Novel Metabolites Associated with Decreased GFR in Finnish Men: A 12-Year Follow-Up of the METSIM Cohort
Abstract
1. Introduction
2. Results
2.1. Baseline Characteristics
2.2. Metabolites in Participants with Decreased and Normal eGFR
2.3. Effects of Glucose Tolerance on Metabolic Profile
2.4. Metabolites Associated with a Decrease in eGFR
2.5. Genetic Variants Associated with Novel Metabolites
3. Discussion
4. Materials and Methods
4.1. Study Population and Laboratory Measurements
4.2. Metabolomics
4.3. Selection of Genetic Variants Decreasing Glomerular Filtration Rate
4.4. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Measurements | NGT (n = 3034) | Pre-Diabetes (n = 5715) | T2D (n = 1410) | p |
---|---|---|---|---|
Age (years) | 56.8 ± 6.9 | 57.4 ± 7.2 | 60.6 ± 6.7 | 1.1 × 10−63 |
Systolic blood pressure (mmHg) | 134.3 ± 15.9 | 138.7 ± 16.2 | 145.2 ± 18.1 | 2.1 × 10−93 |
Body mass index (kg/m2) | 25.8 ± 3.38 | 27.4 ± 3.9 | 30.2 ± 5.2 | 1.1 × 10−247 |
Current smoking (%) | 18.0 | 18.4 | 17.2 | 0.606 |
Total triglycerides (mmol/l) | 1.22 ± 0.65 | 1.49 ± 1.08 | 1.90 ± 1.21 | 1.2 × 10−143 |
Fasting glucose (mmol/l) | 5.24 ± 0.24 | 5.97 ± 0.37 | 7.51 ± 2.01 | <1 × 10−250 |
HbA1C (%) | 5.59 ± 0.31 | 5.71 ± 0.34 | 6.58 ± 1.13 | <1 × 10−250 |
Fasting plasma insulin (mU/l) | 6.25 ± 4.11 | 9.32 ± 6.4 | 19.6 ± 28.5 | <1 × 10−250 |
Creatinine (umol/l) | 84.6 ± 15.9 | 83.4 ± 12.8 | 84. 6 ± 22.3 | 0.0003 |
eGFR (ml/min/1.73 m2) | 87.9 ± 12.3 | 88.6 ± 12.2 | 86.1 ± 14.5 | 4.5 × 10−10 |
Urine albumin (mg/l) | 18.4 ± 110.9 | 20.6 ± 82.5 | 93.5 ± 380.1 | 7.2 × 10−181 |
hs-CRP (mg/l) | 1.82 ± 2.96 | 2.13 ± 4.5 | 3.22 ± 6.07 | 3.4 × 10−40 |
Metabolite | Sub-Class | N | Beta | p * | Beta | p ** |
---|---|---|---|---|---|---|
Amino acids | ||||||
N-acetylmethionine | Methionine, cysteine, taurine metabolism | 7080 | −0.334 | 1.4 × 10−183 | −0.087 | 5.5 × 10−24 |
N-acetylvaline | Leucine, isoleucine, valine metabolism | 7082 | −0.343 | 1.0 × 10−194 | −0.082 | 2.6 × 10−21 |
γ-carboxyglutamate | Glutamate metabolism | 6929 | −0.295 | 1.1 × 10−138 | −0.065 | 2.6 × 10−14 |
3-methylglutaryl- carnitine (2) | Leucine, isoleucine, valine metabolism | 7001 | −0.257 | 1.1 × 10−105 | −0.058 | 5.8 × 10−12 |
Proline | Urea cycle; arginine proline metabolism. | 7081 | −0.107 | 1.3 × 10−19 | −0.048 | 3.9 × 10−9 |
Pro-hydroxy-pro | Urea cycle; arginine proline metabolism | 7079 | −0.155 | 1.9 × 10−39 | −0.047 | 5.2 × 10−9 |
4-guanidinobutanoate | Guanidino acetamido metabolism | 7049 | −0.158 | 1.7 × 10−40 | −0.049 | 2.3 × 10−9 |
N-acetyltaurine | Methionine, cysteine, taurine metabolism | 7048 | −0.208 | 1.4 × 10−69 | −0.041 | 7.6 × 10−7 |
Hydantoin-5-propionate | Histidine metabolism | 6154 | −0.211 | 3.6 × 10−63 | −0.043 | 1.1 × 10−6 |
N-lactoylvaline | Lactoyl amino acid | 6781 | −0.182 | 2.5 × 10−51 | −0.043 | 3.1 × 10−6 |
N-lactoylisoleucine | Lactoyl amino acid | 5437 | −0.189 | 4.4 × 10−45 | −0.043 | 1.6 × 10−5 |
N-lactoylphenylalanine | Lactoyl amino acid | 7033 | −0.233 | 2.7 × 10−87 | −0.037 | 4.4 × 10−5 |
Lipids | ||||||
11beta-hydroxy etiocholanolone glucuronide | Androgenic steroids | 4891 | −0.204 | 2.9 × 10−47 | −0.050 | 4.0 × 10−7 |
3-decenoylcarnitine | Fatty acid metabolism | 5395 | −0.217 | 2.9 × 10−58 | −0.042 | 9.2 × 10−6 |
Cis-3,4-methylene heptanoylglycine | Fatty acid metabolism | 6825 | −0.161 | 5.2 × 10−41 | −0.038 | 4.8 × 10−6 |
2-methylmalonyl carnitine (C4-DC) | Fatty acid metabolism | 5827 | −0.235 | 8.0 × 10−74 | −0.042 | 3.1 × 10−6 |
Propionylglycine | Fatty acid metabolism | 3960 | −0.119 | 4.9 × 10−14 | −0.049 | 1.3 × 10−5 |
Nucleotide | ||||||
5-methyluridine(ribothymidine) | Pyrimidine metabolism | 7082 | −0.134 | 6.8 × 10−30 | −0.038 | 3.1 × 10−6 |
Peptide | ||||||
Pyroglutamylvaline | Modified peptides | 6398 | −0.202 | 7.7E × 10−60 | −0.051 | 2.6 × 10−9 |
Xenobiotics | ||||||
2,3-dihydroxyisovalerate | Food component/plant | 6998 | −0.206 | 3.8 × 10−68 | −0.048 | 6.8 × 10−9 |
(S)-a-amino-omega-caprolactam | Food component/plant | 7007 | −0.296 | 1.3 × 10−141 | −0.050 | 1.0 × 10−8 |
3-methoxycatechol sulfate (2) | Benzoate metabolism | 5379 | −0.185 | 2.0 × 10−42 | −0.044 | 1.9 × 10−6 |
3-methyl catechol sulfate (1) | Benzoate metabolism | 7065 | −0.209 | 3.0 × 10−70 | −0.040 | 2.1 × 10−6 |
3-methoxycatechol sulfate (1) | Benzoate metabolism | 6318 | −0.174 | 4.0 × 10−44 | −0.039 | 5.5 × 10−6 |
2-acetamidophenol sulfate | Food component/plant | 5939 | −0.153 | 2.9 × 10−32 | −0.042 | 3.6 × 10−6 |
N-(2-furoyl)glycine | Food component/plant | 5025 | −0.235 | 5.0 × 10−64 | −0.042 | 2.4 × 10−5 |
2-aminophenol sulfate | Food component/plant | 7066 | −0.147 | 2.8 × 10−35 | −0.036 | 1.1 × 10−5 |
Other metabolites | ||||||
Glutamine_degradant | Partially characterized molecules | 7060 | −0.222 | 7.3 × 10−80 | −0.071 | 2.2 × 10−17 |
Gene-Variant | Metabolite | p |
---|---|---|
KLHDC7B-rs470118 | 5-methyluridine | 9.9 × 10−199 |
CPS1-rs715 | Glycine | 8.1 × 10−90 |
AC007326.4-rs5992344 | Proline | 2.0 × 10−63 |
DOCK3-rs138144932 | N-acetylmethionine | 1.3 × 10−44 |
AOX1-rs7562507 | Hydantoin-5-propionate | 1.4 × 10−17 |
COLEC10-rs13264172 | Pro-hydroxy-pro | 3.5 × 10−10 |
MAGI1-rs264676 | 2.3-dihydroxy-5-methylthio-4-penenoate | 2.9 × 10−8 |
DCBLD2-rs192423025 | Pyroglutamylvaline | 3.4 × 10−8 |
CNTNAP2-rs533473709 | γ-carboxyglutamate | 5.3 × 10−8 |
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Fernandes Silva, L.; Vangipurapu, J.; Oravilahti, A.; Laakso, M. Novel Metabolites Associated with Decreased GFR in Finnish Men: A 12-Year Follow-Up of the METSIM Cohort. Int. J. Mol. Sci. 2024, 25, 10044. https://doi.org/10.3390/ijms251810044
Fernandes Silva L, Vangipurapu J, Oravilahti A, Laakso M. Novel Metabolites Associated with Decreased GFR in Finnish Men: A 12-Year Follow-Up of the METSIM Cohort. International Journal of Molecular Sciences. 2024; 25(18):10044. https://doi.org/10.3390/ijms251810044
Chicago/Turabian StyleFernandes Silva, Lilian, Jagadish Vangipurapu, Anniina Oravilahti, and Markku Laakso. 2024. "Novel Metabolites Associated with Decreased GFR in Finnish Men: A 12-Year Follow-Up of the METSIM Cohort" International Journal of Molecular Sciences 25, no. 18: 10044. https://doi.org/10.3390/ijms251810044
APA StyleFernandes Silva, L., Vangipurapu, J., Oravilahti, A., & Laakso, M. (2024). Novel Metabolites Associated with Decreased GFR in Finnish Men: A 12-Year Follow-Up of the METSIM Cohort. International Journal of Molecular Sciences, 25(18), 10044. https://doi.org/10.3390/ijms251810044