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Background: To investigate the association between cigarette smoking, smoking cessation and the trajectory of cardiometabolic multimorbidity (CMM), and further to examine the association of age at smoking initiation and smoking cessation with CMM. Methods: This study included 298,984 UK Biobank participants without cardiometabolic diseases (CMDs) (including type 2 diabetes, coronary heart diseases, stroke, and hypertension) at baseline. Smoking status was categorized into former, current, and never smokers, with age at smoking initiation and smoking cessation as a proxy for current and former smokers. The multi-state model was performed to evaluate the association between cigarette smoking, smoking cessation and CMM. Results: During a median follow-up of 13.2 years, 59,193 participants developed first cardiometabolic disease (FCMD), 14,090 further developed CMM, and 16,487 died. Compared to former smokers, current smokers had higher risk at all transitions, with hazard ratio (95% confidence interval) = 1.59 (1.55 ∼ 1.63) vs. 1.18 (1.16 ∼ 1.21) (P = 1.48 × 10− 118) from health to FCMD, 1.40 (1.33 ∼ 1.47) vs. 1.09 (1.05 ∼ 1.14) (P = 1.50 × 10− 18) from FCMD to CMM, and 2.87 (2.72 ∼ 3.03) vs. 1.38 (1.32 ∼ 1.45) (P < 0.001) from health, 2.16 (1.98 ∼ 2.35) vs. 1.25 (1.16 ∼ 1.34) (P = 1.18 × 10− 46) from FCMD, 2.02 (1.79 ∼ 2.28) vs. 1.22 (1.09 ∼ 1.35) (P = 3.93 × 10− 17) from CMM to death; whereas quitting smoking reduced the risk attributed to cigarette smoking by approximately 76.5% across all transitions. Reduced risks of smoking cessation were also identified when age at quitting smoking was used as a proxy for former smokers. Conclusions: Cigarette smoking was associated with a higher risk of CMM across all transitions; however, smoking cessation, especially before the age of 35, was associated with a significant decrease in CMM risk attributed to cigarette smoking. [ABSTRACT FROM AUTHOR]

Background: The relation of social deprivation with single cardiometabolic disease (CMD) was widely investigated, whereas the association with cardiometabolic multi-morbidity (CMM), defined as experiencing more than two CMDs during the lifetime, is poorly understood. Methods: We analyzed 345,417 UK Biobank participants without any CMDs at recruitment to study the relation between social deprivation and four CMDs including type II diabetes (T2D), coronary artery disease (CAD), stroke and hypertension. Social deprivation was measured by Townsend deprivation index (TDI), and CMM was defined as occurrence of two or more of the above four diseases. Multivariable Cox models were performed to estimate hazard ratios (HRs) per one standard deviation (SD) change and in quartile (Q1-Q4, with Q1 as reference), as well as 95% confidence intervals (95% CIs). Results: During the follow up, 68,338 participants developed at least one CMD (median follow up of 13.2 years), 16,225 further developed CMM (median follow up of 13.4 years), and 18,876 ultimately died from all causes (median follow up of 13.4 years). Compared to Q1 of TDI (lowest deprivation), the multivariable adjusted HR (95%CIs) of Q4 (highest deprivation) among participants free of any CMDs was 1.23 (1.20 ~ 1.26) for developing one CMD, 1.42 (1.35 ~ 1.48) for developing CMM, and 1.34 (1.27 ~ 1.41) for all-cause mortality. Among participants with one CMD, the adjusted HR (95%CIs) of Q4 was 1.30 (1.27 ~ 1.33) for developing CMM and 1.34 (1.27 ~ 1.41) for all-cause mortality, with HR (95%CIs) = 1.11 (1.06 ~ 1.16) for T2D patients, 1.07 (1.03 ~ 1.11) for CAD patients, 1.07 (1.00 ~ 1.15) for stroke patients, and 1.24 (1.21 ~ 1.28) for hypertension patients. Among participants with CMM, TDI was also related to the risk of all-cause mortality (HR of Q4 = 1.35, 95%CIs 1.28 ~ 1.43). Conclusions: We revealed that people living with high deprived conditions would suffer from higher hazard of CMD, CMM and all-cause mortality. [ABSTRACT FROM AUTHOR]

Trans-ethnic genome-wide association studies have revealed that many loci identified in European populations can be reproducible in non-European populations, indicating widespread trans-ethnic genetic similarity. However, how to leverage such shared information more efficiently in association analysis is less investigated for traits in underrepresented populations. We here propose a statistical framework, trans-ethnic genetic risk score informed gene-based association mixed model (GAMM), by hierarchically modeling single-nucleotide polymorphism effects in the target population as a function of effects of the same trait in well-studied populations. GAMM powerfully integrates genetic similarity across distinct ancestral groups to enhance power in understudied populations, as confirmed by extensive simulations. We illustrate the usefulness of GAMM via the application to 13 blood cell traits (i.e. basophil count, eosinophil count, hematocrit, hemoglobin concentration, lymphocyte count, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, mean corpuscular volume, monocyte count, neutrophil count, platelet count, red blood cell count and total white blood cell count) in Africans of the UK Biobank (n  = 3204) while utilizing genetic overlap shared in Europeans (n  = 746 667) and East Asians (n  = 162 255). We discovered multiple new associated genes, which had otherwise been missed by existing methods, and revealed that the trans-ethnic information indirectly contributed much to the phenotypic variance. Overall, GAMM represents a flexible and powerful statistical framework of association analysis for complex traits in underrepresented populations by integrating trans-ethnic genetic similarity across well-studied populations, and helps attenuate health inequities in current genetics research for people of minority populations. [ABSTRACT FROM AUTHOR]

The effects of air pollutants on cardiometabolic diseases (CMDs) have been widely explored, whereas their influences on cardiometabolic multi-morbidity (CMM) were not clear. We employed the UK Biobank cohort (N = 317,160) to study the association between six air pollutants (PM 2.5 , PM 10 , PM 2.5-10 , PM 2.5abs , NO 2 , and NO x) and four CMDs including type II diabetes (T2D), coronary artery disease (CAD), stroke and hypertension. CMM was defined as occurrence of two or more of the four diseases. Multi-state Cox models were performed to estimate hazard ratio (HR) and its 95% confidence interval (95%CI). During a median follow-up of 12.8 years, 52,211 participants developed only one CMD, 15,446 further developed CMM, and 16,861 ultimately died. It was demonstrated that per interquartile range increase (IQR) increases in PM 2.5 , PM 10 , PM 2.5-10 , PM 2.5abs , NO 2 , and NO x would increase 12% (9%–15%), 4% (1%–7%), 3% (1%–6%), 7% (4%–10%), 11% (8%–15%) and 10% (7%–13%) higher risk of developing one CMD from health baseline; 7% (2%–12%), 8% (3%–13%), 6% (2%–11%), 10% (5%–15%), 13% (7%–18%) and 10% (5%–15%) greater risk of occurring CMM from one CMD baseline; and 11% (−2%∼26%), 22% (7%–38%), 17% (3%–32%), 31% (16%–49%), 33% (17%–51%) and 32% (17%–50%) larger risk of causing death from CMM baseline, respectively. We revealed that people living in areas with high air pollution suffered from higher hazard of CMD, CMM and all-cause mortality; our findings implied keeping clean air was an effective approach to prevent or mitigate initiation, progression, and death from healthy to CMDs and from CMDs to CMM. • A total of 317,160 UK Biobank participants enrolled from 2006 to 2010 were included and followed-up until July 19, 2022, with a median follow-up of 12.8 years. • Air pollution presented significantly long-term adverse effects on the incidence, progress, and prognosis of CMM. • The highest hazard ratio was observed for T2D patients to develop CMM induced by air pollution, and NO 2 presented the highest hazard ratio to cause CMM among people with one CMD and lead to death among people with CMM. [ABSTRACT FROM AUTHOR]

Competing Interests: Conflict of interest: none declared.