Synergism interaction between genetic polymorphisms in drug metabolizing enzymes and NSAIDs on upper gastrointestinal haemorrhage: a multicenter case-control study

Figures & data

Table 1. Motives of the exclusion of cases and controls from the study.

Reasons of exclusion^†	EMPHOGEN I (2004–2007)	EMPHOGEN II (2013–2015)
CASES (N = 3731)	3120	611
Primary exclusions (N = 2655)	2147	508
Age < 18	31	2
Excludable endoscopic diagnosis^‡	1213	377
History of UGIH	121	18
Intrahospital UGIH	89	5
UGIH without endoscopic or surgical diagnosis from admission to discharge	121	3
Nasogastric or percutaneous tube carrier	75	2
<3 months’ residence in study area	42	7
Admission time <24 h	208	8
Admission not due to UGIH	154	80
Death	0	2
Other	93	4
Secondary exclusions (N = 744)	646	98
Refusal to sign informed consent form	21	0
Occurred at weekend or vacations period	57	21
Death	11	2
Endoscopy performed more than 48 h after admission	83	39
Discharge from hospital or visit to healthcare facility in the 15 days prior to admission	54	20
Severe condition	7	1
Psychological disorders	12	4
Illiterate	2	0
Deaf or blind	1	0
Lives in a residence or closed institution and does not know the drugs taken	7	1
Refusal to answer or failure to complete the interview	12	5
Impossible to conduct interview within the 15-day period preceding admission	6	4
Admission time <24 h	0	1
Other	373	0
Excluded from analysis (N = 332)	327	5
Non-white patients	4	0
Unavailable biological material	323	5
CONTROLS (N = 1073)	1071	2
Refused to sign informed consent form	45	0
Age < 18	1	0
History of disease	11	1
Intrahospital UGIH	89	0
Nasogastric or percutaneous tube carrier	2	0
<3 months' residence in study area	1	0
Severe condition	1	0
Psychological disorders	1	0
Deaf or blind	3	0
Refusal to answer or failure to complete the interview	80	0
Impossible to conduct interview within the 15-day period preceding admission	60	0
Date of last admission	0	1
Other	13	0
Non-white patients	15	0
Unavailable biological material	749	0

^†Cases and controls were excluded upon presenting one or more exclusion criteria.

^‡Excludable endoscopic diagnosis included gastritis, esophagitis, oesophageal varices, gastric or duodenal neoplasia, Mallory-Weiss syndrome, angiodysplasia, anastomotic ulcers, diverticulitis, acute alcohol intoxication, hiatal hernia, and papule.

Bold values represent the total per reason of exclusion group and study period.

Figure 1. Flow of the cases and the controls throughout the two stages of the project.

Table 2. Description of the cases and controls included in the study.

Characteristic	Cases (N = 326) № (%)	Controls (N = 748) № (%)	OR (95% CI)	p-Value
Age
<45	41 (12.6%)	95 (12.7%)	1
45–65	117 (35.9%)	271 (36.2%)	1.05 (0.68–1.63)	.8327
>65	161 (49.4%)	370 (49.5%)	1.01 (0.66–1.54)	.9757
missing	7 (2.1%)	12 (1.6%)
BMI
Underweight	10 (3.1%)	24 (3.2%)	0.74 (0.33–1.62)	.4588
Normal weight	114 (35.0%)	204 (37.3%)	1
Overweight	128 (39.3%)	374 (50.0%)	0.61 (0.45–0.83)	.0201
Obese	68 (20.9%)	144 (19.3%)	0.85 (0.58–1.24)	.8676
Missing	6 (1.8%)	2 (0.3%)
Gender
Male	236 (72.4%)	559 (74.7%)	1
Female	87 (26.7%)	189 (25.3%)	1.18 (0.87–1.6)	.2852
Missing	3 (0.9%)	0
Arthrosis
No	219 (67.2%)	469 (62.7%)	1
Yes	86 (26.4%)	216 (28.9%)	0.86 (0.63–1.17)	.3303
Missing	21 (6.4%)	63 (8.4%)
Helicobacter pylori
No or uncertain	27 (8.3%)	138 (18.4%)	1
Yes	276 (84.7%)	574 (76.7%)	2.54 (1.62–3.99)	<.0001
Missing	23 (7.1%)	36 (4.8%)
Source of information
Patients	259 (79.4%)	672 (89.8%)	1
Healthcare assistant/direct relative	67 (20.6%)	76 (10.2%)	2.35 (1.62–3.42)	<.0001
Interview variables
Number of interviews conducted
1	274 (84.0%)	644 (86.1%)	1
≥2	52 (16.0%)	104 (13.9%)	1.27 (0.81–1.99)	.2927
Reliability of the interview
<5	13 (4.0%)	20 (2.7%)	1
5–7	36 (11%)	78 (10.4%)	0.67 (0.29–1.54)	.3466
7–9	134 (41.1%)	310 (41.4%)	0.70 (0.33–1.48)	.3540
≥9	143 (43.9%)	340 (45.5%)	0.67 (0.31–1.41)	.2855
Personal history of gastrointestinal disorders
None or dyspepsia	208 (63.8%)	647 (86.5%)	1
Ulcer	48 (14.7%)	56 (7.5%)	2.74 (1.79–4.21)	<.0001
Bleeding	70 (21.5%)	45 (6.0%)	4.79 (3.15–7.27)	<.0001
Co-medications with drugs that are not NSAIDs
Analgesics not narcotics
No	272 (83.4%)	692 (92.5%)	1
Yes	54 (16.6%)	56 (7.5%)	2.74 (1.81–4.15)	<.0001
Inhibitors of the proton pump
No	290 (89.0%)	682 (91.2%)	1
Yes	36 (11.0%)	66 (8.8%)	1.2 (0.77–1.88)	.4202
Antiaggregant
No	261 (80.1%)	662 (88.5%)	1
Yes	65 (19.9%)	86 (11.5%)	1.94 (1.34–2.8)	.0005
Anticoagulants
No	291 (89.3%)	716 (95.7%)	1
Yes	35 (10.7%)	32 (4.3%)	3.09 (1.85–5.15)	<.0001
Inhibitors of COX2
No	323 (99.1%)	742 (99.2%)	1
Yes	3 (0.9%)	6 (0.8%)	0.88 (0.21–3.77)	.8659

Table 3. Prevalence of the studied genotypes and Hardy–Weinberg equilibrium test.

Gene	Single nucleotide polymorphism reference number	Genotypes	Cases N (%)	Controls N (%)	Hardy–Weinberg equilibrium p-value
CYP4F11, cytochrome P450 family 4 subfamily F member 11	rs1060463	CC	64 (19.6)	127 (17.0)	0.03
		CT	165 (50.6)	398 (53.2)
		TT	97 (29.8)	223 (29.8)
CYP2A6, cytochrome P450 family 2 subfamily A member 6	rs28399433	AA	288 (88.3)	662 (88.5)	Not applicable
		AC	36 (11.0)	80 (10.7)
CYP2B6, cytochrome P450 family 2 subfamily B member 6	rs36079186	TT	326 (100.0)	748 (100.0)	Not applicable
CYP4F11, cytochrome P450 family 4 subfamily F member 11	rs3765070	AA	65 (19.9)	128 (17.1)	0.03
		AG	165 (50.6)	398 (53.2)
		GG	96 (29.4)	222 (29.7)
CYP2A7, cytochrome P450 family 2 subfamily A member 7	rs3869579	AA	94 (28.8)	214 (28.6)	0.05
		AG	147 (45.1)	346 (46.3)
		GG	85 (26.1)	188 (25.1)
CYP11B2, cytochrome P450 family 11 subfamily B member 2	rs4536	CT	7 (2.1)	22 (2.9)	Not applicable
		TT	318 (97.5)	725 (96.9)
CYP24A1, cytochrome P450 family 24 subfamily A member 1	rs4809957	AA	200 (61.3)	450 (60.2)	0.09
		AG	108 (33.1)	271 (36.2)
		GG	18 (5.5)	27 (3.6)
CYP2F1, cytochrome P450 family 2 subfamily F member 1	rs58285195	CC	2 (0.6)	1 (0.1)	0.62
		CT	29 (8.9)	51 (6.8)
		TT	295 (90.5)	696 (93.0)
GSTP1, glutathione S-transferase pi 1	rs1695	AA	132 (40.5)	321 (42.9)	0.52
		AG	157 (48.2)	332 (44.4)
		GG	37 (11.3)	95 (12.7)
GSTA2, glutathione S-transferase alpha 2	rs2180314	CC	50 (15.3)	104 (13.9)	0.13
		CG	139 (42.6)	318 (42.5)
		GG	129 (39.6)	309 (41.3)
GSTA1, glutathione S-transferase alpha 1	rs4715332	AA	104 (31.9)	259 (34.6)	0.29
		AC	159 (48.8)	374 (50.0)
		CC	63 (19.3)	114 (15.2)
GSTA5, glutathione S-transferase alpha 5	rs4715354	AA	55 (16.9)	143 (19.1)	0.71
		AG	160 (49.1)	362 (48.4)
		GG	110 (33.7)	243 (32.5)
NAT2, N-acetyltransferase 1	rs1799931	AA	1 (0.3)	1 (0.1)	0.45
		AG	16 (4.9)	40 (5.3)
		GG	309 (94.8)	707 (94.5)
CHST2, carbohydrate sulfotransferase 2	rs6664	CC	177 (54.3)	419 (56.0)	0.34
		CT	128 (39.3)	275 (36.8)
		TT	21 (6.4)	54 (7.2)
ALB_c, albumin	rs3756067	AA	37 (11.3)	91 (12.2)	0.33
		AG	136 (41.7)	320 (42.8)
		GG	145 (44.5)	332 (44.4)
SLCO3A1, solute carrier organic anion transporter family member 3A1	rs2283458	AA	33 (10.1)	100 (13.4)	1.00
		AG	169 (51.8)	348 (46.5)
		GG	124 (38.0)	300 (40.1)

Table 4. Odds ratios (OR) for UGIH stratified by patients’ genotype and NSAID (any NSAID, aspirin, non-aspirin) exposure and their interaction represented by synergism index (S) and relative excess risk due to interaction (RERI).

SNP (reference number)	Wildtype genotype		Genetic variation		RERI (95% CI)	S (95% CI)
	N (%) (cases/controls)	OR^† (95% CI); p-value	N (%) (cases/controls)	OR^† (95% CI); p-value
rs2180314:C > G
Any NSAID (No)	91 (26.1)/258 (73.9)	1	99 (21.4)/363 (78.6)	0.74 (0.50, 1.09); p = .1229	4.39 (0.70, 8.07)	3.3 (1.24, 8.8)
Any NSAID (Yes)	48 (44.4)/60 (55.6)	3.17 (1.79, 5.63); p = .0001	80 (61.5)/50 (38.5)	7.30 (4.27, 12.48); p < .0001
Non-aspirin NSAID (No)	100 (27.2)/267 (72.8)	1	110 (22.9)/370 (77.1)	0.75 (0.52, 1.09); p = .1343	3.97 (0.44, 7.50)	3.42 (1.12, 10.47)
Non-aspirin NSAID (Yes)	39 (43.3)/51 (56.7)	2.89 (1.57, 5.31); p = .0006	69 (61.6)/43 (38.4)	6.61 (3.82, 11.46); p < .0001
Aspirin intake (No)	115 (30.4)/263 (69.6)	1.0	142 (28.4)/358 (71.6)	0.92 (0.66–1.30); p = .6481	8.39 (−4.20, 20.99)	7.65 (0.81–72.33)
Aspirin intake (Yes)	10 (47.6)/11(52.4)	2.34 (0.84–6.49); p = .1031	14 (70.0)/6 (30.0)	10.65 (3.27–34.71); p = .0001
rs4809957:A > G
Any NSAID (No)	68 (23.4)/222 (76.6)	1	127 (23.5)/414 (76.5)	0.99 (0.66, 1.47); p = .9515	3.46 (−0.40, 7.31)	2.11 (0.9, 4.97)
Any NSAID (Yes)	40 (44.9)/49 (55.1)	4.12 (2.18, 7.79); p < .0001	91 (59.1)/63 (40.9)	7.57 (4.43, 12.93); p < .0001
Non-aspirin NSAID (No)	74 (24.3)/230 (75.7)	1	141 (25.0)/422 (75.0)	1.04 (0.71, 1.53); p = .8433	3.11 (−0.82, 7.05)	2.03 (0.81, 5.08)
Non-aspirin NSAID (Yes)	34 (45.3)/41 (54.7)	3.99 (2.06, 7.75); p < .0001	77 (58.3)/55 (41.7)	7.15 (4.10, 12.46); p < .0001
Aspirin intake (No)	92 (28.8)/227 (71.2)	1.0	170 (29.4)/409 (70.6)	1.09 (0.76–1.54); p = .6474	6.04 (−1.89, 13.98)	7.72 (0.38–158.17)
Aspirin intake (Yes)	6 (40.0)/9 (60.0)	1.81 (0.45–7.37); p = .4045	18 (69.2)/8 (30.8)	7.94 (2.99–21.13); p < .0001
rs6664:C > T
Any NSAID (No)	75 (24.4)/233 (75.6)	1	120 (22.9)/403 (77.1)	1.13 (0.76, 1.68); p = .5438	−1.45 (−6.05, 3.15)	0.78 (0.37, 1.65)
Any NSAID (Yes)	53 (55.8)/42 (44.2)	7.47 (4.02, 13.88); p < .0001	78 (52.7)/70 (47.3)	6.15 (3.60, 10.50); p < .0001
Non-aspirin NSAID (No)	83 (25.6)/241 (74.4)	1	132 (24.3)/411 (75.7)	1.16 (0.79, 1.70); p = .4486	−3.37 (−8.77, 2.03)	0.55 (0.24, 1.25)
Non-aspirin NSAID (Yes)	45 (57.0)/34 (43.0)	8.38 (4.33, 16.18); p < .0001	66 (51.6)/62 (48.4)	5.16 (3.00, 8.90); p < .0001
Aspirin intake (No)	104 (31.0)/231 (69.0)	1.0	158 (28.1)/405 (71.9)	0.95 (0.67–1.34); p = .7793	5.55 (−2.60, 13.70)	5.74 (0.49–67.83)
Aspirin intake (Yes)	8 (47.1)/9 (52.9)	2.22 (0.69–7.17); p = .1829	16 (66.7)/8 (33.3)	7.72 (2.75–21.68); p = .0001
rs2283458:A > G
Any NSAID (No)	107 (26.7)/294 (73.3)	1	88 (20.5)/342 (79.5)	0.69 (0.47, 1.01); p = .0532	0.56 (−2.62, 3.73)	1.15 (0.50, 2.64)
Any NSAID (Yes)	62 (53.4)/54 (46.6)	4.92 (2.83, 8.58); p < .0001	69 (54.3)/58 (45.7)	5.17 (3.07, 8.70); p < .0001
Non-aspirin NSAID (No)	117 (28.1)/300 (71.9)	1	98 (21.8)/352 (78.2)	0.71 (0.49, 1.03); p = .068	0.77 (−2.41, 3.96)	1.24 (0.5, 3.09)
Non-aspirin NSAID (Yes)	52 (52.0)/48 (48.0)	4.46 (2.51, 7.93); p < .0001	59 (55.1)/48 (44.9)	4.95 (2.86, 8.57); p < .0001
Aspirin intake (No)	134 (31.7)/289 (68.3)	1.0	128 (26.9)/347 (73.1)	0.78 (0.56–1.08); p = .1369	0.02 (−6.07, 6.10)	1.01 (0.14–7.55)
Aspirin intake (Yes)	13 (65.0)/7 (35.0)	4.24 (1.38–13.06); p = .0118	11 (52.4)/10 (47.6)	4.03 (1.46–11.15); p = .0072
rs1060463:C > G/C > T
Any NSAID (No)	98 (22.5)/337 (77.5)	1	97 (24.5)/299 (75.5)	1.36 (0.93, 1.99); p = .1143	0.73 (−3.88, 5.33)	1.12 (0.55, 2.29)
Any NSAID (Yes)	67 (52.3)/61 (47.7)	6.67 (3.94, 11.28); p < .0001	64 (55.7)/51 (44.3)	7.75 (4.41, 13.62); p < .0001
Non-aspirin NSAID (No)	103 (22.9)/346 (77.1)	1	112 (26.8)/306 (73.2)	1.42 (0.98, 2.05); p = .0603	0.019 (−4.65, 4.69)	1 (0.46, 2.19)
Non-aspirin NSAID (Yes)	62 (54.4)/52 (45.6)	6.53 (3.81, 11.19); p < .0001	49 (52.7)/44 (47.3)	6.97 (3.81, 12.74); p < .0001
Aspirin intake (No)	138 (28.8)/342 (71.3)	1.0	124 (29.7)/294 (70.3)	1.28 (0.91–1.79); p = .1542	2.07 (−5.66, 9.79)	1.62 (0.27–9.83)
Aspirin intake (Yes)	8 (50.0)/8 (50.0)	4.05 (1.26–12.98); p = .0186	16 (64.0)/9 (36.0)	6.39 (2.35–17.38); p = .0003
rs1695:A > G
Any NSAID (No)	94 (24.5)/289 (75.5)	1	101 (22.5)/347 (77.5)	0.82 (0.56, 1.20); p = .3084	−0.11 (−3.67, 3.46)	0.98 (0.44, 2.18)
Any NSAID (Yes)	63 (59.4)/43 (40.6)	5.70 (3.27, 9.92); p < .0001	68 (49.6)/69 (50.4)	5.41 (3.19, 9.18); p < .0001
Non-aspirin NSAID (No)	101 (25.4)/297 (74.6)	1	114 (24.3)/355 (75.7)	0.90 (0.62, 1.30); p = .5776	−1.24 (−5.08, 2.60)	0.75 (0.32, 1.77)
Non-aspirin NSAID (Yes)	56 (61.5)/35 (38.5)	6.08 (3.40, 10.88); p < .0001	55 (47.4)/61 (52.6)	4.74 (2.72, 8.27); p < .0001
Aspirin intake (No)	133 (31.4)/290 (68.6)	1.0	129 (27.2)/346 (72.8)	0.83 (0.59–1.17); p = .2858	1.14 (−5.04, 7.31)	1.44 (0.18–11.37)
Aspirin intake (Yes)	9 (56.3)/7 (43.8)	3.73 (1.14–12.21); p = .0295	15 (60.0)/10 (40.0)	4.70 (1.76–12.52); p = .0020
rs3756067:G > A
Any NSAID (No)	79 (23.0)/265 (77.0)	1	114 (23.8)/366 (76.3)	0.93 (0.63, 1.38); p = .7199	−0.03 (−3.53, 3.46)	0.99 (0.45, 2.18)
Any NSAID (Yes)	57 (50.9)/55 (49.1)	5.52 (3.15, 9.68); p < .0001	68 (54.4)/57 (45.6)	5.42 (3.10, 9.46); p < .0001
Non-aspirin NSAID (No)	88 (24.3)/274 (75.7)	1	124 (24.9)/373 (75.1)	0.87 (0.60, 1.27); p = .483	0.22 (−3.11, 3.56)	1.06 (0.44, 2.57)
Non-aspirin NSAID (Yes)	48 (51.1)/46 (48.9)	4.79 (2.66, 8.64); p < .0001	58 (53.7)/50 (46.3)	4.89 (2.77, 8.64); p < .0001
Aspirin intake (No)	105 (28.2)/267 (71.8)	1.0	150 (29.2)/364 (70.8)	0.94 (0.67–1.32); p = .7272	0.08 (−6.60, 6.76)	1.02 (0.15–7.02)
Aspirin intake (Yes)	13 (56.5)/10 (43.5)	4.48 (1.62–12.35); p = .0038	10 (58.8)/7 (41.2)	4.50 (1.41–14.40); p = .0113
rs3765070:A > G/A > T
Any NSAID (No)	99 (22.7)/337 (77.3)	1	96 (24.3)/299 (75.7)	1.32 (0.90, 1.93); p = .1534	0.99 (−3.57, 5.54)	1.17 (0.57, 2.40)
Any NSAID (Yes)	66 (52.0)/61 (48.0)	6.46 (3.82, 10.93); p < .0001	65 (56.0)/51 (44.0)	7.77 (4.43, 13.61); p < .0001
Non-aspirin NSAID (No)	104 (23.1)/346 (76.9)	1	111 (26.6)/306 (73.4)	1.38 (0.96, 2.00); p = .0822	0.31 (−4.32, 4.94)	1.05 (0.48, 2.30)
Non-aspirin NSAID (Yes)	61 (54.0)/52 (46.0)	6.33 (3.69, 10.86); p < .0001	50 (53.2)/44 (46.8)	7.02 (3.85, 12.80); p < .0001
Aspirin intake (No)	138 (28.8)/342 (71.3)	1.0	124 (29.7)/294 (70.3)	1.26 (0.9–1.76); p = .1772	2.07 (−5.60, 9.75)	1.63 (0.27–9.96)
Aspirin intake (Yes)	8 (50.0)/8 (50.0)	4.02 (1.26–12.88); p = .0191	16 (64.0)/9 (36.0)	6.35 (2.34–17.27); p = .0003
rs3869579:G > A/G > C
Any NSAID (No)	89 (23.1)/296 (76.9)	1	106 (23.8)/340 (76.2)	1.14 (0.78, 1.67); p = .5035	−0.33 (−4.53, 3.87)	0.94 (0.45, 1.95)
Any NSAID (Yes)	58 (53.7)/50 (46.3)	6.68 (3.78, 11.79); p < .0001	73 (54.1)/62 (45.9)	6.49 (3.82, 11.03); p < .0001
Non-aspirin NSAID (No)	99 (24.6)/303 (75.4)	1	116 (24.9)/349 (75.1)	1.15 (0.80, 1.66); p = .4474	−0.63 (−4.86, 3.59)	0.89 (0.4, 1.99)
Non-aspirin NSAID (Yes)	48 (52.7)/43 (47.3)	6.35 (3.50, 11.50); p < .0001	63 (54.3)/53 (45.7)	5.87 (3.38, 10.19); p < .0001
Aspirin intake (No)	116 (28.4)/293 (71.6)	1.0	146 (29.9)/343 (70.1)	1.09 (0.78–1.52); p = .6258	0.34 (−6.81, 7.50)	1.09 (0.18–6.72)
Aspirin intake (Yes)	10 (58.8)/7 (41.2)	4.69 (1.53–14.36); p = .0068	14 (58.3)/10 (41.7)	5.12 (1.85–14.20); p = .0017
rs4715332:C > A
Any NSAID (No)	98 (23.8)/314 (76.2)	1	97 (23.2)/322 (76.8)	0.88 (0.60, 1.28); p = .507	2.34 (−1.49, 6.16)	1.64 (0.74, 3.65)
Any NSAID (Yes)	61 (50.4)/60 (49.6)	4.76 (2.76, 8.22); p < .0001	70 (57.9)/51 (42.1)	6.98 (4.09, 11.92); p < .0001
Non-aspirin NSAID (No)	110 (25.3)/324 (74.7)	1	105 (24.3)/327 (75.7)	0.85 (0.59, 1.23); p = .3941	2.25 (−1.36, 5.86)	1.75
Non-aspirin NSAID (Yes)	49 (49.5)/50 (50.5)	4.15 (2.31, 7.43); p < .0001	62 (57.4)/46 (42.6)	6.25 (3.62, 10.77); p < .0001		(0.71, 4.32)
Aspirin intake (No)	125 (28.8)/318 (71.8)	1.0	137 (30.1)/318 (69.9)	0.98 (0.70–1.38); p = .9270	1.99 (−6.68, 10.66)	1.61 (0.24–10.9)
Aspirin intake (Yes)	14 (58.3)/10 (41.7)	4.27 (1.62–11.24); p = .0033	10 (62.5)/6 (37.5)	6.24 (1.76–22.12); p = .0046
rs4715354:G > A
Any NSAID (No)	99 (24.7)/302 (75.3)	1	95 (22.1)/334 (77.9)	0.95 (0.65, 1.40); p = .8103	1.53 (−2.25, 5.32)	1.37 (0.63, 2.96)
Any NSAID (Yes)	61 (50.4)/60 (49.6)	5.24 (3.03, 9.08); p < .0001	70 (57.4)/52 (42.6)	6.73 (3.95, 11.46); p < .0001
Non-aspirin NSAID (No)	108 (25.7)/313 (74.3)	1	106 (23.8)/339 (76.2)	0.95 (0.66, 1.37); p = .7886	1.16 (−2.54, 4.85)	1.30 (0.56, 3.04)
Non-aspirin NSAID (Yes)	52 (51.5)/49 (48.5)	4.90 (2.73, 8.79); p < .0001	59 (55.7)/47 (44.3)	6.01 (3.48, 10.36); p < .0001
Aspirin intake (No)	127 (29.4)/305 (70.6)	1.0	135 (29.0)/331 (71.0)	1.02 (0.73–1.42); p = .9198	0.88 (−6.37, 8.13)	1.26 (0.20–8.05)
Aspirin intake (Yes)	14 (58.3)/10 (41.7)	4.39 (1.61–11.97); p = .0039	10 (58.8)/7 (41.2)	5.28 (1.68–16.61); p = .0044
rs1799931:G > A
Any NSAID (No)	186 (23.6)/601 (76.4)	1	9 (20.5)/35 (79.5)	0.98 (0.42, 2.28); p = .9634	−2.49 (−8.06, 3.07)	0.53 (0.08, 3.4)
Any NSAID (Yes)	123 (53.7)/106 (46.3)	6.30 (4.20, 9.46); p < .0001	8 (57.1)/6 (42.9)	3.79 (0.98, 14.63)
Non-aspirin NSAID (No)	203 (24.8)/615 (75.2)	1	12 (24.5)/37 (75.5)	0.99 (0.45, 2.21); p = .9854	−2.07 (−8.31, 4.17)	0.56 (0.06, 5.18)
Non-aspirin NSAID (Yes)	106 (53.5)/92 (46.5)	5.74 (3.77, 8.75); p < .0001	5 (55.6)/4 (44.4)	3.67 (0.74, 18.11); p = .1107
Aspirin intake (No)	280 (28.9)/690 (71.1)	1	14 (26.4)/39 (73.6)	0.91 (0.43, 1.94); p = .8103	−1.63 (−10.30, 7.03)	0.57 (0.01, 24.24)
Aspirin intake (Yes)	29 (63.0)/17 (37.0)	4.87 (2.20, 10.81); p = .0001	3 (60.0)/2 (40.0)	3.15 (0.26, 37.77); p = .3644
rs28399433:A > C
Any NSAID (No)	172 (23.4)/563 (56.6)	1	22 (24.7)/67 (75.3)	0.93 (0.50, 1.72); p = .8125	0.23 (−5.51, 5.96)	1.05 (0.34, 3.2)
Any NSAID (Yes)	116 (54.0)/99 (46.0)	6.02 (3.96, 9.15); p < .0001	14 (51.9)/13 (48.1)	6.18 (2.50, 15.23); p = .0001
Non-aspirin NSAID (No)	190 (24.8)/577 (75.2)	1	24 (25.8)/69 (74.2)	1.01 (0.56, 1.81); p = .9841	−0.86 (−5.92, 4.19)	0.82 (0.23, 2.92)
Non-aspirin NSAID (Yes)	98 (53.6)/85 (46.4)	5.71 (3.69, 8.83); p < .0001	12 (52.2)/11 (47.8)	4.85 (1.84, 12.81); p = .0014
Aspirin intake (No)	258 (28.5)/646 (71.5)	1	34 (30.6)/77 (69.4)	0.97 (0.57, 1.64); p = .9016	0.025 (−10.43, 10.48)	1.01 (0.06, 17.32)
Aspirin intake (Yes)	30 (65.2)/16 (34.8)	4.69 (2.09, 10.50); p = .0002	3 (60.0)/2 (40.0)	4.68 (0.57, 38.56); p = .1514
rs4536:C > T
Any NSAID (No)	191 (23.6)/618 (76.4)	1	4 (19.0)/17 (81.0)	0.32 (0.06, 1.66); p = .1743	−2.80 (−8.08, 2.47)	0.37 (0.02, 7.43)
Any NSAID (Yes)	127 (54.3)/107 (45.7)	6.10 (4.08, 9.12); p < .0001	3 (37.5)/5 (62.5)	2.61 (0.41, 16.49); p = .3070
Non-aspirin NSAID (No)	210 (24.9)/633 (75.1)	1	5 (21.7)/18 (78.3)	0.29 (0.06, 1.53); p = .1450	−2.38 (−7.41, 2.66)	0.39 (0.02, 8.2)
Non-aspirin NSAID (Yes)	108 (54.0)/92 (46.0)	5.60 (3.69, 8.52); p < .0001	2 (33.3)/4 (66.7)	2.52 (0.41, 15.62); p = .3213
Aspirin intake (No)	287 (28.9)/707 (71.1)	1	6 (22.2)/21 (77.8)	0.37 (0.11, 1.27); p = .1139	Not applicable	Not applicable
Aspirin intake (Yes)	31 (63.3)/18 (36.7)	4.63 (2.16, 9.91); p = .0001	1 (50.0)/1 (50.0)	Not applicable
rs58285195:T > C
Any NSAID (No)	173 (22.7)/588 (77.3)	1	22 (31.4)/48 (68.6)	1.57 (0.84, 2.92); p = .1553	7.68 (−12.96, 28.31)	2.35 (0.48, 11.4)
Any NSAID (Yes)	122 (53.0)/108 (47.0)	6.10 (4.05, 9.18); p < .0001	9 (69.2)/4 (30.8)	14.35 (3.38, 60.98); p = .0003
Non-aspirin NSAID (No)	193 (24.2)/604 (75.8)	1	22 (31.4)/48 (68.6)	5.50 (3.60, 8.42); p < .0001	7.23 (−11.67, 26.14)	2.46 (0.5, 12.11)
Non-aspirin NSAID (Yes)	102 (52.6)/92 (47.4)	5.50 (3.60, 8.42); p = .2383	9 (69.2)/4 (30.8)	13.18 (3.12, 55.72); p = .0005
Aspirin intake (No)	264 (28.0)/678 (72.0)	1	30 (37.0)/51 (63.0)	1.70 (0.96, 3.02); p = .0679	Not applicable	Not applicable
Aspirin intake (Yes)	31 (63.3)/18 (36.7)	5.36 (2.45, 11.73); p < .0001	1 (50.0)/1 (50.0)	Not applicable

SNP: single nucleotide polymorphism.

^†Odds Ratio adjusted for: period of patients’ recruitment, previous history of arthrosis, infection with Helicobacter pylori, gastrointestinal disorders (ulcer and bleeding), exposure to inhibitors of the proton pump, exposure to antiaggregant, exposure to anticoagulants, and the interview variables (the number and the reliability of the interview).

Data availability statement

The data that support the findings of this study are available in [FigShare] at [10.6084/m9.figshare.11822223].