PCSK9 genetic variants and risk of vascular and non-vascular diseases in Chinese and UK populations

Abstract

Aims: Lowering low-density lipoprotein cholesterol (LDL-C) through PCSK9 inhibition represents a new therapeutic approach to preventing and treating cardiovascular disease (CVD). Phenome-wide analyses of PCSK9 genetic variants in large biobanks can help to identify unexpected effects of PCSK9 inhibition.

Methods and results: In the prospective China Kadoorie Biobank, we constructed a genetic score using three variants at the PCSK9 locus associated with directly measured LDL-C [PCSK9 genetic score (PCSK9-GS)]. Logistic regression gave estimated odds ratios (ORs) for PCSK9-GS associations with CVD and non-CVD outcomes, scaled to 1 SD lower LDL-C. PCSK9-GS was associated with lower risks of carotid plaque [n = 8340 cases; OR = 0.61 (95% confidence interval: 0.45-0.83); P = 0.0015], major occlusive vascular events [n = 15 752; 0.80 (0.67-0.95); P = 0.011], and ischaemic stroke [n = 11 467; 0.80 (0.66-0.98); P = 0.029]. However, PCSK9-GS was also associated with higher risk of hospitalization with chronic obstructive pulmonary disease [COPD: n = 6836; 1.38 (1.08-1.76); P = 0.0089] and with even higher risk of fatal exacerbations amongst individuals with pre-existing COPD [n = 730; 3.61 (1.71-7.60); P = 7.3 × 10-4]. We also replicated associations for a PCSK9 variant, reported in UK Biobank, with increased risks of acute upper respiratory tract infection (URTI) [pooled OR after meta-analysis of 1.87 (1.38-2.54); P = 5.4 × 10-5] and self-reported asthma [pooled OR of 1.17 (1.04-1.30); P = 0.0071]. There was no association of a polygenic LDL-C score with COPD hospitalization, COPD exacerbation, or URTI.

Conclusion: The LDL-C-lowering PCSK9 genetic variants are associated with lower risk of subclinical and clinical atherosclerotic vascular disease but higher risks of respiratory diseases. Pharmacovigilance studies may be required to monitor patients treated with therapeutic PCSK9 inhibitors for exacerbations of respiratory diseases or respiratory tract infections.

Lay summary: Genetic analyses of over 100 000 participants of the China Kadoorie Biobank, mimicking the effect of new drugs intended to reduce cholesterol by targeting the PCSK9 protein, have identified potential severe effects of lower PCSK9 activity in patients with existing respiratory disease.PCSK9 genetic variants that are associated with lower cholesterol and reduced rates of cardiovascular disease are also associated with increased risk of a range of respiratory diseases, including asthma, upper respiratory tract infections, and hospitalization with chronic obstructive pulmonary disease (COPD).These genetic variants are not associated with whether or not individuals have COPD; instead, they are specifically associated with an increase in the chance of those who already have COPD being hospitalized and even dying, suggesting that careful monitoring of such patients should be considered during development of and treatment with anti-PCSK9 medication.

Keywords: Chronic obstructive pulmonary disease; Exacerbation; Mendelian randomization; PCSK9 inhibition; Target-mediated adverse effects; Upper respiratory tract infection.

Figure 1

Associations of PCSK9 genetic score with major blood lipids and apolipoproteins. Estimates are standardized beta coefficients from linear regressions of the weighted PCSK9 genetic score, scaled to a 1 SD lowering of low-density lipoprotein cholesterol, calculated as an inverse-variance-weighted average of region-specific estimates with adjustment for age, age-squared, sex, ascertainment, and region-specific principal components. CI, confidence interval; HDL, high-density lipoprotein; LDL, low-density lipoprotein.

Figure 2

Associations of genetic scores for (A) PCSK9 and (B) low-density lipoprotein cholesterol with risk of vascular and non-vascular disease endpoints. Odds ratios are estimated using logistic regression of the weighted PCSK9 and low-density lipoprotein cholesterol genetic scores, each scaled to the effect corresponding to a predicted 1 SD lowering of low-density lipoprotein cholesterol, calculated as the inverse-variance-weighted mean of region-specific estimates with adjustment for age, age-squared, sex, ascertainment, and region-specific principal components. CI, confidence interval; COPD, chronic obstructive pulmonary disease; LDL-C, low-density lipoprotein cholesterol; OR, odds ratio.

Figure 3

Replication in China Kadoorie Biobank of previously reported associations in UK Biobank of PCSK9 genetic scores with disease outcomes. Estimates in UK Biobank (open boxes) originate from data published by Rao et al. and are scaled to a corresponding 1 SD lowering of low-density lipoprotein cholesterol. Odds ratios in China Kadoorie Biobank (filled boxes) are estimated using logistic regression of the weighted PCSK9 genetic score, scaled to a 1 SD lowering of low-density lipoprotein cholesterol, calculated as an inverse-variance-weighted average of region-specific estimates with adjustment for age, age-squared, sex, ascertainment, and region-specific principal components. Trans-ancestry estimates (diamonds) are derived from inverse-variance-weighted fixed-effect meta-analysis. CI, confidence interval; CKB, China Kadoorie Biobank; OR, odds ratio.

Figure 4

Associations of PCSK9 and low-density lipoprotein cholesterol genetic scores with respiratory disease endpoints. Odds ratios are estimated using logistic regression of the weighted PCSK9 genetic score, scaled to 1 SD lower low-density lipoprotein cholesterol, calculated as an inverse-variance-weighted average of region-specific estimates with adjustment for age, age-squared, sex, ascertainment, and region-specific principal components. Prevalent chronic obstructive pulmonary disease defined on basis of spirometry (see Methods). COPD exacerbations are incident events occurring in individuals with spirometry-defined prevalent chronic obstructive pulmonary disease. P-het is the P-value from a test for heterogeneity for estimates of PCSK9 and low-density lipoprotein cholesterol genetic instruments. CI, confidence interval; COPD, chronic obstructive pulmonary disease; LDL-C, low-density lipoprotein cholesterol; OR, odds ratio; URTI, upper respiratory tract infection.