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Lp(a) (lipoprotein[a])-lowering therapy to reduce cardiovascular disease is under investigation in phase 3 clinical trials. High Lp(a) may be implicated in peripheral artery disease (PAD), abdominal aortic aneurysms (AAAs), and major adverse limb events (MALE). The authors investigated the association of high Lp(a) levels and corresponding LPA genotypes with risk of PAD, AAA, and MALE. The authors included 108,146 individuals from the Copenhagen General Population Study. During follow-up, 2,450 developed PAD, and 1,251 AAAs. Risk of MALE was assessed in individuals with PAD at baseline and replicated in the Copenhagen City Heart Study. Higher Lp(a) was associated with a stepwise increase in risk of PAD and AAA (P for trend <0.001). For individuals with Lp(a) levels ≥99th (≥143 mg/dL, ≥307 nmol/L) vs <50th percentile (≤9 mg/dL, ≤17 nmol/L), multivariable-adjusted HRs were 2.99 (95% CI: 2.09-4.30) for PAD and 2.22 (95% CI: 1.21-4.07) for AAA. For individuals with PAD, the corresponding incidence rate ratio for MALE was 3.04 (95% CI: 1.55-5.98). Per 50 mg/dL (105 nmol/L) genetically higher Lp(a) risk ratios were 1.39 (95% CI: 1.24-1.56) for PAD and 1.21 (95% CI: 1.01-1.44) for AAA, consistent with observational risk ratios of 1.33 (95% CI: 1.24-1.43) and 1.27 (95% CI: 1.15-1.41), respectively. In women smokers aged 70 to 79 years with Lp(a) <50th and ≥99th percentile, absolute 10-year risks of PAD were 8% and 21%, and equivalent risks in men 11% and 29%, respectively. For AAA, corresponding risks were 2% and 4% in women, and 5% and 12% in men. High Lp(a) levels increased risk of PAD, AAA, and MALE by 2- to 3-fold in the general population, opening opportunities for prevention given future Lp(a)-lowering therapies. [Display omitted] [ABSTRACT FROM AUTHOR]

Introduction: Observational studies have found lower concentrations of plasma bilirubin in current smokers compared with former and never smokers. However, whether there is a causal relationship between smoking and bilirubin is unknown. In a Mendelian randomization analysis, we tested the hypothesis that higher tobacco consumption is causally associated with lower concentrations of plasma bilirubin.Methods: We genotyped 103 557 individuals aged 20-100 years from the Copenhagen General Population Study for the CHRNA3 rs1051730 genotype, known to be associated with higher tobacco consumption. Tobacco consumption was defined as daily and cumulative tobacco consumption.Results: In observational multivariable-adjusted analyses, a 10 g/day higher daily tobacco consumption was associated with a 0.28 µmol/L (95% confidence interval = 0.20 to 0.35) lower concentration of plasma bilirubin in current smokers, and a 10 pack-year higher cumulative tobacco consumption was associated with a 0.19 µmol/L (0.17 to 0.21) lower concentration of plasma bilirubin in former and current smokers. Using the CHRNA3 rs1051730 genotype as a proxy for daily and cumulative tobacco consumption, the difference in plasma bilirubin per T-allele was -0.12 µmol/L (-0.23 to -0.002) in current smokers and -0.09 µmol/L (-0.15 to -0.01) in current and former smokers combined. Furthermore, observationally bilirubin concentrations increased with time from smoking cessation in former smokers.Conclusion: Higher daily and cumulative tobacco consumption were associated with lower concentrations of plasma bilirubin in observational and genetic analyses, suggesting that the association is causal.Implications: Our results are compatible with two possible interpretations of previous observational studies, either that bilirubin is a mediator of smoking-induced respiratory disease or that the association between plasma bilirubin and respiratory disease stems from residual confounding because of smoking. Future studies should examine whether bilirubin is a causal risk factor for respiratory disease, or merely a marker of smoking status. [ABSTRACT FROM AUTHOR]

Background: Urate is a strong antioxidant in plasma and may protect against lung function impairment. We tested the hypothesis that high plasma urate is causally associated with better lung function and low risk of respiratory symptoms and COPD.Methods: We measured lung function and plasma urate in 114 979 individuals from the Copenhagen City Heart Study and the Copenhagen General Population Study and genotyped for SLC2A9 rs7442295 and ABCG2 rs2231142 variants, previously associated with high plasma urate, in 110 152 individuals.Results: In the two studies combined, multivariable-adjusted 100 µmol/L higher plasma urate was associated with -1.54% (95% CI -1.67 to -1.40) lower FEV1 % predicted and -1.57% (95% CI -1.69 to -1.44) lower FVC % predicted observationally; the corresponding estimates for genetically determined 100 µmol/L higher plasma urate were -0.46% (95% CI -1.17 to 0.25) and -0.40% (95% CI -1.03 to 0.23). High plasma urate was also associated with higher risk of respiratory symptoms; however, genetically determined high plasma urate was not associated with respiratory symptoms. Finally, we identified 14 151 individuals with COPD and found ORs of 1.08 (95% CI 1.06 to 1.11) for COPD observationally and 1.01 (95% CI 0.88 to 1.15) genetically per 100 µmol/L higher plasma urate.Conclusion: High plasma urate was associated with worse lung function and higher risk of respiratory symptoms and COPD in observational analyses; however, genetically high plasma urate was not associated with any of these outcomes. Thus, our data do not support a direct causal relationship. [ABSTRACT FROM AUTHOR]

Background: It is unknown if an unhealthy diet can affect the risk of developing psoriasis., Objectives: We hypothesised that individuals with an unhealthy diet have increased risk of prevalent and incident psoriasis., Methods: We included 105,332 adults from the Copenhagen General Population Study, who were invited between 2003 and 2015. Response-rate was 43%. An unhealthy versus healthy diet was defined according to adherence to general national dietary guidelines. The participants were grouped into low, intermediate, and high adherence to general national dietary guidelines based on information from a food frequency questionnaire. Identification of psoriasis was made using ICD codes., Results: Of the 105,332 individuals, 580 had a diagnosis of psoriasis at the time of enrolment and 640 received a diagnosis during the median follow-up of 9 years. Risk of prevalent psoriasis increased according to non-adherence to general national dietary guidelines in a stepwise manner with an age and sex adjusted odds ratio of 1.70 (95% confidence interval 1.26-2.30) in individuals with low vs. high adherence to dietary guidelines. Results were similar in a multivariable adjusted model. Prospective analyses adjusted for age and sex showed a weak association between non-adherence to dietary guidelines and risk of incident psoriasis (P for trend 0.04). This association disappeared, when adjusting for multiple confounders (P for trend 0.50)., Conclusions: Although individuals with psoriasis have an unhealthier diet, diet alone does not appear to independently increase the risk of developing psoriasis., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Complement C3 plays a role in asthma development and severity. We tested the hypothesis that high plasma complement C3 concentration is associated with high risks of asthma hospitalisation and exacerbation.We prospectively assessed the risk of asthma hospitalisation in 101 029 individuals from the Copenhagen General Population Study with baseline measurements of plasma complement C3, and genotyped for rs1065489, rs429608 and rs448260 determining levels of complement C3. Risk of asthma exacerbation was further assessed in 2248 individuals with allergic asthma.The multivariable adjusted hazard ratio of asthma hospitalisation was 1.23 (95% CI 1.04-1.45) for individuals in the highest tertile (>1.19 g·L -1 ) of plasma complement C3 compared with those in the lowest tertile (<1.03 g·L -1 ). The C3 rs448260 genotype was associated with risk of asthma hospitalisation with an observed hazard ratio of 1.17 (95% CI 1.06-1.28) for the CC genotype compared with the AA genotype. High plasma complement C3 was associated with high levels of blood eosinophils and IgE (p for trends ≤6×10 -9 ), but only the SKIV2L rs429608 genotype was positively associated with blood eosinophil count (p=3×10 -4 ) and IgE level (p=3×10 -4 ). In allergic asthma, the multivariable adjusted incidence rate ratio for risk of exacerbation was 1.69 (95% CI 1.06-2.72) for individuals in the highest plasma complement C3 tertile (>1.24 g·L -1 ) versus the lowest (<1.06 g·L -1 ).In conclusion, a high concentration of plasma complement C3 was associated with a high risk of asthma hospitalisation in the general population and with a high risk of asthma exacerbation in individuals with allergic asthma. Our findings support a causal role of the complement system in asthma severity., Competing Interests: Conflict of interest: S. Vedel-Krogh has nothing to disclose. Conflict of interest: K.L. Rasmussen has nothing to disclose. Conflict of interest: B.G. Nordestgaard has nothing to disclose. Conflict of interest: S.F. Nielsen has nothing to disclose., (Copyright ©ERS 2021.)

Background: Genome-wide association studies have identified numerous genetic regions that influence cross-sectional lung function. Longitudinal decline in lung function also includes a heritable component but the genetic determinants have yet to be defined., Objectives: We aimed to determine whether regions associated with cross-sectional lung function were also associated with longitudinal decline and to seek novel variants which influence decline., Methods: We analysed genome-wide data from 4167 individuals from the Busselton Health Study cohort, who had undergone spirometry (12 695 observations across eight time points). A mixed model was fitted and weighted risk scores were calculated for the joint effect of 26 known regions on baseline and longitudinal changes in FEV 1 and FEV 1 /FVC. Potential additional regions of interest were identified and followed up in two independent cohorts., Results: The 26 regions previously associated with cross-sectional lung function jointly showed a strong effect on baseline lung function (p=4.44×10 -16 for FEV 1 /FVC) but no effect on longitudinal decline (p=0.160 for FEV 1 /FVC). This was replicated in an independent cohort. 39 additional regions of interest (48 variants) were identified; these associations were not replicated in two further cohorts., Conclusions: Previously identified genetic variants jointly have a strong effect on cross-sectional lung function in adults but little or no effect on the rate of decline of lung function. It is possible that they influence COPD risk through lung development. Although no genetic variants have yet been associated with lung function decline at stringent genome-wide significance, longitudinal change in lung function is heritable suggesting that there is scope for future discoveries., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)