 424 females) controls from different European populations. All the SNPs were in Hardy-Weinberg equilibrium (p>0.001), with the exception of the PXR SNP rs2461818 that was therefore excluded from the analysis. We found no association of any of the genotyped SNPs with MM risk. In the same way, haplotype distribution showed no differences between cases and controls. This was the first comprehensive investigation of genetic variation in xenobiotic regulators genes PXR and CAR in relation to MM risk and our data suggest that common variants in these genes have no impact in modifying MM risk.Table IGenotype distribution of the PXR and CAR SNPs among MM cases and controls.SNP (rs)Cases (%)Controls (%)OR*95%C.I.p-valuep-trendPXRC/C429 (69.5)623 (70.7)1.00Ref0.423rs10511395A/C160 (25.9)228 (25.9)1.020.81 – 1.300.851A/A28 (4.6)30 (3.4)1.380.81 – 2.350.232PXRC/C452 (74.0)656 (74.8)1.00Ref0.451rs1054190C/T137 (22.4)200 (22.8)1.000.78 – 1.280.993T/T22 (3.6)21 (2.4)1.560.84 – 2.880.155PXRC/C412 (65.9)591 (67.2)1.00Ref0.819rs11917714C/T190 (30.4)250 (28.5)1.070.85 – 1.350.535T/T23 (3.7)38 (4.3)0.840.49 – 1.440.536PXRC/C223 (36.3)296 (33.7)1.00Ref0.126rs12488820C/T289 (47.0)407 (46.4)0.930.74 – 1.180.574T/T103 (16.7)175 (19.9)0.790.58 – 1.060.119PXRG/G430 (69.6)593 (67.4)1.00Ref0.807rs13071341A/G166 (26.9)269 (30.6)0.850.67 – 1.070.158A/A22 (3.5)18 (2.0)1.700.90 – 3.220.102PXRA/A352 (58.7)516 (39.4)1.00Ref0.981rs3237359A/G209 (34.8)291 (33.5)1.040.83 – 1.300.720G/G39 (6.5)62 (7.1)0.900.59 – 1.370.619PXRC/C255 (41.2)383 (43.6)1.00Ref0.815rs13059232C/T299 (48.3)390 (44.4)1.160.93 – 1.440.192T/T65 (10.5)106 (12.0)0.940.66 – 1.330.711PXRA/A300 (48.7)437 (49.7)1.00Ref0.258rs3732357A/G240 (39.0)361 (41.0)0.940.75 – 1.170.589G/G76 (12.3)82 (9.3)1.310.92 – 1.850.130PXRT/T328 (53.6)463 (52.9)1.00Ref0.424rs1357459C/T249 (40.7)345 (39.4)1.020.82 – 1.270.850C/C35 (5.7)67 (7.7)0.750.49 – 1.170.206CARA/A218 (35.4)335 (38.1)1.00Ref0.571rs3003596A/G296 (48.0)393 (44.7)1.160.93 – 1.460.191G/G102 (16.6)151 (17.2)1.040.77 – 1.410.799CARG/G264 (42.7)371 (42.0)1.00Ref0.642rs3813627G/T276 (44.7)392 (44.4)0.980.79 – 1.230.882T/T78 (12.6)120 (13.6)0.910.66 – 1.260.581CARA/A441 (73.1)635 (73.5)1.00Ref0.911rs11265571A/T147 (24.4)207 (24.0)1.010.79 – 1.290.911T/T15 (2.5)22 (2.5)0.970.49 – 1.890.921CART/T404 (64.2)575 (65.7)1.00Ref0.836rs2307418G/T193 (31.1)268 (30.6)1.020.81 – 1.270.879G/G23 (3.7)32 (3.7)1.050.60 – 1.830.863CARC/C348 (56.6)508 (57.7)1.00Ref0.527rs2502805C/T220 (35.8)313 (35.6)1.050.84 – 1.300.693T/T47 (7.6)59 (6.7)1.160.77 – 1.740.484CARA/A245 (39.8)346 (39.4)1.00Ref0.770rs4073054A/C291 (47.2)412 (46.9)0.980.78 – 1.220.855C/C80 (13.0)120 (13.7)0.940.68 – 1.310.720CARC/C360 (57.6)524 (59.8)1.00Ref0.391rs4233368A/C225 (36.0)302 (34.4)1.090.88 – 1.360.439A/A40 (6.4)51 (5.8)1.150.74 – 1.780.538Genotype distribution among MM cases and controls in the overall population.*OR are adjusted for age, gender and region of origin. Differences in samples numbers are due to failures in genotyping. Disclosures:No relevant conflicts of interest to declare.