RATIONALE & OBJECTIVE
Chronic kidney disease (CKD) is a major cause of death in Mexico and blood pressure (BP) may be an important contributor. This study investigated the associations of BP with CKD, albuminuria, and death from kidney failure.
STUDY DESIGN
Prospective cohort study.
SETTING & PARTICIPANTS
133,470 adults aged ≥35 to <85 years without CKD or other chronic disease (except diabetes), recruited from two districts of Mexico City between 1998 and 2004, and who survived ≥5 years after recruitment. A random subset of 9198 underwent additional evaluation 2015-2019.
EXPOSURES
Systolic BP (SBP), diastolic BP (DBP) and hypertension (participant report of taking blood pressure lowering medication or BP ≥140/90 mm Hg).
OUTCOMES
Kidney failure mortality during follow-up, and CKD (self-report and/or eGFR <60 mL/min/1.73m2) and albuminuria at the time of repeat clinical evaluation.
ANALYTICAL APPROACH
Multivariable Cox regression for the association of BP with kidney failure mortality and multivariable logistic regression for the association of baseline BP with CKD and albuminuria at the time of re-evaluation.
RESULTS
Among all participants, SBP showed a continuous "log-linear" association with kidney failure mortality; each 20 mm Hg lower SBP being associated with 24% lower risk at ages 40-84 years (kidney failure death hazard ratio [HR] 0.76, 95% confidence interval 0.69-0.84). The association was stronger among those without diabetes (HR 0.54, 0.45-0.69) than with diabetes (HR 0.90, 0.80-1.01) but the absolute excess risk associated with higher BP was similar in these subgroups. Hypertension accounted for 9% of kidney failure deaths. Among those re-evaluated, 6% had developed CKD and 25% had albuminuria. 20 mm Hg lower baseline SBP was associated with 24% lower odds of both CKD (odds ratio [OR] 0.76, 0.68-0.85) and albuminuria (OR 0.76, 0.68-0.84) at the time of re-evaluation. Results were similar for DBP.
LIMITATIONS
Baseline urine samples were unavailable and kidney function trends over time could not be assessed.
CONCLUSIONS
This large prospective study in Mexican adults highlights elevated BP as a major modifiable risk factor for kidney failure mortality, CKD, and albuminuria.
Doreen Zhu, P. Kuri-Morales, Rachel Wade et al.· American Journal of Kidney D...· 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
