The evidence between your observational studies and MR analyses was concordant for three outcomes where both meta-analyses of observational studies and MR analyses weren’t statistically significant ( em P? /em ?0.05). 196 MR analyses, covering an array of final results. The overwhelming most the meta-analyses of observational research reported a nominally statistically significant result (95/113, 84.1%); nevertheless, a lot of the meta-analyses shown significant heterogeneity (47.8%), little study results (39.8%) or excess significance (41.6%). Just two final results, cardiovascular mortality and venous thromboembolism, demonstrated convincing proof association with CRP amounts. When evaluating the MR books, we discovered MR research for 53/113 final results analyzed in the observational research meta-analyses but significant support for the causal association with CRP had not been observed for just about any phenotype. Regardless of the dazzling amount of analysis on CRP, convincing evidence for associations and causal results is bound remarkably. Electronic supplementary materials The online edition of this content (10.1007/s10654-020-00681-w) contains supplementary materials, which is open to authorized users. distribution. Excess statistical significance was claimed at two-sided value of the largest study in the meta-analysis was? ?0.05. The associations with gene). The latter approach for selecting instruments is more likely to incorporate invalid instruments that have pleiotropic effects [22]. Indeed, a genome-wide association study (GWAS) of CRP has revealed a large number of genetic variants, which were not specific to CRP, but influence other inflammatory cytokines including interleukin-6 receptor (IL-6R) and interleukin 1 family member 10 (ILF10) [23]. For MR analyses restricted to variants located in the gene, we considered MR evidence as BGB-102 potentially supportive when the main analysis reported a Acute coronary syndrome; Atrial fibrillation; anti-tumor necrosis factor; Ankylosing spondylitis; Assessment in BGB-102 Ankylosing Spondylitis response criteria; Bath Ankylosing Spondylitis Disease Activity Index; Coronary artery disease; Coronary heart disease; confidence interval; Chronic obstructive pulmonary disease; C-reactive protein; Cardiovascular disease; Hazard ratio; Henoch-Sch?nlein purpura; Major Adverse Cardiac Events; Myocardial infarction; Not pertinent; Not significant; Odds ratio; Relative risk; ST-elevation myocardial infarction aRandom-effects refers to summary relative risk (95% CI) BGB-102 using the meta-analysis random-effects model bLargest study (smallest standard error) cgene locus, and 112 used instruments from throughout the genome The SNPs used as instruments varied vastly among studies. The four most commonly used SNPs among the 196 MR associations were rs1130864 (n?=?78; 39.8% of the comparisons), rs1205 (n?=?74; 37.8%), rs2794520 (n?=?74; 37.8%), and rs3093077 (n?=?65; 33.2%); all these variants fall within or close the CRP gene region. Table?2 Health outcome and characteristics of Mendelian randomization studies. Only studies with instruments from your CRP gene are offered. One study is usually selected per end result based on the largest sample sizeone-sample Mendelian randomization; two-sample Mendelian randomization; body mass index; Coronary artery disease; chronic obstructive pulmonary disease; c-reactive protein; diastolic blood pressure; forced expiratory flow; Forced expiratory volume in 1?s; Forced vital capacity; Generalized least squares regression; Geometric Means Ratio; high density lipoprotein; Homeostatic Model Assessment for Insulin Resistance; Hazard ratio; irritable bowel syndrome; individual participant data; Instrumental variable; Inverse variance weighted; imply difference; Myocardial infarction; not reported; odds ratio; published summary data; Relative risk; systolic blood pressure; single nucleotide polymorphism aFull list of Mendelian randomization studies in Additional file bCausal effect estimate of all variants combined cCausal effect em P /em -value Overall, 12 unique phenotypes offered significant associations at a em P? /em ?0.01, of which four (Crohns disease, ischemic heart disease, systolic and diastolic blood pressure) presented significant associations ( em P? /em ?0.01) when the devices were restricted to CRP gene locus (Appendix Furniture?4 and 5). However, impartial MR analyses did not show consistent evidence for Crohns disease and ischemic heart disease, and none of the aforementioned phenotypes experienced support from sensitivity analyses. Nine phenotypes offered significant ( em P? /em ?0.01) causal effect estimates when devices from throughout the genome were considered and of those, only schizophrenia and bipolar disorder presented consistent evidence in sensitivity analyses and in analysis restricted to SNPs within CRP locus, but only at em P? /em ?0.05. Nonetheless, the result on bipolar disorder [113] was not confirmed by an earlier study [107] where MR using only CRP gene SNPs did not reach statistical significance at em P? /em ?0.05. Schizophrenia experienced evidence from independent studies and sensitivity analysis (weighted median and inverse variant weighted estimate), but this was not supported by MR Egger analysis and the sensitivity analysis using only CRP gene SNPs ( em P? /em =?0.04). Overall, only 14 outcomes had evidence available from both MR analyses and meta-analyses of observational studies (Table?3). The evidence between the observational studies and MR analyses was concordant for three outcomes where both meta-analyses of observational studies and MR analyses were not statistically significant ( em P? /em ?0.05). The remaining studies showed various degree of evidence (poor, suggestive, highly suggestive) with meta-analyses of observational studies and no evidence or limited inconsistent evidence from MR. Finally, MR did not support causality for venous thromboembolism whose evidence was graded as strong in the observational meta-analysis evidence..Only studies with instruments from your CRP gene are presented. analyses, covering a wide range of outcomes. The overwhelming majority of the meta-analyses of observational studies reported a nominally statistically significant result (95/113, 84.1%); however, the majority of the meta-analyses displayed substantial heterogeneity (47.8%), small study effects (39.8%) or excess significance (41.6%). Only two outcomes, cardiovascular mortality and venous thromboembolism, showed convincing evidence of association with CRP levels. When examining the MR literature, we found MR studies for 53/113 outcomes examined in the observational study meta-analyses but substantial support for a causal association with CRP was not observed for any phenotype. Despite the striking amount of research on CRP, convincing evidence for associations and causal effects is remarkably limited. Electronic supplementary material The online version of this article (10.1007/s10654-020-00681-w) contains supplementary material, which is available to authorized users. distribution. Excess statistical significance was claimed at two-sided value of the largest study in the meta-analysis was? ?0.05. The associations with gene). The latter approach for selecting instruments is more likely to incorporate invalid instruments that have pleiotropic effects [22]. Indeed, a genome-wide association study (GWAS) of CRP has revealed a large number of genetic variants, which were not specific to CRP, but influence other inflammatory cytokines including interleukin-6 receptor (IL-6R) and interleukin 1 family member 10 (ILF10) [23]. For MR analyses restricted to variants located in the gene, we considered MR evidence as potentially supportive when the main analysis reported a Acute coronary syndrome; Atrial fibrillation; anti-tumor necrosis factor; Ankylosing spondylitis; Assessment in Ankylosing Spondylitis response criteria; Bath Ankylosing Spondylitis Disease Activity Index; Coronary artery disease; Coronary heart disease; confidence interval; Chronic obstructive pulmonary disease; C-reactive protein; Cardiovascular disease; Hazard ratio; Henoch-Sch?nlein purpura; Major Adverse Cardiac Events; Myocardial infarction; Not pertinent; Not significant; Odds ratio; Relative risk; ST-elevation myocardial infarction aRandom-effects refers to summary relative risk (95% CI) using the meta-analysis random-effects model bLargest study (smallest standard error) cgene locus, and 112 used instruments from throughout the genome The SNPs used as instruments varied vastly among studies. The four most commonly used SNPs among the 196 MR associations were rs1130864 (n?=?78; 39.8% of the comparisons), rs1205 (n?=?74; 37.8%), rs2794520 (n?=?74; 37.8%), and rs3093077 (n?=?65; 33.2%); all these variants fall within or close the CRP gene region. Table?2 Health outcome and characteristics of Mendelian randomization studies. Only studies with instruments from the CRP gene are presented. One study is selected per outcome based on the largest sample sizeone-sample Mendelian randomization; two-sample Mendelian randomization; body mass index; Coronary artery disease; chronic obstructive pulmonary disease; c-reactive protein; diastolic blood pressure; forced expiratory flow; Forced expiratory volume in 1?s; Forced vital capacity; Generalized least squares regression; Geometric Means Ratio; high density lipoprotein; Homeostatic Model Assessment for Insulin Resistance; Hazard ratio; irritable bowel syndrome; individual participant data; Instrumental variable; Inverse variance weighted; mean difference; Myocardial infarction; not reported; odds ratio; published summary data; Relative risk; systolic blood pressure; single nucleotide polymorphism aFull list of Mendelian randomization studies in Additional file bCausal effect estimate of all variants combined cCausal effect em P /em -value Overall, 12 distinct phenotypes presented significant associations at a em P? /em ?0.01, of which four (Crohns disease, ischemic heart disease, systolic and diastolic blood pressure) presented significant associations ( em P? /em ?0.01) when the instruments were restricted to CRP gene locus (Appendix Tables?4 and 5). However, independent MR analyses did not show consistent evidence for Crohns disease and ischemic heart disease, and none of the aforementioned phenotypes had support from sensitivity analyses. Nine phenotypes presented significant ( em P? /em ?0.01) causal effect estimates when instruments from throughout the genome were considered and of those, only schizophrenia and bipolar disorder presented consistent evidence in sensitivity analyses and in analysis restricted to SNPs within CRP locus, but only at em P? /em ?0.05. Nonetheless, the result on bipolar disorder [113] was not confirmed by an earlier study [107] where MR using only CRP gene SNPs did not reach statistical significance at em P? /em ?0.05. Schizophrenia had evidence from independent studies and sensitivity analysis.human papillomaviruses and cervix cancer) [115C119]. majority of the meta-analyses displayed substantial heterogeneity (47.8%), small study effects (39.8%) or excess significance (41.6%). Only two outcomes, cardiovascular mortality and venous thromboembolism, showed convincing evidence of association with CRP levels. When examining the MR literature, we found MR studies for 53/113 outcomes examined in the observational study meta-analyses but substantial support for a causal association with CRP was not observed for any phenotype. Despite the striking amount of research on CRP, convincing evidence for associations and causal effects is remarkably limited. Electronic supplementary material The online version of this article (10.1007/s10654-020-00681-w) contains supplementary material, which is available to authorized users. distribution. Extra statistical significance was claimed at two-sided value of the largest study in the meta-analysis was? ?0.05. The associations with gene). The second option approach for selecting instruments is more likely to incorporate invalid instruments that have pleiotropic effects [22]. Indeed, a genome-wide association study (GWAS) of CRP offers revealed a large number of genetic variants, which were not specific to CRP, but influence additional inflammatory cytokines including interleukin-6 receptor (IL-6R) and interleukin 1 family member 10 (ILF10) [23]. For MR analyses restricted to variants located in the gene, we regarded as MR evidence as potentially supportive when the main analysis reported a Acute coronary syndrome; Atrial fibrillation; anti-tumor necrosis element; Ankylosing spondylitis; Assessment in Ankylosing Spondylitis response criteria; Bath Ankylosing Spondylitis Disease Activity Index; Coronary artery disease; Coronary heart disease; confidence interval; Chronic obstructive pulmonary disease; C-reactive protein; Cardiovascular disease; Risk percentage; Henoch-Sch?nlein purpura; Major Adverse Cardiac Events; Myocardial infarction; Not pertinent; Not significant; Odds percentage; Relative risk; ST-elevation myocardial infarction aRandom-effects refers to summary relative risk (95% CI) using the meta-analysis random-effects model bLargest study (smallest standard error) cgene locus, and 112 used instruments from throughout the genome The SNPs used as instruments assorted vastly among studies. The four most commonly used SNPs among the 196 MR associations were rs1130864 (n?=?78; 39.8% of the comparisons), rs1205 (n?=?74; 37.8%), rs2794520 (n?=?74; 37.8%), and rs3093077 (n?=?65; 33.2%); all these variants fall within or close the CRP gene region. Table?2 Health outcome and characteristics of Mendelian randomization studies. Only studies with instruments from your CRP gene are offered. One study is definitely selected per end result based on the largest sample sizeone-sample Mendelian randomization; two-sample Mendelian randomization; body mass index; Coronary artery disease; chronic obstructive pulmonary disease; c-reactive protein; diastolic blood pressure; pressured expiratory flow; Pressured expiratory volume in 1?s; Pressured vital capacity; Generalized least squares regression; Geometric Means Percentage; high denseness lipoprotein; Homeostatic Model Assessment for Insulin Resistance; Risk ratio; irritable bowel syndrome; individual participant data; Instrumental variable; Inverse variance weighted; imply difference; Myocardial infarction; not reported; odds percentage; published summary data; Relative risk; systolic blood pressure; solitary nucleotide polymorphism aFull list of Mendelian randomization studies in Additional file bCausal effect estimate of all variants combined cCausal effect em P /em -value Overall, 12 unique phenotypes offered significant associations at a em P? /em ?0.01, of which four (Crohns disease, ischemic heart disease, systolic and diastolic blood pressure) presented significant associations ( em P? /em ?0.01) when the tools were restricted to CRP gene locus (Appendix Furniture?4 and 5). However, self-employed MR analyses did not show consistent evidence for Crohns disease and ischemic heart disease, and none of the aforementioned phenotypes experienced support from level of sensitivity analyses. Nine phenotypes offered significant ( em P? /em ?0.01) causal effect estimates when tools from throughout the genome were considered and of those, only schizophrenia and bipolar disorder presented consistent evidence in level of sensitivity analyses and in analysis restricted to SNPs within CRP locus, but only at em P? /em ?0.05. Nonetheless, the result on bipolar disorder [113] was not confirmed by an earlier study [107] where MR using only CRP gene SNPs did not reach statistical significance at em P? /em ?0.05. Schizophrenia experienced evidence from independent studies and level of sensitivity analysis (weighted median and inverse variant weighted estimate), but this was not supported by MR Egger analysis and the level of sensitivity analysis using only CRP gene SNPs ( em P? /em =?0.04). Overall, only 14 results had evidence available from both MR analyses and meta-analyses of observational studies (Table?3). The evidence between the observational studies and MR analyses was concordant for three results where both meta-analyses of observational studies and MR analyses were not statistically significant ( em P? /em ?0.05). The remaining studies showed various degree of evidence (fragile, suggestive, highly suggestive) with.Only 14 phenotypes had evidence from meta-analysis of observational studies and MR analyses. the diagnostic value of CRP for infections. We found 113 meta-analytic comparisons of observational studies and 196 MR analyses, covering a wide range of results. The overwhelming majority of the meta-analyses of observational studies reported a nominally statistically significant result (95/113, 84.1%); however, the majority of the meta-analyses displayed substantial heterogeneity (47.8%), small study effects (39.8%) or excess significance (41.6%). Only two outcomes, cardiovascular mortality and venous thromboembolism, showed convincing evidence of association with CRP levels. When examining the MR literature, we found MR studies for 53/113 outcomes examined in the observational study meta-analyses but substantial support for any causal association with CRP was not observed for any phenotype. Despite the striking amount of research on CRP, convincing evidence for associations and causal effects is amazingly limited. Electronic supplementary material The online version of this article (10.1007/s10654-020-00681-w) contains supplementary material, which is available to authorized users. distribution. Excess statistical significance was claimed at two-sided value of the largest study in the meta-analysis was? ?0.05. The associations with gene). The latter approach for selecting instruments is more likely to incorporate invalid instruments that have pleiotropic effects [22]. Indeed, a genome-wide association study (GWAS) of CRP has revealed a large number of genetic variants, which were not specific to CRP, but influence other inflammatory cytokines including interleukin-6 receptor (IL-6R) and interleukin 1 family member 10 (ILF10) [23]. For MR analyses restricted to variants located in the gene, we considered MR evidence as potentially supportive when the main analysis reported a Acute coronary syndrome; Atrial fibrillation; anti-tumor necrosis factor; Ankylosing spondylitis; Assessment in Ankylosing Spondylitis response criteria; Bath Ankylosing Spondylitis Disease Activity Index; Coronary artery disease; Coronary heart disease; confidence interval; Chronic obstructive pulmonary disease; C-reactive protein; Cardiovascular disease; Hazard ratio; Henoch-Sch?nlein purpura; Major Adverse Cardiac Tmem1 Events; Myocardial infarction; Not pertinent; Not significant; Odds ratio; Relative risk; ST-elevation myocardial infarction aRandom-effects refers to summary relative risk (95% CI) using the meta-analysis random-effects model bLargest study (smallest standard error) cgene locus, and 112 used instruments from throughout the genome The SNPs used as instruments varied vastly among studies. The four most commonly used SNPs among the 196 MR associations were rs1130864 (n?=?78; 39.8% of the comparisons), rs1205 (n?=?74; 37.8%), rs2794520 (n?=?74; 37.8%), and rs3093077 (n?=?65; 33.2%); all these variants fall within or close the CRP gene region. Table?2 Health outcome and characteristics of Mendelian randomization studies. Only studies with instruments from your CRP gene are offered. One study is usually selected per end result based on the largest sample sizeone-sample Mendelian randomization; two-sample Mendelian randomization; body mass index; Coronary artery disease; chronic obstructive pulmonary disease; c-reactive protein; diastolic blood pressure; forced expiratory flow; Forced expiratory volume in 1?s; Forced vital capacity; Generalized least squares regression; Geometric Means Ratio; high density lipoprotein; Homeostatic Model Assessment for Insulin Resistance; Hazard ratio; irritable bowel syndrome; individual participant data; Instrumental variable; Inverse variance weighted; imply difference; Myocardial infarction; not reported; odds ratio; published summary data; Relative risk; systolic blood pressure; single nucleotide polymorphism aFull list of Mendelian randomization studies in Additional file bCausal effect estimate of all variants combined cCausal effect em P /em -value Overall, 12 unique phenotypes offered significant associations at a em P? /em ?0.01, of which four (Crohns disease, ischemic heart disease, systolic and diastolic blood pressure) presented significant associations ( em P? /em ?0.01) when the devices were restricted to CRP gene locus (Appendix Furniture?4 and 5). However, impartial MR analyses did not show consistent evidence for Crohns disease and ischemic heart disease, and none of the aforementioned phenotypes experienced support from sensitivity analyses. Nine phenotypes offered significant ( em P? /em ?0.01) causal effect estimates when devices from throughout the genome were considered and of those, only schizophrenia and bipolar disorder presented consistent evidence in sensitivity analyses and in analysis restricted to SNPs within CRP locus, but only at em P? /em ?0.05. Nonetheless, the result on bipolar disorder [113] was not confirmed by an earlier.