Albuminuria-Related Genetic Biomarkers: Replication and Predictive Evaluation in Individuals with and without Diabetes from the UK Biobank
<p>Diagram showing the genes with the most significant associations (<span class="html-italic">p</span> < 0.001) across phenotypes and cohorts.</p> "> Figure 2
<p>Summary of the SNPs found to be associated with the different phenotypes in each cohort. DM: diabetic cohort. KDIGO: Kidney Disease: Improving Global Outcomes. nonDM: non-diabetic cohort. SNP: single nucleotide polymorphism. UACR: urine albumin/creatinine ratio. SNP information is shown as chromosome|gene|rs identifier|counted allele|alternate allele. * Number of models including the SNP. ** Number of phenotypes associated with the SNP. Green color means the counted allele increases the beta coefficient and red is used for alleles decreasing the beta coefficient.</p> "> Figure 3
<p>Beta coefficients and standard errors for the five single nucleotide polymorphisms with more associations across phenotypes. SNP information is shown as chromosome|gene|rs identifier|counted allele|alternate allele. The absence of dots and values means no association of the SNP with that phenotype/cohort. SNP: single nucleotide polymorphism. UACR: urine albumin-to-creatinine ratio.</p> ">
Abstract
:1. Introduction
2. Results
2.1. Multivariable Analysis
2.1.1. Association with UACR-Derived Phenotypes
2.1.2. Association with Kidney Damage
2.1.3. Specific Association in Patients with Diabetes
3. Discussion
4. Methods and Materials
4.1. Study Design and Population
4.2. Phenotypic Variables
4.2.1. Outcome Variables
Kidney Damage
Macroalbuminuria
Microalbuminuria
UACR
4.2.2. Independent Variables (Confounders)
Anti-Hypertensive Medication
Cholesterol Medication
Diabetes
Insulin
Other
4.3. Statistical Analysis
4.3.1. Descriptive Analysis
4.3.2. Bivariate Analysis
4.3.3. Genotyping, Imputation, and Quality Control
4.3.4. Genetic Risk Score Derivation
4.3.5. Multivariable Analysis
4.3.6. ROC Analysis
4.3.7. Power Calculations
5. Conclusions
Future Perspectives
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
ACEi | angiotensin-converting enzyme inhibitors |
AER | albumin excretion rate |
AUROC | area under the receiver operating characteristic curve |
BMI | body mass index |
CKD | chronic kidney disease |
CKD-EPI | Chronic Kidney Disease Epidemiology Collaboration |
DKD | diabetic kidney disease |
DM | diabetes mellitus |
eGFR | estimated glomerular filtration rate |
ESRD | end-stage renal disease |
GFR | glomerular filtration rate |
GTEx | gene tissue expression |
GWAS | genome-wide association studies |
HWE | Hardy-Weinberg equilibrium |
LD | linkage disequilibrium |
KDIGO | Kidney Disease: Improving Global Outcomes |
MAF | minor allele frequency |
mAlb | microalbuminuria |
PCA | principal component analysis |
PRS | polygenic risk scores |
ROC | receiver operating characteristic curve |
QC | quality control |
SNP | single nucleotide polymorphism |
UACR | urine albumin-to-creatinine ratio |
UKB | UK Biobank |
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Overall Cohort | Non-Diabetic Cohort | Diabetic Cohort | ||||
---|---|---|---|---|---|---|
Variable | N | n (%) Mean ± sd|P50 [P25-P75] | N | n (%) Mean ± sd|P50 [P25-P75] | N | n (%) Mean ± sd|P50 [P25-P75] |
Age (years) | 389,206 | 56.9 ± 8.0 | 353,400 | 56.7 ± 8.0 | 35,806 | 58.6 ± 7.6 |
Sex (male) | 389,206 | 179,240 (46.1) | 353,400 | 159,874 (45.2) | 35,806 | 19,366 (54.1) |
Body Mass Index (kg/m2) | 389,206 | 27.4 ± 4.7 | 353,400 | 27.2 ± 4.6 | 35,806 | 29.4 ± 5.7 |
Diabetes (yes) | 389,206 | 35,806 (9.2) | 353,400 | 0 (0) | 35,806 | 35,806 (100) |
Ever Smoker (yes) | 389,206 | 176,499 (45.4) | 353,400 | 158,263 (44.8) | 35,806 | 18,236 (50.9) |
Hypertensive Medication (yes) | 389,172 | 91,381 (23.5) | 353,374 | 74,674 (21.1) | 35,798 | 16,707 (46.7) |
Cholesterol Medication (yes) | 389,206 | 69,617 (17.9) | 353,400 | 52,285 (14.8) | 35,806 | 17,332 (48.4) |
Insulin (yes) | 389,206 | 3931 (1.0) | 351,942 | 0 (0) | 35,522 | 3931 (11.1) |
Microalbuminuria | sex-specific (yes) | 389,206 | 56,682 (14.6) | 353,400 | 49,639 (14.1) | 35,806 | 7043 (19.7) |
Microalbuminuria | KDIGO (yes) | 389,206 | 29,260 (7.5) | 353,400 | 25,161 (7.1) | 35,806 | 4099 (11.5) |
Macroalbuminuria (yes) | 389,206 | 1429 (0.4) | 353,400 | 1017 (0.3) | 35,806 | 412 (1.2) |
Kidney Damage (yes) | 368,108 | 56,279 (15.3) | 333,316 | 43,763 (13.1) | 34,792 | 12,516 (36.0) |
UACR (mg/g) | 389,206 | 9.8 [6.1–16.5] | 353,400 | 9.7 [6.1–16.3] | 35,806 | 10.3 [6.4–17.9] |
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Cañadas-Garre, M.; Kunzmann, A.T.; Anderson, K.; Brennan, E.P.; Doyle, R.; Patterson, C.C.; Godson, C.; Maxwell, A.P.; McKnight, A.J. Albuminuria-Related Genetic Biomarkers: Replication and Predictive Evaluation in Individuals with and without Diabetes from the UK Biobank. Int. J. Mol. Sci. 2023, 24, 11209. https://doi.org/10.3390/ijms241311209
Cañadas-Garre M, Kunzmann AT, Anderson K, Brennan EP, Doyle R, Patterson CC, Godson C, Maxwell AP, McKnight AJ. Albuminuria-Related Genetic Biomarkers: Replication and Predictive Evaluation in Individuals with and without Diabetes from the UK Biobank. International Journal of Molecular Sciences. 2023; 24(13):11209. https://doi.org/10.3390/ijms241311209
Chicago/Turabian StyleCañadas-Garre, Marisa, Andrew T. Kunzmann, Kerry Anderson, Eoin P. Brennan, Ross Doyle, Christopher C. Patterson, Catherine Godson, Alexander P. Maxwell, and Amy Jayne McKnight. 2023. "Albuminuria-Related Genetic Biomarkers: Replication and Predictive Evaluation in Individuals with and without Diabetes from the UK Biobank" International Journal of Molecular Sciences 24, no. 13: 11209. https://doi.org/10.3390/ijms241311209
APA StyleCañadas-Garre, M., Kunzmann, A. T., Anderson, K., Brennan, E. P., Doyle, R., Patterson, C. C., Godson, C., Maxwell, A. P., & McKnight, A. J. (2023). Albuminuria-Related Genetic Biomarkers: Replication and Predictive Evaluation in Individuals with and without Diabetes from the UK Biobank. International Journal of Molecular Sciences, 24(13), 11209. https://doi.org/10.3390/ijms241311209