To: JH
From: AKV
Subject: MR pain
Date: 2018-08-01
Follow-up from previous work:
Task: explore relationship between statin use and mi/stroke (since most with a stroke or mi will be on a statin)
Table 1. Proportion of MI and stroke sufferers taking a statin at baseline
| No statin | Statin | |
|---|---|---|
| Had MI | 1,928 (16.6%) | 9,666 (83.4%) |
| Had stroke | 2,354 (30.7%) | 5,303 (69.3%) |
Collinearity diagnostics are not well-defined for categeorical predictors, but I fitted models without MI and stroke and the effect of statins is very stable.
Task: Explore association of statin use and pain constructs in full UKB sample (not QC'd subsample)
Table 2. Regression of musculoskeletal pain on statin use and other individual-level characteristics in full UKB sample (blockwise addition of predictors)
| Effect of statins | ||
|---|---|---|
| n | OR | |
| Just statins | 500268 | 1.361 |
| + age and sex | 500268 | 1.406 |
| + BMI | 498073 | 1.289 |
| + SBP and DBP | 497621 | 1.278 |
| + alcohol and smoking | 495392 | 1.246 |
| + stroke, MI, and angina | 494490 | 1.148 |
| + hypertension & diabetes | 493231 | 1.058 |
| + aspirin & bp meds | 493231 | 1.071 |
Table 3. Regression of general pain on statin use and other individual-level characteristics in full UKB sample (blockwise addition of predictors)
| Effect of statins | ||
|---|---|---|
| n | OR | |
| Just statins | 501778 | 1.263 |
| + age and sex | 501778 | 1.358 |
| + BMI | 499514 | 1.203 |
| + SBP and DBP | 499055 | 1.199 |
| + alcohol and smoking | 496108 | 1.173 |
| + stroke, MI, and angina | 495062 | 1.077 |
| + hypertension & diabetes | 493784 | 1.005 |
| + aspirin & bp meds | 493784 | 1.003 |
Table 4. Regression of arthritic pain on statin use and other individual-level characteristics in full UKB sample (blockwise addition of predictors)
| Effect of statins | ||
|---|---|---|
| n | OR | |
| Just statins | 501778 | 1.387 |
| + age and sex | 501778 | 1.319 |
| + BMI | 499514 | 1.149 |
| + SBP and DBP | 499055 | 1.140 |
| + alcohol and smoking | 496108 | 1.120 |
| + stroke, MI, and angina | 495062 | 1.064 |
| + hypertension & diabetes | 493784 | 1.020 |
| + aspirin & bp meds | 493784 | 1.030 |
Question for JH: Other known/possible risk factors for pain: SES, employment status, physical activity/exercise, mental health, sleep, nutrition, race - should I be considering these as well?
Task: examine prevalence of pain by two functional SNPs: rs12916 and rs17238484
**Notes:**
- Dosage was recoded to represent number of LDL lowering alleles
- rs17238484 has non-integer dosage values, so frequency table is not included
Table 5. Baseline prevalence of musculoskeletal pain, by dosage in rs12916
| Allele count | No MSK pain | MSK pain | Overall | P-value (Chi-Square) |
|---|---|---|---|---|
| 0 | 40,044 (16.1%) | 14,085 (16.0%) | 54,129 (16.1%) | 0.550 |
| 1 | 119,365 (47.9%) | 42,436 (48.1%) | 161,801 (48.0%) | |
| 2 | 89,573 (36.0%) | 31,617 (35.9%) | 121,190 (35.9%) |
Table 6. Association of functional SNPs and musculoskeletal pain
| SNP | Participants | EAF | Cases | Controls | OR (95% CI) | P |
|---|---|---|---|---|---|---|
| rs12916 | 337120 | 0.599 | 88138 | 248982 | 1.000 (0.989,1.011) | 0.997 |
| rs17238484 | 337120 | 0.775 | 88138 | 248982 | 1.005 (0.992,1.018) | 0.430 |
Task : Create polygenic risk score using SNPs from Ference et al.
Fig1. Distribution of HMGCR polygenic risk score using SNPs from Ference et al. (2016)
UKB participants below the median on the HMGCR GRS were slightly more likely (1% absolute difference) to use a statin compared to those above the median (Table 7).
Table 7. Proportion of UKB participants who reported using a statin, stratified by genetic LDL-lowering risk (below or above the median)
| GRS score | No statin | Statin | Overall | P |
|---|---|---|---|---|
| Below median | 142,421 (83.1%) | 29,044 (16.9%) | 171,465 | <.001 |
| Above median | 139,621 (84.1%) | 26,416 (15.9%) | 166,037 |
Table 8. Association of genetically determined statin use (using median-split GRS) for each of the pain constructs
| Phenotype | Participants | Controls | Cases | OR (95% CI) | P |
|---|---|---|---|---|---|
| Musculoskeletal pain | 337120 | 248982 (73.9) | 88138 (26.1) | 1.004 (0.989,1.020) | 0.609 |
| General pain | 337533 | 133781 (39.6) | 203752 (60.4) | 0.998 (0.984,1.012) | 0.748 |
| Arthritic pain | 337533 | 198232 (58.7) | 139301 (41.3) | 0.999 (0.985,1.013) | 0.878 |
Table 9. Associationof genetically determined statin use (using continuous GRS) for each of the pain constructs
| Phenotype | Participants | Controls | Cases | OR (95% CI) | P |
|---|---|---|---|---|---|
| Musculoskeletal pain | 337120 | 248982 (73.9) | 88138 (26.1) | 1.018 (0.964,1.075) | 0.525 |
| General pain | 337533 | 133781 (39.6) | 203752 (60.4) | 0.998 (0.950,1.047) | 0.919 |
| Arthritic pain | 337533 | 198232 (58.7) | 139301 (41.3) | 1.000 (0.953,1.050) | 0.986 |
Table 10. Baseline Characteristics of Participants, According to HMGCR Genetic Score (N = 337,534)
| Characteristic | Below median score (N=171,480) | Above median (N=166,054) | P-value |
|---|---|---|---|
| Male - no. (%) | 79,426 (46.3%) | 76,841 (46.3%) | 0.801 |
| Age - mean (yrs) | 56.9 ± 8.0 | 56.8 ± 8.0 | 0.003 |
| BMI - mean??? | 27.3 ± 4.7 | 27.5 ± 4.8 | <.001 |
| Biomarkers | |||
| Systolic blood pressure - mean (mm Hg) | 138 ± 19.0 | 138 ± 19.0 | 0.627 |
| Diastolic blood pressure - mean (mm Hg) | 82.3 ± 10.1 | 82.3 ± 10.1 | 0.390 |
| Ever smoked - no. (%) | 77,238 (45.2%) | 75,264 (45.5%) | 0.084 |
| Ever drank - no. (%) | 166,077 (96.9%) | 160,769 (96.9%) | 0.819 |
| Previous disease - no. (%) | |||
| MI | 3,967 (2.32%) | 3,832 (2.31%) | 0.909 |
| Angina | 5,449 (3.18%) | 5,181 (3.12%) | 0.336 |
| Stroke | 2,576 (1.50%) | 2,628 (1.58%) | 0.058 |
| Hypertension | 46,415 (27.1%) | 44,723 (27.0%) | 0.371 |
| Diabetes | 8,046 (4.70%) | 8,177 (4.93%) | 0.002 |
| Prior medication - no. (%) | |||
| Blood pressure | 35,607 (20.9%) | 34,509 (20.9%) | 0.964 |
| Aspirin | 24,027 (14.1%) | 22,983 (14.0%) | 0.176 |
Table 11. SNPs used in HMGCR risk scores (Ference vs Katerina's diabetes work)
| Ference et al. | Katerina |
|---|---|
| rs12916 | rs12916 |
| rs5909 | rs3857388 |
| rs2303152 | rs10515198 |
| rs2006760 | rs12173076 |
| rs17238484 | rs7711235 |
| rs10066707 |