Association of Polygenic Variants with Type 2 Diabetes Risk and Their Interaction with Lifestyles in Asians
Abstract
:1. Introduction
2. Materials and Methods
2.1. Subjects
2.2. Demographic, Anthropometric, and Biochemical Parameters of the Participants
2.3. T2DM Definition
2.4. Estimation of Usual Food Intake Using a Semi-Quantitative Food Frequency Questionnaire (SQFFQ)
2.5. Dietary Patterns by Principal Component Analysis (PCA)
2.6. Genotyping Using a Korean Chip and Quality Control
2.7. Genotype-Tissue Expression (GTEx) of Genetic Mutations and Distribution of Identified Tissue/Organ-Specific Expressed SNPs
2.8. Selection of the Genetic Variants That Influence the T2DM Risk and the Best Model with SNP-SNP Interactions
2.9. Statistical Analysis
3. Results
3.1. Demographic and Lifestyle Characteristics
3.2. Polygenetic Variants with Their Interaction Related to the T2DM Risk
3.3. GTEx and Frequency of Tissue/organ-Specific Expression
3.4. Metabolism Related to the Genetic Variants for T2DM Risk
3.5. Interaction of PRS with Lifestyle Factors to Influence T2DM Risk
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Men (n = 20,293) | Women (n = 38,408) | Adjusted ORs and 95% CI | |||
---|---|---|---|---|---|
Control (n = 17,656) | T2M (n = 2637) | Control (n = 35,662) | T2DM (n = 2746) | ||
Age (years) | 55.7 ± 0.06 b | 58.7 ± 0.15 b | 52.3 ± 0.04 c | 55.5 ± 0.14 b *** +++ | 1.875 (1.740–2.022) |
Education | |||||
≤Middle school | 1467 (13.7) | 286 (16.1) ‡‡ | 5887 (21.1) | 851 (34.8) ‡‡‡ | 1 |
High school | 8103 (75.7) | 1331 (75.1) | 20,360 (72.9) | 1511 (61.8) | 0.723(0.664–0.786) |
≥College | 1136 (10.6) | 155 (8.75) | 1698 (6.08) | 84 (3.43) | 0.646 (0.550–0.760) |
Income | |||||
≤USD 2000 | 1338 (7.96) | 268 (10.7) ‡‡‡ | 3677 (11.0) | 495 (19.1) ‡‡‡ | 1 |
USD 2000–4000 | 7082 (42.1) | 1125 (44.9) | 14,700(43.8) | 1285 (49.7) | 0.846 (0.770–0.928) |
>USD 4000 | 8389 (49.9) | 1111 (44.4) | 15,163(45.2) | 807 (31.2) | 0.748 (0.676–0.827) |
BMI (kg/m2) | 24.3 ± 0.02 b | 25.0 ± 0.06 a | 23.5 ± 0.02 c | 25.0 ± 0.06 a *** +++ ### | 1.692 (1.557–1.838) |
Waist circumferences (cm) | 84.2 ± 0.04 b | 85.2 ± 0.10 a | 78.7 ± 0.03 d | 79.8 ± 0.09 c *** +++ | 1.916 (1.752–2.095) |
SMI (kg/m2) | 7.33 ± 0.01 a | 7.20 ± 0.01 b | 6.22 ± 0.01 c | 6.06 ± 0.004 d *** +++ ### | 0.768 (0.638–0.924) |
Fat mass (%) | 23.1 ± 0.03 d | 24.0 ± 0.07 c | 31.0 ± 0.02 b | 32.6 ± 0.07 a *** +++ ### | 1.578 (1.429–1.742) |
Serum glucose (mg/dL) | 93.3 ± 0.17 c | 133.8 ± 0.40 a | 90.3 ± 0.12 d | 129.1 ± 0.42 b *** +++ ### | |
HbA1c (%) | 5.52 ± 0.01 b | 7.04 ± 0.02 a | 5.56 ± 0.01 b | 7.08 ± 0.02 a ** +++ | |
Insulin resistance (%) | 680 (3.65) | 1632 (61.9) ‡‡‡ | 791 (2.22) | 1501 (54.7) ‡‡‡ | 58.81 (51.59–67.04) |
Men (n = 20,293) | Women (n = 38,408) | Adjusted ORs and 95% CI | |||
---|---|---|---|---|---|
Control (n = 17,656) | T2DM (n = 2637) | Control (n = 35,662) | T2DM (n = 2746) | ||
Energy intake (EER %) 1 | 86.0 ± 0.06 1 b | 85.4 ± 0.13 c | 104 ± 0.05 a | 1040 ± 0.09 a *** ### | 0.958 (0.767–1.196) |
CHO (En%) 2 | 71.6 ± 0.08 | 71.3 ± 0.17 | 71.7 ± 0.06 | 71.6 ± 0.12 | 0.997 (0.932–1.067) |
Fat (En%) 3 | 13.9 ± 0.06 a b | 14.2 ± 0.12 a b | 13.9 ± 0.04 b | 14.1 ± 0.09 a ## | 0.987 (0.893–1.091) |
Protein (En%) 4 | 13.3 ± 0.03 c | 13.4 ± 0.05 b | 13.6 ± 0.02 a | 13.6 ± 0.04 a *** + # | 1.054 (0.978–1.136) |
Fiber (g) 5 | 14.3 ± 0.07 a | 14.3 ± 0.12 a | 14.8 ± 0.07 b | 14.9 ± 0.08 b *** | 0.740 (0.266–2.054) |
Calcium (mg) 6 | 383 ± 1.61 c | 385 ± 4.00 c | 475 ± 1.11 a | 463 ± 3.91 b *** # | 0.985 (0.906–1.071) |
Vitamin C (mg) 7 | 89.3 ± 0.47 c | 89.0 ± 1.16 c | 114.2 ± 0.32 a | 110 ± 1.13 b *** ++ # | 0.918 (0.857–0.983) |
Vitamin D (ug) 8 | 5.24 ± 0.04 c | 4.98 ± 0.08 d | 7.18 ± 0.04 a | 6.95 ± 0.06 b *** ++ | 0.967 (0.871–1.075) |
DII (scores) 9 | −18.3 ± 0.12 c | −18.5 ± 0.29 c | −21.6 ± 0.28 a | −20.7 ± 0.08 b *** ++ | 1.109 (1.028–1.195) |
Flavonoids (mg) 10 | 30.0 ± 0.24 c | 29.9 ± 0.60 d | 43.1 ± 0.17 a | 40.0 ± 0.59 b *** +++ | 0.891 (0.809–0.981) |
KBD (%) 11 | 6671 (39.6) | 1430(41.7) ‡ | 9165 (30.1) | 2303(28.8) ‡ | 0.958 (0.910–1.008) |
PBD (%) 11 | 3488 (20.7) | 710 (20.7) | 12,346 (40.6) | 3032(37.9 ‡‡‡ | 0.890 (0.827–0.958) |
WSD (%) 11 | 8489 (50.4) | 1933 (56.3) ‡‡‡ | 10,333 (34.0) | 2788(34.8) | 1.269 (1.207–1.335) |
RMD (%) 11 | 5376 (31.9) | 1089(31.7) | 10,370 (34.1) | 2736(34.2) | 1.018 (0.970–1.068) |
Alcohol (g) 12 | 35.7 ± 0.38 a | 36.6 ± 0.94 a | 5.37 ± 0.26 b | 4.96 ± 0.91 b *** | 0.878 (0.818–0.942) |
Exercise (%) 13 | 10,323 (58.7) | 1629 (61.9) ‡‡ | 18,537 (52.2) | 1487 (54.3) ‡ | 1.143 (1.073–1.217) |
Non-smoking (%) | 5150 (29.2) | 629 (23.9) ‡‡‡ | 34,442 (96.9) | 2618 (95.7) ‡‡‡ | 1 |
Former smoking | 7541 (42.8) | 1254 (47.7) | 427 (1.2) | 33 (1.21) | 1.289 (1.163–1.430) |
Smoking | 4919 (27.9) | 745 (28.4) | 664 (1.87) | 85 (3.11) | 1.602 (1.431–1.792) |
Chr 1 | SNP 2 | Position | Mi 3 | Ma 4 | OR and 95% CI for City 5 | p Value Adjusted 6 | p Value Adjusted 7 | MAF 8 | p Value for HWE 9 | Gene | Functional Consequence |
---|---|---|---|---|---|---|---|---|---|---|---|
3 | rs7631705 | 23632234 | C | T | 0.888 | 8.00 × 10−9 | 0.0395 | 0.3341 | 0.5715 | UBE2E2 | 3_prime_utr |
6 | rs35612982 | 20682622 | C | T | 1.342 | 9.35 × 10−39 | 1.27 × 10−8 | 0.4649 | 0.1131 | CDKAL1 | Intron |
7 | rs2191349 | 15064309 | G | T | 0.891 | 2.91 × 10−7 | 0.0175 | 0.3233 | 0.04656 | DGKB | Intron |
7 | rs61160304 | 127249659 | T | C | 1.492 | 6.34 × 10−26 | 2.11 × 10−7 | 0.0738 | 0.2274 | PAX4 | Downstream |
8 | rs13266634 | 118184783 | T | C | 0.853 | 8.22 × 10−12 | 0.00255 | 0.398 | 0.9656 | SLC30A8 | Missense |
9 | rs7034200 | 4289050 | A | C | 1.113 | 2.05 × 10−7 | 0.0150 | 0.4064 | 0.3467 | GLIS3 | Nmd transcript |
9 | rs10811661 | 22134094 | C | T | 0.797 | 6.33 × 10−24 | 1.08 × 10−6 | 0.4387 | 0.1998 | CDKN2A/B | Non-coding transcript |
10 | rs12764758 | 94516663 | T | C | 1.285 | 5.00 × 10−10 | 0.0304 | 0.0586 | 0.3958 | IDE | Intron |
11 | rs60808706 | 2857233 | A | G | 0.787 | 6.65 × 10−25 | 8.17 × 10−7 | 0.3913 | 0.2251 | KCNQ1 | Downstream |
17 | rs11651052 | 36102381 | A | G | 1.157 | 5.17 × 10−10 | 0.008245 | 0.3009 | 0.4383 | HNF1B | Intron |
Covariates | Adjusted for Age, Gender, BMI, Education, Income, Income, Area | Adjusted for Age, Gender, BMI, Education, Income, Income, Area, Smoke, Exercise, Alcohol, and Energy Intake | ||||||||
---|---|---|---|---|---|---|---|---|---|---|
Models | TRBA | TEBA | p Value | CVC | TRBA | TEBA | p Value | CVC | ||
CDKAL1_rs35612982 | 0.5411 | 0.5412 | 0.001 | 10 | 0.5411 | 0.5412 | 0.001 | 10 | ||
CDKN2A/B_rs10811661 plus model 1 | 0.5529 | 0.5493 | 0.001 | 10 | 0.5529 | 0.5493 | 0.001 | 10 | ||
KCNQ1_rs60808706 plus model 2 | 0.5599 | 0.5589 | 0.001 | 10 | 0.5599 | 0.5589 | 0.001 | 10 | ||
GLIS3_rs7034200 plus model 3 | 0.5665 | 0.5578 | 0.001 | 9 | 0.5665 | 0.5578 | 0.001 | 9 | ||
UBE2E2_rs7631705 plus model 4 | 0.5778 | 0.5552 | 0.001 | 8 | 0.5778 | 0.5552 | 0.001 | 8 | ||
HNF1B_rs11651052 plus model 5 | 0.5985 | 0.5393 | 0.001 | 7 | 0.5985 | 0.5393 | 0.001 | 7 | ||
SLC30A8_rs13266634 plus model 6 | 0.6395 | 0.5294 | 0.001 | 7 | 0.6395 | 0.5294 | 0.001 | 7 | ||
PAX4_rs61160304 plus model 7 | 0.706 | 0.5208 | 0.001 | 10 | 0.706 | 0.5208 | 0.001 | 10 | ||
IDE_rs12764758 plus model 8 | 0.7644 | 0.5215 | 0.001 | 10 | 0.7644 | 0.5215 | 0.001 | 10 | ||
DGKB_rs2191349 plus model 9 | 0.812 | 0.5218 | 0.001 | 10 | 0.812 | 0.5218 | 0.001 | 10 |
Pathways | No. of Genes 1 | Beta 2 | SD 3 | p Value 4 | p Value Bonferroni 5 | Participating Genes |
---|---|---|---|---|---|---|
Regulation of gene expression in endocrine committed neurog3plus progenitor cells | 2 | 1.677 | 0.0229 | 2.92 × 10−15 | 4.45 × 10−11 | PAX6, HNF1α, HNF1β |
Maturity onset diabetes of the young | 16 | 0.6309 | 0.0243 | 3.88 × 10−13 | 5.92 × 10−09 | PDX1, HNF1β, HNF1a, HNF4α, NeuroD1 |
Regulation of β-cell development | 24 | 0.4618 | 0.0218 | 8.64 × 10−10 | 1.32 × 10−05 | HNF1β, FGF10, ONECUT3, HNF6, PDX1 |
Pancreatic endocrine progenitor | 6 | 0.8761 | 0.0207 | 1.12 × 10−09 | 1.72 × 10−05 | |
Negative regulation of hormone secretion | 34 | 0.3263 | 0.0183 | 6.46 × 10−08 | 9.85 × 10−04 | |
Negative regulation of insulin secretion | 22 | 0.3953 | 0.0179 | 1.58 × 10−07 | 0.0024 | ADR2α, CRHR2, KLF7, PDE1c, UCP2 |
Low-PRS (n = 14,420) | Medium-PRS (n = 21,641) | High-PRS (n = 4201) | Gene-Nutrient Interaction p Value | |
---|---|---|---|---|
Low energy 1 High energy | 1 | 1.771 (1.505–2.084) 2.237 (1.661–3.012) | 2.960 (2.503–3.502) 3.592 (2.650 4.870 | 0.0002 |
Low KBD 2 High KBD | 1 | 1.857 (1.611–2.141) 1.961 (1.636–2.351) | 3.005 (2.597–3.477) 3.220 (2.674 3.878) | 0.6555 |
Low PBD 2 High PBD | 1 | 1.891 (1.638–2.183) 1.917 (1.621–2.266) | 2.903 (2.453–3.508) 3.130 (2.700 3.627) | 0.3048 |
Low WSD 2 High WSD | 1 | 1.891 (1.638–2.183) 1.963 (1.632–2.361) | 3.130 (2.700–3.627) 3.329 (2.754 4.023) | 0.0347 |
Low RMD 2 High RMD | 1 | 1.891 (1.638–2.183) 1.995 (1.677–2.374) | 3.130 (2.700–3.627) 3.221 (2.694 3.850) | 0.0715 |
Low alcohol 3 High alcohol | 1 | 1.867 (1.548–2.253) 1.937 (1.550–2.421) | 3.048 (2.513–3.697) 3.254 (2.588 4.093) | 0.3049 |
Low exercise 4 High exercise | 1 | 2.229 (1.758–2.827) 1.711 (1.428–2.049) | 3.667 (2.874–4.679) 2.845 (2.363 3.426) | 0.4115 |
Non-smoking + former smoking Smoking | 1 | 1.835 (1.580–2.131) 3.021 (1.979–4.611) | 3.068 (2.631–3.577) 4.889 (3.154– 7.576) | 0.0006 |
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Hur, H.J.; Yang, H.J.; Kim, M.J.; Lee, K.-H.; Kim, M.-S.; Park, S. Association of Polygenic Variants with Type 2 Diabetes Risk and Their Interaction with Lifestyles in Asians. Nutrients 2022, 14, 3222. https://doi.org/10.3390/nu14153222
Hur HJ, Yang HJ, Kim MJ, Lee K-H, Kim M-S, Park S. Association of Polygenic Variants with Type 2 Diabetes Risk and Their Interaction with Lifestyles in Asians. Nutrients. 2022; 14(15):3222. https://doi.org/10.3390/nu14153222
Chicago/Turabian StyleHur, Haeng Jeon, Hye Jeong Yang, Min Jung Kim, Kyun-Hee Lee, Myung-Sunny Kim, and Sunmin Park. 2022. "Association of Polygenic Variants with Type 2 Diabetes Risk and Their Interaction with Lifestyles in Asians" Nutrients 14, no. 15: 3222. https://doi.org/10.3390/nu14153222