A Case–Control Study Supports Genetic Contribution of the PON Gene Family in Obesity and Metabolic Dysfunction Associated Steatotic Liver Disease
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Populations
2.2. Weight and Length Assessment
2.3. Liver Assessment
2.4. smMIPs Sequencing
2.5. Primary Data Analysis
2.5.1. Raw Data Processing
2.5.2. Quality Control
2.6. Optimization of Variant Calling
2.6.1. GnomAD
2.6.2. Sanger Sequencing
2.7. Statistical Analysis
3. Results
3.1. Genetic Variant Calling
3.2. Single Variant Association Tests Show No Associations with Obesity
3.3. Gene-Based Association Tests Indicate an Association between Rare PON1 Variants and Obesity
3.4. Single Variant Association Tests Indicate an Association between PON1 Common Variants and Several MASLD-Related Features
3.5. Gene-Based Association Tests Indicate an Association between Rare PON2 Variants and MASLD-Related Liver Fibrosis
4. Discussion
Advantages, Limitations, and Future Perspectives
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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Patients with Obesity (n= 744) | Lean Cohort (n = 507) | |
---|---|---|
Age (years ± SD) | 43.3 ± 12.6 | 34.8 ± 7.0 |
BMI (kg/m2 ± SD) | 38.7 ± 6.2 | 22.0 ± 1.6 |
Gender (female/male) | 532/212 | 315/192 |
Mean ± SD | Minimum–Maximum | |
---|---|---|
Age (years) | 43.29 ± 12.57 | 18–74 |
Weight (kg) | 110.86 ± 21.45 | 68.8–226.6 |
Height (m) | 1.69 ± 0.09 | 1.47–2.06 |
BMI (kg/m2) | 38.75 ± 6.22 | 26.16–69.13 |
Waist circumference (cm) | 116.91 ± 14.35 | 83.5–193.0 |
Hip circumference (cm) | 122.09 ± 10.29 | 95.0–160.0 |
Waist-to-hip ratio | 0.96 ± 0.11 | 0.67–1.35 |
Fat free mass (kg) | 56.35 ± 12.28 | 36.5–110.0 |
Fat mass (kg) | 54.34 ± 15.02 | 22.5–134.5 |
Fat mass percentage | 48.82 ± 7.52 | 26.0–65.3 |
Total abdominal adipose tissue (cm2) | 800.56 ± 182.02 | 338–1386 |
Visceral abdominal tissue (cm2) | 199.01 ± 89.70 | 29–567 |
Subcutaneous abdominal tissue (cm2) | 601.55 ± 155.39 | 230–1059 |
Systolic blood pressure (mmHg) | 127.50 ± 14.52 | 90–180 |
Diastolic blood pressure (mmHg) | 75.62 ± 10.25 | 49–115 |
Creatinine kinase (mg/dL) | 0.81 ± 0.18 | 0.38–1.64 |
Aspartate aminotransferase (U/L) | 23.52 ± 13.27 | 7–133 |
Alanine aminotransferase (U/L) | 35.36 ± 22.17 | 7–265 |
Alkaline phosphatase (U/L) | 80.29 ± 22.16 | 30.00–236.03 |
Gamma-glutamyltransferase (U/L) | 43.42 ± 33.75 | 11.79–315.16 |
Total cholesterol (mg/dL) | 199.37 ± 39.43 | 75.00–400.44 |
High-density lipoprotein cholesterol (mg/dL) | 51.03 ± 14.05 | 24.00–107.17 |
Triglycerides (mg/dL) | 154.04 ± 82.82 | 33.04–823.01 |
Low-density lipoprotein cholesterol (mg/dL) | 117.78 ± 34.79 | 17.60–294.76 |
HOMA-IR | 4.30 ± 6.66 | 0.07–147.65 |
LD Block | Gene | Genomic Position (hg19) | Genetic Region | Amino Acid Change | SNP ID | Obesity | Steatosis Grade | Lobular Inflammation | Hepatocellular Ballooning | Fibrosis Stage | MASLD Stage | ||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
p-Value | q-Value | p-Value | q-Value | p-Value | q-Value | p-Value | q-Value | p-Value | q-Value | p-Value | q-Value | ||||||
1 | PON1 | 7:94927677A>G | 3′UTR | rs854551 | 0.96 | 0.98 | 0.11 | 0.84 | 0.45 | 0.71 | 0.86 | 1.00 | 0.01 | 0.08 | 0.54 | 0.93 | |
PON1 | 7:94927924C>T | 3′UTR | rs854552 | 0.71 | 0.97 | 0.79 | 0.97 | 0.57 | 0.76 | 0.80 | 1.00 | <0.001 | 0.01 | 0.20 | 0.84 | ||
2 | PON1 | 7:94927708T>C | 3′UTR | rs3917577 | 1.00 | 0.98 | 0.02 | 0.52 | 0.05 | 0.27 | 0.39 | 1.00 | 0.10 | 0.38 | 0.12 | 0.75 | |
3 | PON1 | 7:94937446T>C | Exonic | p.Q192R | rs662 | 0.59 | 0.97 | 0.29 | 0.93 | 0.04 | 0.24 | 0.74 | 1.00 | 0.03 | 0.13 | 0.80 | 0.95 |
4 | PON1 | 7:94946084A>T | Exonic | p.L55M | rs854560 | 0.12 | 0.91 | 1.00 | 0.98 | 0.13 | 0.42 | 0.49 | 1.00 | 0.67 | 0.80 | 0.02 | 0.32 |
5 | PON1 | 7:94953895G>A | 5′UTR | rs705379 | 0.93 | 0.98 | 0.11 | 0.84 | 0.01 | 0.09 | 0.05 | 1.00 | 0.06 | 0.26 | <0.001 | 0.01 | |
6 | PON1 | 7:94953949T>C | 5′UTR | rs705381 | 0.77 | 0.97 | 0.40 | 0.95 | 0.08 | 0.29 | 0.86 | 1.00 | 0.29 | 0.64 | 0.29 | 0.88 | |
7 | PON3 | 7:95001555C>T | Exonic | p.A99A | rs1053275 | 0.51 | 0.96 | 0.87 | 0.98 | 1.00 | 0.84 | 0.55 | 1.00 | 0.83 | 0.84 | 0.44 | 0.92 |
PON3 | 7:95024046A>G | Intronic | rs11970910 | 0.46 | 0.96 | 0.94 | 0.98 | 0.72 | 0.80 | 0.16 | 1.00 | 0.94 | 0.85 | 0.36 | 0.90 | ||
8 | PON3 | 7:95025600G>A | Exonic | p.F21F | rs13226149 | 0.37 | 0.95 | 0.58 | 0.97 | 0.74 | 0.80 | 0.31 | 1.00 | 0.53 | 0.76 | 0.39 | 0.91 |
9 | PON2 | 7:95034253G>GTTA | 3′UTR | rs3918 | 0.19 | 0.91 | 0.78 | 0.97 | 1.00 | 0.84 | 0.39 | 1.00 | 1.00 | 0.86 | 0.79 | 0.95 | |
PON2 | 7:95034775G>C | Exonic | p.S311C | rs7493 | 0.23 | 0.95 | 0.92 | 0.98 | 0.86 | 0.82 | 0.48 | 1.00 | 0.93 | 0.85 | 0.72 | 0.95 | |
PON2 | 7:95039445C>T | Intronic | rs2286232 | 0.18 | 0.91 | 0.71 | 0.97 | 0.93 | 0.84 | 0.34 | 1.00 | 0.94 | 0.85 | 0.86 | 0.96 | ||
PON2 | 7:95041016G>C | Exonic | p.A148G | rs12026 | 0.21 | 0.91 | 0.51 | 0.96 | 0.93 | 0.84 | 0.39 | 1.00 | 0.94 | 0.85 | 0.72 | 0.95 | |
10 | PON2 | 7:95034821A>T | Intronic | rs9641164 | 0.84 | 0.98 | 0.26 | 0.93 | 0.31 | 0.63 | 0.93 | 1.00 | 0.93 | 0.85 | 0.70 | 0.95 |
Gene | Rare Variants (N) | Very Rare Variants (N) |
---|---|---|
PON1 | 21 | 17 |
PON2 | 21 | 19 |
PON3 | 37 | 25 |
PON1 | PON2 | PON3 | |||||
---|---|---|---|---|---|---|---|
Rare Variants | Very Rare Variants | Rare Variants | Very Rare Variants | Rare Variants | Very Rare Variants | ||
Obesity | C-alpha | 0.01 | 0.37 | 0.01 | 0.14 | 0.03 | 0.15 |
Fisher | <0.01 | 0.04 | 0.05 | 0.44 | 0.44 | 1.00 | |
KBAC | <0.001 | 0.01 | 0.96 | 0.93 | 0.78 | 0.57 | |
VT | <0.01 | 0.03 | 0.96 | 0.93 | 0.92 | 0.77 | |
Steatosis Grade | C-alpha | 0.63 | 0.39 | 0.59 | 0.88 | 0.72 | 0.80 |
Fisher | 0.61 | 0.36 | 1.00 | 1.00 | 0.38 | 1.00 | |
KBAC | 0.72 | 0.81 | 0.41 | 0.22 | 0.13 | 0.41 | |
VT | 0.59 | 0.75 | 0.62 | 0.39 | 0.22 | 0.46 | |
Lobular Inflammation | C-alpha | 0.14 | 0.13 | 0.94 | 0.79 | 0.41 | 0.49 |
Fisher | 0.82 | 0.58 | 0.72 | 1.00 | 0.07 | 1.00 | |
KBAC | 0.11 | 0.50 | 0.73 | 0.55 | 0.02 | 0.29 | |
VT | 0.08 | 0.61 | 0.56 | 0.37 | 0.04 | 0.29 | |
Hepatocellular Ballooning | C-alpha | 0.79 | 0.63 | 0.52 | 0.50 | 0.78 | 0.83 |
Fisher | 0.82 | 0.78 | 0.44 | 0.68 | 0.79 | 0.64 | |
KBAC | 0.47 | 0.65 | 0.12 | 0.15 | 0.33 | 0.61 | |
VT | 0.51 | 0.67 | 0.20 | 0.27 | 0.31 | 0.59 | |
Fibrosis Stage | C-alpha | 0.01 | 0.05 | <0.001 | <0.01 | 0.09 | 0.83 |
Fisher | 1.00 | 0.42 | <0.01 | 0.01 | 0.14 | 1.00 | |
KBAC | 0.34 | 0.67 | <0.01 | 0.01 | 0.05 | 0.58 | |
VT | 0.74 | 0.77 | <0.001 | <0.01 | 0.05 | 0.61 | |
MASLD Stage | C-alpha | 0.14 | 0.14 | 0.27 | 0.28 | 0.68 | 0.82 |
Fisher | 0.35 | 1.00 | 0.43 | 0.43 | 0.19 | 1.00 | |
KBAC | 0.04 | 0.24 | 0.29 | 0.29 | 0.12 | 0.35 | |
VT | 0.07 | 0.35 | 0.11 | 0.14 | 0.11 | 0.37 |
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Van Dijck, E.; Diels, S.; Fransen, E.; Cremers, T.C.; Verrijken, A.; Dirinck, E.; Hoischen, A.; Vandeweyer, G.; Vanden Berghe, W.; Van Gaal, L.; et al. A Case–Control Study Supports Genetic Contribution of the PON Gene Family in Obesity and Metabolic Dysfunction Associated Steatotic Liver Disease. Antioxidants 2024, 13, 1051. https://doi.org/10.3390/antiox13091051
Van Dijck E, Diels S, Fransen E, Cremers TC, Verrijken A, Dirinck E, Hoischen A, Vandeweyer G, Vanden Berghe W, Van Gaal L, et al. A Case–Control Study Supports Genetic Contribution of the PON Gene Family in Obesity and Metabolic Dysfunction Associated Steatotic Liver Disease. Antioxidants. 2024; 13(9):1051. https://doi.org/10.3390/antiox13091051
Chicago/Turabian StyleVan Dijck, Evelien, Sara Diels, Erik Fransen, Tycho Canter Cremers, An Verrijken, Eveline Dirinck, Alexander Hoischen, Geert Vandeweyer, Wim Vanden Berghe, Luc Van Gaal, and et al. 2024. "A Case–Control Study Supports Genetic Contribution of the PON Gene Family in Obesity and Metabolic Dysfunction Associated Steatotic Liver Disease" Antioxidants 13, no. 9: 1051. https://doi.org/10.3390/antiox13091051