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. 2011 Aug 18;7(8):e1002237. doi: 10.1371/journal.pgen.1002237

Table 3. PD risk conditioned on GRIN2A genotype and coffee use.

GRIN2A Coffee NGRC (Discovery) Pooled Replications Pooled NGRC+Replications
N Case N Control OR (SE) P N Case N Control OR (SE) P N Case N Control OR (SE) P
Coffee irrespective of genotype
- Light 946 544 Ref 621 1012 Ref 1567 1556 Ref
- Heavy 512 387 0.66 (0.06) 6×10−6 393 905 0.79 (0.07) 2×10−3 905 1292 0.73 (0.04) 3×10−7
GRIN2A rs4998386 genotype irrespective of coffee
CC - 1227 716 Ref 837 1558 Ref 2064 2274 Ref
TC 219 204 0.62 (0.07) 2×10−5 163 344 0.89 (0.10) 0.14 382 548 0.75 (0.06) 2×10−4
TT 12 11 0.53 (0.23) 0.15 14 15 26 26 Heterogeneity P = 0.06*
CC Heavy 441 283 Ref 330 706 Ref. 771 989 Ref
TC Heavy 69 99 0.42 (0.08) 2×10−6 54 192 0.59 (0.10) 1×10−3 123 291 0.51 (0.06) 7×10−8
TT Heavy 2 5 0.19 (0.16) 0.05 9 7 11 12 Heterogeneity P = 0.04*
CC Light 786 433 Ref 507 852 Ref. 1293 1285 Ref
TC Light 150 105 0.81 (0.12) 0.16 109 152 1.24 (0.18) 0.93 259 257 1.00 (0.10) 0.99
TT Light 10 6 0.81 (0.44) 0.70 5 8 15 14
Joint effects of GRIN2A rs4998386 and coffee
CC Light 786 433 Ref. 507 852 Ref. 1293 1285 Ref
CC Heavy 441 283 0.75 (0.08) 6×10−3 330 706 0.88 (0.08) 0.08 771 989 0.82 (0.06) 3×10−3
TC Light 150 105 0.81 (0.12) 0.15 109 152 1.24 (0.18) 0.07 259 257 1.00 (0.10) 0.99
TC Heavy 69 99 0.32 (0.06) 7×10−11 54 192 0.52 (0.09) 5×10−5 123 291 0.41 (0.05) 6×10−13
TT Light 10 6 0.81 (0.44) 0.70 5 8 15 14
TT Heavy 2 5 0.14 (0.12) 0.02 9 7 11 12
Interaction of GRIN2A rs4998386 genotypes and coffee consumption
1446 920 0.52 (0.12) 4×10−3 1000 1902 0.48 (0.11) 5×10−4 2446 2822 0.51 (0.08) 3×10−5
Genotype specific dose-dependent effect of coffee
CC ≤25% 334 189 Ref 117 98 Ref. 451 287 Ref
25%–≤50% 344 178 1.03 (0.14) 0.84 120 92 1.11 (0.12) 0.70 464 270 1.06 (0.12) 0.61
50%–≤75% 366 203 0.91 (0.12) 0.47 91 87 0.83 (0.17) 0.19 457 290 0.89 (0.10) 0.30
>75% 183 146 0.58 (0.09) 3×10−4 75 82 0.68 (0.15) 0.04 258 228 0.61 (0.08) 6×10−5
TC ≤25% 69 55 Ref 27 18 Ref. 96 73 Ref
25%–≤50% 65 41 1.31 (0.37) 0.34 22 16 0.89 (0.41) 0.40 87 57 1.24 (0.30) 0.36
50%–≤75% 59 56 0.71 (0.20) 0.21 16 22 0.40 (0.19) 0.03 75 78 0.63 (0.15) 0.05
>75% 26 52 0.31 (0.10) 2×10−4 13 21 0.37 (0.18) 0.02 39 73 0.34 (0.09) 5×10−5
TT ≤25% 6 0 2 2 8 2
25%–≤50% 2 3 0 3 2 6
50%–≤75% 2 4 3 1 5 5
>75% 2 4 3 1 5 5

C genotype was associated with reduced risk consistently across studies. rs4998386_TT frequency varied significantly across studies. The a-priori hypothesis for replication that among heavy drinkers GRIN2A_rs4998386_T carriers had a lower risk of PD than GRIN2A_rs4998386_CC was replicated under three conditions: comparing TC to CC (excluding rare and variable TT genotype) shown here, Dominant model (TT+TC vs. CC) and Additive model (TT vs. TC vs CC) shown in Table S3. As predicted from the Discovery phase, genotype had no effect on risk of PD among light coffee drinkers. The joint effects of genotype and coffee showed a significant 59% drop in PD risk in people who had the rs4998386_TC genotype and were heavy drinkers, but little or no effect in other combinations. A formal interaction test demonstrated that the effects of coffee and genotype are dependent on each other. By definition, statistical interaction exists if the joint effect of gene (g) and exposure (e) is significantly different from the product of their individual effects. Interaction OR is the ratio of the OR of disease when g and e are present, divided by the product of the individual OR; i.e., ORinteraction = ORg+e/(ORg×ORe). (F) Dose-dependent risk reduction by coffee was clear and strong for rs4998386_TC genotype. Analyses were repeated with smoking (Table S4) or caffeinated soda/tea (Table S5) as additional covariates, results were unchanged.

*Heterogeneity P: Breslow-Day test statistics to assess between-study heterogeneity conducted for coffee and genotypes and found to be significant only for TT genotype. Analyses were adjusted for sex and age at interview in each dataset, and also for study in the pooled analyses. Expanded analysis including results for individual replication data sets are shown in Table S3.