Abstract
As adult height is linked to various health outcomes, further investigation of its causal effects on kidney function later in life is warranted. This study involved a cross-sectional observational analysis and summary-level Mendelian randomization (MR) analysis. First, the observational association between height and estimated GFR determined by creatinine (eGFRcreatinine) or cystatin C (eGFRcystatinC) was investigated in 467,182 individuals aged 40–69 using UK Biobank. Second, the genetic instrument for adult height, as reported by the GIANT consortium, was implemented, and summary-level MR of eGFRcreatinine and CKDcreatinine in a CKDGen genome-wide association study was performed (N = 567,460), with multivariable MR being adjusted for the effects of genetic predisposition on body mass index. To replicate the findings, additional two-sample MR using the summary statistics of eGFRcystatinC and CKDcystatinC in UK Biobank was performed (N = 321,405). In observational analysis, adult height was inversely associated with both eGFRcreatinine (per 1 SD, adjusted beta -1.039, standard error 0.129, P < 0.001) and eGFRcystatinC (adjusted beta -1.769, standard error 0.161, P < 0.001) in a multivariable model adjusted for clinicodemographic, anthropometric, metabolic, and social factors. Moreover, multivariable summary-level MR showed that a taller genetically predicted adult height was causally linked to a lower log-eGFRcreatinine (adjusted beta -0.007, standard error 0.001, P < 0.001) and a higher risk of CKDcreatinine (adjusted beta 0.083, standard error 0.019, P < 0.001). Other pleiotropy-robust sensitivity MR analysis results supported the findings. In addition, similar results were obtained by two-sample MR of eGFRcystatinC (adjusted beta -1.303, standard error 0.140, P < 0.001) and CKDcystatinC (adjusted beta 0.153, standard error 0.025, P < 0.001) in UK Biobank. In conclusion, the results of this study suggest that a taller adult height is causally linked to worse kidney function in middle-aged to elderly individuals, independent of the effect of body mass index.
Highlights
Kidney disease is a major category of comorbidity, and the prevalence of chronic kidney disease (CKD) is increasing with the aging population and global obesity epidemic [1]
Considering that serum creatinine has a limitation in that it can be affected by body mass or dietary factors, the advantage of using a cystatin C-based estimated glomerular filtration rate (eGFR), which is less affected by such bias, has been reported [4, 5]
The study incorporated three databases or their findings: 1) the previous GIANT consortium genome-wide association study (GWAS) meta-analysis for height, which was implemented to identify genetic instruments for height; 2) the previous CKDGen consortium GWAS for kidney function traits based on serum creatinine values, which was implemented as the outcome summary statistics for summary-level Mendelian randomization (MR); and 3) UK Biobank data, which were used for cross-sectional observational analysis
Summary
Kidney disease is a major category of comorbidity, and the prevalence of chronic kidney disease (CKD) is increasing with the aging population and global obesity epidemic [1]. Impaired kidney function negatively affects quality of life and various disorders. Identifying various factors affecting kidney function is important. Kidney function is commonly evaluated by estimated values, namely, the estimated glomerular filtration rate (eGFR), due to its greater availability than a directly measured GFR. Because of widespread serum creatinine testing and robustly developed eGFR equations [3, 4], eGFR is often determined in routine health exams or when assessing the general medical condition of a patient. Lower eGFR, indicating a kidney function decline, is a sensitive biomarker related to risks of various health outcomes. Considering that serum creatinine has a limitation in that it can be affected by body mass or dietary factors, the advantage of using a cystatin C-based eGFR, which is less affected by such bias, has been reported [4, 5]
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