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We recently received comments on our findings[1] from Liu et al for which we are grateful, and we appreciate their careful scholarship and thoughtfulness. We would like to respond to the comments of Liu et al as follows:
First, Liu et al argue that a major issue in our study is the failure to account for sample overlap. However, as pointed out by Liu et al, the bias due to sample overlap is mainly due to false-positive errors, whereas our findings are not significant. However, we also replaced venous thromboembolism (VTE) data from different data sources ([Table 1])[2] for validation in this response, and the results showed that our conclusions were stable ([Table 2]).
Table 1 Summary information on the included exposure/outcome phenotypesPhenotypic name
No. of cases
No. of controls
Sample size
Ancestry
Sex
Consortium (cohort)/author
Public release year
Study reference or description URL
Age of initiation of regular smoking
NA
NA
728,826
Mixed (84.35%European)
Both sexes
GSCAN/Gretchen R. B. Saunders et al[3]
2022
Nature. 2022 Dec;612(7941):720–724. doi: 10.1038/s41586-022-05477-4.
Ever smoked regularly
NA
NA
3,383,199
Mixed (79.11%European)
Both sexes
GSCAN/Gretchen R. B. Saunders et al[3]
2022
Nature. 2022 Dec;612(7941):720–724. doi: 10.1038/s41586-022-05477-4.
Cigarettes per day
NA
NA
784,353
Mixed (79.03%European)
Both sexes
GSCAN/Gretchen R. B. Saunders et al[3]
2022
Nature. 2022 Dec;612(7941):720–724. doi: 10.1038/s41586-022-05477-4.
Smoking cessation
NA
NA
1,400,535
Mixed (82.26%European)
Both sexes
GSCAN/Gretchen R. B. Saunders et al[3]
2022
Nature. 2022 Dec;612(7941):720–724. doi: 10.1038/s41586-022-05477-4.
Venous thromboembolism
21,021
391,160
412,181
European
Both sexes
FinnGen.R10/Mitja I. Kurki et al[2]
2023
Deep venous thrombosis
6,501
357,111
363,612
European
Both sexes
FinnGen.R10/Mitja I. Kurki et al[2]
2023
Pulmonary embolism
10,046
401,128
411,174
European
Both sexes
FinnGen.R10/Mitja I. Kurki et al[2]
2023
Table 2 Associations of smoking-related phenotypes with VTE (including its subtypes) estimated by five MR methodsOutcome
Exposure
Method
No. of SNPs
Beta
SE
p-Value
OR (95% CI)
Venous thromboembolism
Age of initiation of regular smoking
Inverse variance weighted
6
0.332
0.253
0.190
1.393 (0.848, 2.289)
MR Egger
6
[minus]0.043
0.630
0.949
0.958 (0.279, 3.291)
Weighted median
6
0.124
0.285
0.663
1.132 (0.648, 1.979)
Weighted mode
6
0.054
0.383
0.894
1.055 (0.498, 2.235)
Simple mode
6
[minus]0.051
0.449
0.913
0.950 (0.394, 2.290)
Ever smoked regularly
Inverse variance weighted
254
0.099
0.053
0.064
1.104 (0.994, 1.225)
MR Egger
254
0.360
0.193
0.063
1.433 (0.982, 2.092)
Weighted median
254
0.108
0.070
0.122
1.114 (0.971, 1.278)
Weighted mode
254
0.136
0.210
0.517
1.146 (0.759, 1.729)
Simple mode
254
0.167
0.221
0.451
1.182 (0.766, 1.822)
Cigarettes per day
Inverse variance weighted
61
0.116
0.065
0.076
1.123 (0.988, 1.276)
MR Egger
61
0.065
0.108
0.548
1.067 (0.864, 1.319)
Weighted median
61
0.022
0.076
0.769
1.022 (0.881, 1.186)
Weighted mode
61
0.047
0.067
0.481
1.048 (0.920, 1.194)
Simple mode
61
0.225
0.155
0.152
1.252 (0.924, 1.696)
Smoking cessation
Inverse variance weighted
18
[minus]0.030
0.108
0.785
0.971 (0.785, 1.201)
MR Egger
18
0.151
0.316
0.639
1.163 (0.627, 2.159)
Weighted median
18
[minus]0.073
0.157
0.641
0.930 (0.684, 1.263)
Weighted mode
18
0.003
0.191
0.989
1.003 (0.690, 1.457)
Simple mode
18
0.024
0.245
0.922
1.025 (0.633, 1.657)
Past tobacco smoking
Inverse variance weighted
95
[minus]0.144
0.084
0.089
0.866 (0.734, 1.022)
MR Egger
95
[minus]0.450
0.348
0.200
0.638 (0.322, 1.263)
Weighted median
95
[minus]0.091
0.097
0.345
0.913 (0.755, 1.103)
Weighted mode
95
0.041
0.224
0.857
1.041 (0.671, 1.616)
Simple mode
95
0.008
0.231
0.973
1.008 (0.641, 1.585)
Current tobacco smoking
Inverse variance weighted
35
0.188
0.299
0.530
1.206 (0.671, 2.168)
MR Egger
35
[minus]0.593
1.114
0.598
0.553 (0.062 ,4.902)
Weighted median
35
0.054
0.375
0.885
1.056 (0.507, 2.200)
Weighted mode
35
[minus]0.087
0.589
0.883
0.916 (0.289, 2.908)
Simple mode
35
0.248
0.709
0.729
1.281 (0.319, 5.143)
Deep venous thrombosis
Age of initiation of regular smoking
Inverse variance weighted
6
0.988
0.482
0.041
2.685 (1.043, 6.910)
MR Egger
6
1.759
1.188
0.213
5.809 (0.566, 59.662)
Weighted median
6
1.485
0.469
0.002
4.417 (1.762, 11.073)
Weighted mode
6
1.572
0.574
0.041
4.817 (1.562, 14.848)
Simple mode
6
1.499
0.693
0.083
4.478 (1.151, 17.416)
Ever smoked regularly
Inverse variance weighted
254
0.204
0.093
0.028
1.226 (1.023, 1.470)
MR Egger
254
0.440
0.337
0.193
1.553 (0.802, 3.006)
Weighted median
254
0.214
0.125
0.087
1.239 (0.969, 1.584)
Weighted mode
254
0.483
0.325
0.139
1.620 (0.857, 3.064)
Simple mode
254
0.539
0.389
0.167
1.714 (0.800, 3.671)
Smoking cessation
Inverse variance weighted
18
[minus]0.104
0.190
0.586
0.901 (0.621, 1.309)
MR Egger
18
0.679
0.546
0.232
1.972 (0.676, 5.755)
Weighted median
18
0.049
0.250
0.844
1.050 (0.643, 1.715)
Weighted mode
18
0.120
0.348
0.733
1.128 ( 0.571, 2.229)
Simple mode
18
0.047
0.428
0.915
1.048 (0.453, 2.425)
Cigarettes per day
Inverse variance weighted
61
0.065
0.085
0.441
1.067 (0.904, 1.260)
MR Egger
61
[minus]0.062
0.139
0.657
0.940 (0.715, 1.235)
Weighted median
61
[minus]0.099
0.125
0.430
0.906 (0.709, 1.158)
Weighted mode
61
[minus]0.036
0.118
0.762
0.965 (0.766, 1.216)
Simple mode
61
0.389
0.275
0.161
1.476 (0.862, 2.529)
Past tobacco smoking
Inverse variance weighted
95
[minus]0.159
0.120
0.184
0.853 (0.675, 1.078)
MR Egger
95
[minus]0.307
0.496
0.537
0.736 (0.278, 1.945)
Weighted median
95
[minus]0.150
0.165
0.363
0.861 (0.623, 1.189)
Weighted mode
95
[minus]0.173
0.360
0.631
0.841 (0.415 ,1.704)
Simple mode
95
[minus]0.447
0.442
0.314
0.640 (0.269 ,1.520)
Current tobacco smoking
Inverse variance weighted
35
[minus]0.182
0.418
0.664
0.834 (0.367 ,1.892)
MR Egger
35
[minus]0.523
1.543
0.737
0.593 (0.029 ,12.211)
Weighted median
35
0.405
0.580
0.485
1.500 (0.481 ,4.677)
Weighted mode
35
0.747
1.133
0.514
2.111 (0.229 ,19.464)
Simple mode
35
0.888
1.279
0.492
2.430 (0.198 ,29.813)
Pulmonary embolism
Age of initiation of regular smoking
Inverse variance weighted
6
0.307
0.292
0.292
1.360 (0.768 ,2.408)
MR Egger
6
0.265
0.762
0.745
1.304 (0.293 ,5.805)
Weighted median
6
0.238
0.386
0.538
1.269 (0.595 ,2.706)
Weighted mode
6
0.273
0.476
0.591
1.314 (0.517 ,3.340)
Simple mode
6
0.157
0.562
0.792
1.170 (0.388 ,3.521)
Ever smoked regularly
Inverse variance weighted
254
0.169
0.071
0.017
1.184 (1.031 ,1.359)
MR Egger
254
0.460
0.256
0.073
1.584 (0.959 ,2.617)
Weighted median
254
0.167
0.100
0.095
1.181 (0.972 ,1.436)
Weighted mode
254
0.454
0.281
0.108
1.574 (0.907 ,2.733)
Simple mode
254
0.454
0.318
0.155
1.574 (0.843 ,2.939)
Smoking cessation
Inverse variance weighted
18
0.094
0.154
0.543
1.098 (0.812 ,1.486)
MR Egger
18
0.115
0.442
0.799
1.121 (0.472 ,2.667)
Weighted median
18
0.218
0.211
0.303
1.243 (0.822 ,1.880)
Weighted mode
18
0.209
0.244
0.404
1.232 (0.763 ,1.990)
Simple mode
18
0.144
0.305
0.642
1.155 (0.635 ,2.102)
Cigarettes per day
Inverse variance weighted
61
0.119
0.093
0.200
1.127 (0.939 ,1.352)
MR Egger
61
0.137
0.154
0.377
1.147 (0.848 ,1.552)
Weighted median
61
0.038
0.104
0.714
1.039 (0.848 ,1.273)
Weighted mode
61
0.014
0.096
0.885
1.014 (0.840 ,1.223)
Simple mode
61
[minus]0.015
0.253
0.953
0.985 (0.599 ,1.619)
Past tobacco smoking
Inverse variance weighted
95
[minus]0.051
0.113
0.652
0.950 (0.761 ,1.186)
MR Egger
95
[minus]0.061
0.469
0.898
0.941 (0.375 ,2.361)
Weighted median
95
0.125
0.140
0.374
1.133 (0.861 ,1.490)
Weighted mode
95
0.343
0.332
0.303
1.410 (0.736 ,2.700)
Simple mode
95
0.225
0.389
0.564
1.252 (0.584 ,2.685)
Current tobacco smoking
Inverse variance weighted
35
0.675
0.421
0.109
1.963 (0.860 ,4.480)
MR Egger
35
[minus]0.490
1.566
0.757
0.613 (0.028 ,13.205)
Weighted median
35
0.258
0.502
0.607
1.295 (0.484 ,3.464)
Weighted mode
35
[minus]0.086
0.868
0.921
0.917 (0.167 ,5.031)
Simple mode
35
1.307
1.038
0.217
3.694 (0.483 ,28.267)
Abbreviation: MR, Mendelian randomization.
Second, Liu et al identified a second major issue in this study is the choice of data, including the use of outdated datasets and an incomplete consideration of the exposure phenotype. In response to their point about outdated datasets, we employed the Round 10 VTE GWAS (genome-wide association study) summary statistics released in 2023 by FinnGen in our current response, and it is clear that the results ([Table 2]) are also consistent with our previous findings.
Incomplete consideration of smoking phenotypes, which we must recognize as correct, does not affect our results. Please note that we also included this time four smoking phenotypes ([Table 1])[3] published by the GWAS and Sequencing Consortium of Alcohol and Nicotine use (GSCAN) in 2022, and the results showed that the association of all six smoking phenotypes with VTE was not statistically significant ([Table 2]). As for their subtypes, we note that the inverse variance-weighted (IVW) method suggests possible age of initiation of regular smoking–DVT (deep vein thrombosis), ever smoked regularly–DVT, and ever smoked regularly–PE (pulmonary embolism) associations ([Table 2]), but we must point out that the age of initiation of regular smoking–DVT association suffers from too small several instrumental variables and large differences in the estimates of the five methods. As for the ever smoked regularly–DVT and ever smoked regularly–PE associations, none of the methods were significant except for the IVW method. Moreover, considering that the associations of all six smoking phenotypes with VTE were not statistically significant, the significant results in their subtypes should be treated with caution.
In addition, and also due to the third question posed to us by Liu et al, the instrumental variables addressed in our current response did not undergo the exclusion of single nucleotide polymorphisms (SNPs) associated with confounders to control for horizontal pleiotropy as described in our previous studies.[1] For the conflicting association results in VTE and its subtypes, it is likely that bias due to SNPs associated with confounders was attributed.
Publication HistoryReceived: 30 July 2024
Accepted: 15 September 2024
Article published online:
03 October 2024
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