Abstract 5014

Exposure 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 I.

Genotype distribution of the PXR and CAR SNPs among MM cases and controls.

SNP (rs)Cases (%)Controls (%)OR*95%C.I.p-valuep-trend
PXR C/C 429 (69.5) 623 (70.7) 1.00 Ref  0.423 
rs10511395 A/C 160 (25.9) 228 (25.9) 1.02 0.81 – 1.30 0.851  
A/A 28 (4.6) 30 (3.4) 1.38 0.81 – 2.35 0.232  
PXR C/C 452 (74.0) 656 (74.8) 1.00 Ref  0.451 
rs1054190 C/T 137 (22.4) 200 (22.8) 1.00 0.78 – 1.28 0.993  
T/T 22 (3.6) 21 (2.4) 1.56 0.84 – 2.88 0.155  
PXR C/C 412 (65.9) 591 (67.2) 1.00 Ref  0.819 
rs11917714 C/T 190 (30.4) 250 (28.5) 1.07 0.85 – 1.35 0.535  
T/T 23 (3.7) 38 (4.3) 0.84 0.49 – 1.44 0.536  
PXR C/C 223 (36.3) 296 (33.7) 1.00 Ref  0.126 
rs12488820 C/T 289 (47.0) 407 (46.4) 0.93 0.74 – 1.18 0.574  
T/T 103 (16.7) 175 (19.9) 0.79 0.58 – 1.06 0.119  
PXR G/G 430 (69.6) 593 (67.4) 1.00 Ref  0.807 
rs13071341 A/G 166 (26.9) 269 (30.6) 0.85 0.67 – 1.07 0.158  
A/A 22 (3.5) 18 (2.0) 1.70 0.90 – 3.22 0.102  
PXR A/A 352 (58.7) 516 (39.4) 1.00 Ref  0.981 
rs3237359 A/G 209 (34.8) 291 (33.5) 1.04 0.83 – 1.30 0.720  
G/G 39 (6.5) 62 (7.1) 0.90 0.59 – 1.37 0.619  
PXR C/C 255 (41.2) 383 (43.6) 1.00 Ref  0.815 
rs13059232 C/T 299 (48.3) 390 (44.4) 1.16 0.93 – 1.44 0.192  
T/T 65 (10.5) 106 (12.0) 0.94 0.66 – 1.33 0.711  
PXR A/A 300 (48.7) 437 (49.7) 1.00 Ref  0.258 
rs3732357 A/G 240 (39.0) 361 (41.0) 0.94 0.75 – 1.17 0.589  
G/G 76 (12.3) 82 (9.3) 1.31 0.92 – 1.85 0.130  
PXR T/T 328 (53.6) 463 (52.9) 1.00 Ref  0.424 
rs1357459 C/T 249 (40.7) 345 (39.4) 1.02 0.82 – 1.27 0.850  
C/C 35 (5.7) 67 (7.7) 0.75 0.49 – 1.17 0.206  
CAR A/A 218 (35.4) 335 (38.1) 1.00 Ref  0.571 
rs3003596 A/G 296 (48.0) 393 (44.7) 1.16 0.93 – 1.46 0.191  
G/G 102 (16.6) 151 (17.2) 1.04 0.77 – 1.41 0.799  
CAR G/G 264 (42.7) 371 (42.0) 1.00 Ref  0.642 
rs3813627 G/T 276 (44.7) 392 (44.4) 0.98 0.79 – 1.23 0.882  
T/T 78 (12.6) 120 (13.6) 0.91 0.66 – 1.26 0.581  
CAR A/A 441 (73.1) 635 (73.5) 1.00 Ref  0.911 
rs11265571 A/T 147 (24.4) 207 (24.0) 1.01 0.79 – 1.29 0.911  
T/T 15 (2.5) 22 (2.5) 0.97 0.49 – 1.89 0.921  
CAR T/T 404 (64.2) 575 (65.7) 1.00 Ref  0.836 
rs2307418 G/T 193 (31.1) 268 (30.6) 1.02 0.81 – 1.27 0.879  
G/G 23 (3.7) 32 (3.7) 1.05 0.60 – 1.83 0.863  
CAR C/C 348 (56.6) 508 (57.7) 1.00 Ref  0.527 
rs2502805 C/T 220 (35.8) 313 (35.6) 1.05 0.84 – 1.30 0.693  
T/T 47 (7.6) 59 (6.7) 1.16 0.77 – 1.74 0.484  
CAR A/A 245 (39.8) 346 (39.4) 1.00 Ref  0.770 
rs4073054 A/C 291 (47.2) 412 (46.9) 0.98 0.78 – 1.22 0.855  
C/C 80 (13.0) 120 (13.7) 0.94 0.68 – 1.31 0.720  
CAR C/C 360 (57.6) 524 (59.8) 1.00 Ref  0.391 
rs4233368 A/C 225 (36.0) 302 (34.4) 1.09 0.88 – 1.36 0.439  
A/A 40 (6.4) 51 (5.8) 1.15 0.74 – 1.78 0.538  
SNP (rs)Cases (%)Controls (%)OR*95%C.I.p-valuep-trend
PXR C/C 429 (69.5) 623 (70.7) 1.00 Ref  0.423 
rs10511395 A/C 160 (25.9) 228 (25.9) 1.02 0.81 – 1.30 0.851  
A/A 28 (4.6) 30 (3.4) 1.38 0.81 – 2.35 0.232  
PXR C/C 452 (74.0) 656 (74.8) 1.00 Ref  0.451 
rs1054190 C/T 137 (22.4) 200 (22.8) 1.00 0.78 – 1.28 0.993  
T/T 22 (3.6) 21 (2.4) 1.56 0.84 – 2.88 0.155  
PXR C/C 412 (65.9) 591 (67.2) 1.00 Ref  0.819 
rs11917714 C/T 190 (30.4) 250 (28.5) 1.07 0.85 – 1.35 0.535  
T/T 23 (3.7) 38 (4.3) 0.84 0.49 – 1.44 0.536  
PXR C/C 223 (36.3) 296 (33.7) 1.00 Ref  0.126 
rs12488820 C/T 289 (47.0) 407 (46.4) 0.93 0.74 – 1.18 0.574  
T/T 103 (16.7) 175 (19.9) 0.79 0.58 – 1.06 0.119  
PXR G/G 430 (69.6) 593 (67.4) 1.00 Ref  0.807 
rs13071341 A/G 166 (26.9) 269 (30.6) 0.85 0.67 – 1.07 0.158  
A/A 22 (3.5) 18 (2.0) 1.70 0.90 – 3.22 0.102  
PXR A/A 352 (58.7) 516 (39.4) 1.00 Ref  0.981 
rs3237359 A/G 209 (34.8) 291 (33.5) 1.04 0.83 – 1.30 0.720  
G/G 39 (6.5) 62 (7.1) 0.90 0.59 – 1.37 0.619  
PXR C/C 255 (41.2) 383 (43.6) 1.00 Ref  0.815 
rs13059232 C/T 299 (48.3) 390 (44.4) 1.16 0.93 – 1.44 0.192  
T/T 65 (10.5) 106 (12.0) 0.94 0.66 – 1.33 0.711  
PXR A/A 300 (48.7) 437 (49.7) 1.00 Ref  0.258 
rs3732357 A/G 240 (39.0) 361 (41.0) 0.94 0.75 – 1.17 0.589  
G/G 76 (12.3) 82 (9.3) 1.31 0.92 – 1.85 0.130  
PXR T/T 328 (53.6) 463 (52.9) 1.00 Ref  0.424 
rs1357459 C/T 249 (40.7) 345 (39.4) 1.02 0.82 – 1.27 0.850  
C/C 35 (5.7) 67 (7.7) 0.75 0.49 – 1.17 0.206  
CAR A/A 218 (35.4) 335 (38.1) 1.00 Ref  0.571 
rs3003596 A/G 296 (48.0) 393 (44.7) 1.16 0.93 – 1.46 0.191  
G/G 102 (16.6) 151 (17.2) 1.04 0.77 – 1.41 0.799  
CAR G/G 264 (42.7) 371 (42.0) 1.00 Ref  0.642 
rs3813627 G/T 276 (44.7) 392 (44.4) 0.98 0.79 – 1.23 0.882  
T/T 78 (12.6) 120 (13.6) 0.91 0.66 – 1.26 0.581  
CAR A/A 441 (73.1) 635 (73.5) 1.00 Ref  0.911 
rs11265571 A/T 147 (24.4) 207 (24.0) 1.01 0.79 – 1.29 0.911  
T/T 15 (2.5) 22 (2.5) 0.97 0.49 – 1.89 0.921  
CAR T/T 404 (64.2) 575 (65.7) 1.00 Ref  0.836 
rs2307418 G/T 193 (31.1) 268 (30.6) 1.02 0.81 – 1.27 0.879  
G/G 23 (3.7) 32 (3.7) 1.05 0.60 – 1.83 0.863  
CAR C/C 348 (56.6) 508 (57.7) 1.00 Ref  0.527 
rs2502805 C/T 220 (35.8) 313 (35.6) 1.05 0.84 – 1.30 0.693  
T/T 47 (7.6) 59 (6.7) 1.16 0.77 – 1.74 0.484  
CAR A/A 245 (39.8) 346 (39.4) 1.00 Ref  0.770 
rs4073054 A/C 291 (47.2) 412 (46.9) 0.98 0.78 – 1.22 0.855  
C/C 80 (13.0) 120 (13.7) 0.94 0.68 – 1.31 0.720  
CAR C/C 360 (57.6) 524 (59.8) 1.00 Ref  0.391 
rs4233368 A/C 225 (36.0) 302 (34.4) 1.09 0.88 – 1.36 0.439  
A/A 40 (6.4) 51 (5.8) 1.15 0.74 – 1.78 0.538  

Genotype 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.

Author notes

*

Asterisk with author names denotes non-ASH members.