Table 1.
Selected Mendelian randomization studies on dietary/lifestyle factors and biomarkers.
| Author, year | Study design, subjects | Exposure variables | Gene, variants | Outcomes | Major findings |
|---|---|---|---|---|---|
| Minelli, (2004)18 | Meta-analysis | Homocysteine | MTHFR C677T (rs1801133) | CHD | Estimated OR for CHD per unit (1.0 μmol/liter) change in homocysteine level was 1.07 (1.02–1.14) |
| Lewis, (2005)25 | Meta-analysis | Alcohol | ALDH2, glutamic acid to lysine variant at residue 487 | Esophageal cancer | Expected relative risk (RR = 2.54; *1*1 vs *2*2 genotypes) was comparable to the meta-analysis on the unconfounded genetic association (RR = 2.77) |
| Davey Smith, (2005)47 | 3,529 women, 60–79 y | CRP | CRP, rs1800947 | Blood pressure, hypertension | In IV analysis, the estimated causal effect for a doubling of CRP was 0.08 (−6.52–6.69) mmHg for systolic blood pressure and OR for hypertension was 1.03 (0.61–1.73) |
| Casas, (2005)43 | Meta-analysis | Homocysteine | MTHFR C677T (rs1801133) | Stroke | The genetic associations (OR = 1.26, 1.14–1.40) for TT vs. CC homozygotes were similar to the expected OR of 1.20 (P = 0.29) |
| Timpson, (2005)15 | 3,218 women, 60–79 y | CRP | CRP haplotype; rs1800947, rs1130864, and rs1205 | Metabolic syndrome | Linear regression and IV analysis gave conflicting results for the associations of CRP with BMI (P = 0.0002), IR (P = 0.0139), triglycerides (P = 0.0313), and HDL-C (P = 0.0688) |
| Keavney, (2006)42 | 3,460 (from 8,145) men and women, 30–64 y; and meta-analysis | Fibrinogen | FGB (FIBB), –148C/T (rs# not available) | MI | Fibrinogen corresponding to the genetic effect of 0.14 g/l difference per allele was not associated with MI risk |
| Casas, (2006)49 | 4,659 (association with CRP) and 6,201 (association with MI) men | CRP | CRP, rs1130864 | Coronary event | The observed OR for non-fatal MI corresponding to the genetic difference in CRP (0.68 mg/l) was 1.01 (0.74–1.38), lower than expected ORs (>1.20) based on observed data or meta-analysis |
| Sacerdote, (2007)29 | 634 healthy men and women | Dairy and cruciferous vegetables | LCT rs4988235; and TAS2R38 rs713598 and rs1726866 | Cancer | LCT variant was associated with consumption of dairy products (ice cream, P = 0.004); the haplotypes of TAS2R38 were related to cruciferous vegetable intake (P = 0.02) |
| Kivimaki, (2007)16 | 1,609 men and women, 24–39 y | CRP | CRP, rs2794521, rs3091244, rs1800947, rs1130864, rs1205 | CIMT | Associations from standard regression analysis and IV analysis were conflicting |
| Qi, (2007)41 | 1,348 (from 1730) women | IL-6 | IL6R, rs8192284 | Type 2 diabetes | IV analysis estimate of diabetes risk 1.59 (0.45–5.66) per unit log(IL-6) was similar to the estimate from logistic regression analysis, 1.78 (1.49–2.10) |
| Frayling, (2007)40 | 1,671 men and women, 65–80 y | IL-18 | IL18, rs5744256 | Physical function | IL-18 was significantly associated with Short Physical Performance Battery Score in both logistic regression analysis (P = 0.00016) and IV analysis (P = 0.019) |
| Chen, (2008)19 | Meta-analysis | Alcohol | ALDH2, glutamic acid to lysine variant at residue 487 | Blood pressure and hypertension | IV meta-analysis estimates of the effect of alcohol intake on diastolic blood pressure was 0.16 (0.11–0.21) mmHg per g/d; on systolic blood pressure it was 0.24 (0.16–0.32) mmHg per g/d |
| Kivimaki, (2008)17 | 2,230 men and women; 24–39 y | Body mass index | FTO, rs9939609 | CIMT and atherosclerotic risk factors | Standard regression analysis and IV analysis showed consistency in the association with adult CIMT, systolic blood pressure, and glucose and insulin resistance |
| Brunner, (2008)52 | 4,674 (from 5,274) men and women | CRP | CRP, rs11308641, rs1205, and rs3093077 | HbA1c and HOMA-IR; type 2 diabetes | Association between CRP levels and HbA1c and HOMA-IR obtained from standard regression and IV estimates were different. CRP haplotypes were not associated with diabetes risk in three samples |
| Kivimaki, (2008)51 | 4,435 (from 5,274) men and women | CRP | CRP, rs11308641, rs1205, and rs3093077 | CIMT | No inferred association between CRP and CIMT in IV analysis |
| Linsel-Nitschke, (2008)22 | 1,324 CAD cases and 6,255 controls | LDL-C | LDLR, rs2228671 | CAD | Adjustment for LDL-C levels in Mendelian randomization model abolished the significant association between rs2228671 with CAD |
Abbreviations: ALDH2, aldehyde dehydrogenase 2 family gene; CAD, coronary artery disease; CHD, coronary heart disease; CIMT, carotid intima-media thickness; CRP, C-reactive protein; CRP, CRP gene; FGB, fibrinogen beta chain gene; FTO, fat mass and obesity associated gene; GSTM1, glutathione S-transferase M1 gene; GSTT1, glutathione S-transferase theta 1 gene; HbA1c, hemoglobin A1c; HDL-C, high-density lipoprotein cholesterol; HOMA-IR, homeostasis model assessment insulin resistance; IL-6, interleukin-6; IL6R, IL-6 receptor gene; IL-18, interleukin-18; IL18, IL-18 gene; IV, instrumental variable; LCT, lactase gene; LDL-C, low-density lipoprotein cholesterol; LDLR, low-density lipoprotein receptor gene; MI, myocardial infarction; MTHFR, 5,10-methylenetetrahydrofolate reductase gene; OR, odds ratio; TAS2R38, taste receptor, type 2, member 38 gene.