Abstract Background Adiposity is associated with increased risk of breast cancer in post-menopausal women, while the association appears to be the inverse among premenopausal women in Western populations, but is unclear for Chinese women. Methods Using data on 284 538 women with no history of cancer, hysterectomy, oophorectomy, or breast surgery at baseline in 2004–8 from the China Kadoorie Biobank (a prospective cohort study), Cox regression was used to estimate adjusted hazard ratios (HRs) for breast cancer and its subtypes by measured body mass index (BMI) and other adiposity measures (waist circumference, fat percentage, waist–hip ratio, fat mass) and by self-reported BMI at age 25 years. Results Mean BMI was 23.8 (3.5 SD) kg/m2 at baseline (mean age 51.4 years) and 21.9 (2.7 SD) kg/m2 at age 25 years. During 10 years of follow-up, there were 2379 incident breast cancer cases. Higher BMI was associated with a higher risk of breast cancer in women who were post-menopausal [HR = 1.35, 95% confidence interval (CI) 1.24–1.47] and premenopausal (HR = 1.13, 95% CI 1.03–1.24) at baseline, but not when censoring at age 50 years to capture mainly premenopausal cancers. Among post-menopausal women, BMI was associated with oestrogen-receptor positive (ER ) (HR = 1.47, 95% CI 1.24–1.74), but not with oestrogen-receptor negative (ER−) breast cancer (HR = 1.02, 95% CI 0.75–1.37). Waist circumference and fat percentage were associated with a higher risk of breast cancer. Conclusion In this cohort of Chinese women, higher levels of general and central adiposity were associated with a higher risk of breast cancer, in both women who were premenopausal and women who were post-menopausal at baseline. Among post-menopausal women, adiposity was associated with ER but not ER − breast cancer.
C. Kartsonaki, N. Wright, I. Millwood et al.· International Journal of Epi...· 0 citations
BACKGROUND
Most drugs target proteins, and proteome-wide genetic analyses in diverse populations could discover potential novel and repurposed targets for improved prevention and treatment of ischemic heart disease (IHD) beyond statin therapy.
OBJECTIVES
The purposes of this study were to use cis-acting single nucleotide polymorphisms (cis-pQTLs) identified for plasma proteins in East Asians and Europeans to discover and validate potential drug targets for IHD.
METHODS
We measured plasma levels of 9,520 (Olink/SomaScan: 2,923/7,297) proteins in a case-cohort study of IHD (1,976 incident cases and 2,001 subcohort controls) in statin-free individuals in the prospective China Kadoorie Biobank (CKB). Genome-wide association studies identified 2,895 (Olink/SomaScan: 1,301/1,594) cis-pQTLs for these proteins in CKB. Two-sample Mendelian randomization (MR) and colocalization analyses assessed associations of all available cis-pQTLs for these proteins with IHD in East Asians (n = 29,319 cases), with further replication in Europeans (n = 181,522 cases) and comparison with findings in previous MR studies.
RESULTS
In CKB observational analyses, a total of 959 (Olink/SomaScan: 426/533) proteins were associated at false discovery rate-corrected P < 0.05 with IHD after adjusting for major IHD risk factors. Two-sample MR analyses provided genetic support for 54 unique (Olink/SomaScan: 36/28) proteins in IHD etiology. Colocalization analyses confirmed shared gene-protein-IHD associations (posterior probability of hypothesis 4 [PPH4] ≥0.8) for 15 unique (Olink/SomaScan: 10/10) proteins, including 8 lipid-related, 3 inflammation-related, 1 blood pressure-related, and 3 alcohol-related proteins in East Asians. In Europeans, MR analyses of 12 non-alcohol-related proteins showed directionally concordant results for 8 proteins, with 5 having strong colocalization evidence of shared gene-protein-IHD associations (PPH4 ≥0.8), including 4 lipid-related (proprotein convertase subtilisin/kexin type 9, LPA, APOE, cadherin-1) and 1 systolic blood pressure-related (fibroblast growth factor 5) protein. However, 4 proteins showed directionally discordant MR results, including 2 lipid-related (APOA5, SORT1) and 1 inflammation-related (transforming growth factor beta 1) proteins with strong colocalization evidence of shared gene-protein-IHD associations (PPH4 ≥0.8). Comparison with previous MR studies revealed little consistency across studies in the number and identity of target proteins for IHD beyond well-established lipid-related (low-density lipoprotein cholesterol, lipoprotein(a), and triglycerides) or inflammation-related (interleukin-6) protein targets.
CONCLUSIONS
The findings support a role for lipid-driven chronic inflammation in IHD etiology, and treatment strategies simultaneously targeting multiple lipid and inflammation pathways should be prioritized for further research to improve drug treatment of IHD beyond statin therapy.
Mohsen Mazidi, N. Wright, A. Pozarickij et al.· Journal of the American Coll...· 1 citation
Although air pollution is recognized as a contributor to accelerated biological aging, its associations with clinically significant liver-related outcomes and the potential role of proteomic aging remain unclear. We aimed to evaluate the associations of key air pollutants with liver-related outcomes and the potential mediating role of proteomic aging clocks. Among 504,006 China Kadoorie Biobank participants without liver disease or cancer, we used time-varying Cox regression to assess associations of PM2.5, PM10, NO2, and warm-season O3, and their mixtures with liver-related events (LRE) and liver-related mortality (LRM), and mediation analyses to examine the role of proteomic aging clocks (i.e., ProtAge). Long-term exposure to PM2.5, PM10, NO2, and warm-season O3 showed significant positive associations with LRE, while PM2.5, PM10, and NO2 were also positively associated with LRM. A 1-unit increment in the weighted pollutant score was associated with an 81% higher risk of LRE (hazard ratio [HR]=1.81 [1.65-1.98]) and a 17% higher risk of LRM (HR=1.17 [1.05-1.31]). Acceleration in ProtAge was associated with higher risks of LRE (HR=1.86 [1.16-2.97]) and LRM (HR=4.43 [3.02-6.50]). ProtAge accounted for an estimated 7.1% and 12.5% of the associations of pollutant mixtures with LRE and LRM, respectively. Among proteins in ProtAge, CD248, GDF15, TNFRSF6B, and XG showed concordant associations in pollutant mixture-protein and protein-LRE analyses. Long-term air pollution was associated with higher risks of clinically significant liver-related outcomes. These findings suggest a possible role of proteomic aging in the association between air pollution and liver-related outcomes, warranting further investigation.