Extended Data Table 2.
Participant characteristics across the clusters in the prospective UK Biobank cohort for liver outcome (n = 213,180) (A), for cardiovascular outcome (n = 195,739) (B), and for type 2 diabetes outcome (n = 196,791) (C)
| Participant characteristics across the clusters in the prospective UK Biobank cohort for liver outcome (n=213,180) (A) | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Cluster 1 | Cluster 2 | Cluster 3 | Cluster 4 | Cluster 5 | Cluster 6 | Adj-p | CTRL Cluster | Adj-p 2 vs CTRL | Adj-p 5 vs CTRL | Adj-p 2 vs 5 | |
| N | 53’430 | 5’231 | 20 | 141’570 | 4’366 | 8’563 | − | 203’583 | − | − | − |
| Clinical data | |||||||||||
| Age, years | 61 (6.1) | 59.7 (6.7) | 44 (3.3) | 56.7 (7.6) | 51.8 (7.7) | 43.2 (2.2) | <0.001 | 57.2 (7.9) | <0.001 | <0.001 | <0.001 |
| Women, n (%) | 21,548 (40%) | 1,452 (28%) | 17 (85%) | 73,280 (52%) | 1,101 (25%) | 5,636 (66%) | <0.001 | 100,481 (49%) | <0.001 | <0.001 | 0.016 |
| BMI, kg/m2 | 30 (4.5) | 32.4 (5.4) | 55.4 (1.5) | 29.4 (3.8) | 31.2 (4.2) | 28.2 (3.2) | <0.001 | 29.5 (4) | <0.001 | <0.001 | <0.001 |
| <25 | 1,011 (2%) | 220 (4%) | 0 (0%) | 293 (0%) | 8 (0%) | 61 (1%) | <0.001 | 1,365 (1%) | <0.001 | <0.001 | <0.001 |
| 25–30 | 31,283 (59%) | 1,692 (32%) | 0 (0%) | 94,536 (67%) | 1,983 (45%) | 6,749 (79%) | 132,568 (65%) | ||||
| ≥30 | 21,136 (40%) | 3,319 (63%) | 20 (100%) | 46,741 (33%) | 2,375 (54%) | 1,753 (20%) | 69,650 (34%) | ||||
| Waist circumference, cm | 98.1 (12.2) | 106.7 (13.3) | 136.4 (12.4) | 94.9 (10.8) | 102.4 (11.1) | 88.5 (9.9) | <0.001 | 95.5 (11.3) | <0.001 | <0.001 | <0.001 |
| Significant alcohol intake (n)1 | 10419 (20%) | 928 (18%) | 0 (0%) | 29407 (21%) | 1322 (30%) | 1716 (20%) | <0.001 | 41542 (20%) | < 0.001 | < 0.001 | < 0.001 |
| Liver imaging | |||||||||||
| PDFF, % | 3.8 (2.4–7.1) | 7.7 (4.2–13) | − | 3.9 (2.5–7.1) | 9.6 (4.7–16.3) | 2.6 (1.9–4) | <0.001 | 3.8 (2.5–7) | <0.001 | <0.001 | 0.287 |
| PDFF NA, n (%) | 51,799 (97%) | 5,140 (98%) | 20 (100%) | 136’209 (96%) | 4,199 (96%) | 8,216 (96%) | <0.001 | 196,244 (96%) | <0.001 | 1 | <0.001 |
| Steatosis by PDFF>5.5%, n (%) | 537 (33%) | 58 (64%) | − | 1’819 (34%) | 112 (67%) | 62 (18%) | <0.001 | 2,418 (33%) | <0.001 | <0.001 | 1 |
| cT1, msec | 710 (676–748) | 757.5 (706.5–786) | − | 705 (672–742) | 746 (698–786) | 693 (662–728) | 0.064 | 705 (672–743) | <0.001 | <0.001 | 1 |
| cT1 NA, n (%) | 52,406 (98%) | 5,177 (99%) | 20 (100%) | 138’067 (98%) | 4,261 (98%) | 8,325 (97%) | <0.001 | 198,818 (98%) | <0.001 | 1 | <0.001 |
| MASH by PDFF>5.5% and cT1>800 msec, n (%) | 71 (5%) | 12 (18%) | − | 226 (5%) | 19 (15%) | 13 (4%) | <0.001 | 310 (5%) | <0.001 | <0.001 | 1 |
| Glycolipid profile | |||||||||||
| Glucose, mg/dL | 95.7 (23.4) | 165.8 (75) | 92.5 (22.3) | 90.7 (14.1) | 95.2 (23) | 87.1 (14.4) | <0.001 | 91.9 (17.3) | <0.001 | <0.001 | <0.001 |
| HbA1c, % | 5.5 (5.3–5.8) | 7.7 (6.7–8.7) | 5.5 (5.3–5.7) | 5.4 (5.2–5.6) | 5.4 (5.2–5.7) | 5.1 (4.9–5.3) | <0.001 | 5.4 (5.2–5.6) | <0.001 | <0.001 | <0.001 |
| Total cholesterol, mmol/L | 4.5 (0.6) | 4.6 (0.9) | 4.7 (0.6) | 6.3 (0.9) | 5.8 (1.1) | 4.7 (0.5) | <0.001 | 5.8 (1.2) | <0.001 | 0.089 | <0.001 |
| LDL cholesterol, mmol/L | 2.6 (0.4) | 2.8 (0.7) | 2.9 (0.4) | 4.1 (0.7) | 3.7 (0.8) | 2.8 (0.3) | <0.001 | 3.7 (0.9) | <0.001 | <0.001 | <0.001 |
| HDL cholesterol, mmol/L | 1.3 (0.4) | 1.1 (0.3) | 1.1 (0.2) | 1.4 (0.3) | 1.2 (0.3) | 1.4 (0.3) | <0.001 | 1.4 (0.3) | <0.001 | <0.001 | <0.001 |
| Triglycerides, mmol/L | 1.5 (1.1–2.1) | 3.1 (2.1–4.5) | 1.6 (1.2–2) | 1.8 (1.3–2.5) | 2.2 (1.6–3.2) | 1 (0.8–1.4) | <0.001 | 1.7 (1.2–2.3) | <0.001 | <0.001 | <0.001 |
| Liver function tests | |||||||||||
| ALT, U/L | 22.1 (17.2–28.9) | 34.9 (25.5–47.3) | 22.5 (16.4–26.9) | 21.7 (16.7–29) | 73.7 (65.2–86.7) | 16.6 (12.9–22.1) | <0.001 | 21.6 (16.6–28.8) | <0.001 | <0.001 | <0.001 |
| AST, U/L | 25.2 (21.7–29.6) | 29.3 (23.4–37.7) | 23.3 (20.9–25.8) | 24.6 (21.2–28.7) | 48 (39.8–59.8) | 21.2 (18.4–25.1) | <0.001 | 24.6 (21.2–28.9) | <0.001 | <0.001 | <0.001 |
| ALP, U/L | 82.1 (69.1–97.5) | 88.8 (73.7–106.1) | 86.2 (76.7–107.1) | 82.4 (69.6–97.5) | 87.2 (72.4–106.1) | 70.9 (60–83.7) | <0.001 | 81.8 (69–97) | <0.001 | <0.001 | 0.246 |
| GGT, U/L | 29.4 (21–44) | 48.2 (32.8–76) | 25.8 (21.8–46.3) | 29.1 (20.6–44.1) | 71 (47.1–116.3) | 19 (14.5–27) | <0.001 | 28.7 (20.3–43.4) | <0.001 | <0.001 | <0.001 |
| Bilirubin, mg/dL | 0.5 (0.3) | 0.5 (0.2) | 0.4 (0.1) | 0.5 (0.2) | 0.6 (0.3) | 0.5 (0.3) | <0.001 | 0.5 (0.2) | 0.015 | <0.001 | <0.001 |
| Albumin, g/dL | 4.5 (0.3) | 4.5 (0.3) | 4.2 (0.2) | 4.5 (0.3) | 4.6 (0.3) | 4.5 (0.3) | <0.001 | 4.5 (0.3) | 1 | <0.001 | <0.001 |
| Platelets, 10e3/uL | 244 (59.5) | 246.7 (63.2) | 289.1 (67.4) | 257.8 (58.2) | 245.1 (56.7) | 256.3 (57.7) | <0.001 | 254.1 (58.8) | <0.001 | <0.001 | 1 |
| Comorbidities | |||||||||||
| Hypertension, n (%) | 30,851 (58%) | 3,797 (73%) | 10 (50%) | 38,678 (27%) | 1,545 (35%) | 893 (10%) | <0.001 | 70,432 (35%) | <0.001 | 0.844 | <0.001 |
| Dyslipidemia, n (%) | 31,124 (58%) | 3,943 (75%) | 6 (30%) | 16,948 (12%) | 864 (20%) | 403 (5%) | <0.001 | 48,481 (24%) | <0.001 | <0.001 | <0.001 |
| Type 2 diabetes, n (%) | 8,007 (15%) | 3,948 (75%) | 5 (25%) | 2,369 (2%) | 243 (6%) | 130 (2%) | <0.001 | 10,511 (5%) | <0.001 | 0.72 | <0.001 |
| Genetic variants | |||||||||||
| PNPLA3 rs738409 C>G, n (%) | 33,068 (62%) | 3,156 (60%) | 8 (40%) | 88,103 (62%) | 2,081 (48%) | 5,332 (62%) | <0.001 | 126,511 (62%) / 67,779 (33%) / 9,111 (4%) | 0.005 | <0.001 | <0.001 |
| CC | 17,836 (33%) | 1,792 (34%) | 11 (55%) | 47,093 (33%) | 1,811 (41%) | 2,839 (33%) | |||||
| CG | 2,482 (5%) | 280 (5%) | 1 (5%) | 6,243 (4%) | 472 (11%) | 385 (4%) | |||||
| GG | |||||||||||
| TM6SF2 rs58542926 C>T, n (%) | 44,769 (84%) | 4,426 (85%) | 19 (95%) | 121,870 (86%) | 3474 (80%) | 7133 (83%) | <0.001 | 173791 (86%) | 0.622 | <0.001 | <0.001 |
| CC | 8,047 (15%) | 758 (15%) | 1 (5%) | 18,881 (13%) | 837 (19%) | 1331 (16%) | 28260 (14%) | ||||
| CT | 487 (1%) | 33 (1%) | 0 (0%) | 473 (0%) | 47 (1%) | 79 (1%) | 1039 (1%) | ||||
| TT | |||||||||||
| MBOAT7 rs641738 C>T, n (%) | 16,639 (31%) | 1,664 (32%) | 6 (30%) | 43,966 (31%) | 1,221 (28%) | 2,675 (31%) | <0.001 | 63286 (31%) | 0.908 | <0.001 | <0.001 |
| CC | 26,255 (50%) | 2,505 (48%) | 10 (50%) | 69,222 (49%) | 2,177 (50%) | 4,223 (50%) | 99710 (49%) | ||||
| CT | 10,093 (19%) | 1,017 (20%) | 4 (20%) | 27,205 (19%) | 924 (21%) | 1,605 (19%) | 38907 (19%) | ||||
| TT | |||||||||||
| GCKR rs1260326 C>T, n (%) | 20,307 (38%) | 1,905 (37%) | 8 (40%) | 51,475 (37%) | 1,493 (34%) | 3,341 (39%) | 0.010 | 75,131 (37%) | 0.649 | 0.002 | 0.217 |
| CC | 25,140 (47%) | 2,466 (47%) | 9 (45%) | 67,510 (48%) | 2,143 (49%) | 3,983 (47%) | 96,642 (48%) | ||||
| CT | 7,775 (15%) | 842 (16%) | 3 (15%) | 21,985 (16%) | 712 (16%) | 1,205 (14%) | 30,968 (15%) | ||||
| TT | |||||||||||
| PRS–HFC | 0.193 (0.126–0.394) | 0.256 (0.126–0.394) | 0.329 (0.128–0.394) | 0.193 (0.126–0.394) | 0.331 (0.128–0.459) | 0.193 (0.126–0.394) | <0.001 | 0.193 (0.126–0.394) | 0.01 | <0.001 | <0.001 |
| PRS-HFC cut-offs, n (%) | <0.001 | 12,474 (6%) | 0.004 | <0.001 | <0.001 | ||||||
| <10° percentile | 3,326 (6%) | 300 (6%) | 2 (10%) | 8,622 (6%) | 163 (4%) | 524 (6%) | 171,816 (84%) | ||||
| 10°–90° percentile | 44,515 (83%) | 4,360 (83%) | 16 (80%) | 120,155 (85%) | 3,334 (76%) | 7,130 (83%) | 19,293 (9%) | ||||
| >90° percentile | 5,589 (10%) | 571 (11%) | 2 (10%) | 12,793 (9%) | 869 (20%) | 909 (11%) | |||||
| Liver events | |||||||||||
| CLD, n (%) | 787 (1.473%) | 210 (4.015%) | 1 (5%) | 1,417 (1.001%) | 194 (4.443%) | 67 (0.782%) | <0.001 | 2,272 (1.116%) | <0.001 | <0.001 | 0.922 |
| Follow-up, years | 13.3 (12.4–14) | 13.2 (12.3–14) | 13.9 (12.9–14.3) | 13.4 (12.7–14.1) | 13.5 (12.7–14.2) | 13.5 (12.8–14.2) | <0.001 | 13.4 (12.6–14.1) | <0.001 | <0.001 | <0.001 |
| Participant characteristics across the clusters in the prospective UK Biobank cohort for cardiovascular outcome (n=195,739) (B) | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Cluster 1 | Cluster 2 | Cluster 3 | Cluster 4 | Cluster 5 | Cluster 6 | Adj-p | CTRL Cluster | Adj-p 2 vs CTRL | Adj-p 5 vs CTRL | Adj-p 2 vs 5 | |
| N | 42,093 | 3,999 | 19 | 137,039 | 4,137 | 8,452 | − | 187603 | − | − | − |
| Clinical data | |||||||||||
| Age, years | 60.5 (6.3) | 59.1 (6.9) | 43.5 (2.7) | 56.5 (7.6) | 51.6 (7.6) | 43.2 (2.2) | <0.001 | 56.8 (7.9) | <0.001 | <0.001 | <0.001 |
| Women, n (%) | 18,394 (44%) | 1,197 (30%) | 16 (84%) | 71,263 (52%) | 1042 (25%) | 5,579 (66%) | <0.001 | 95,252 (51%) | <0.001 | <0.001 | <0.001 |
| BMI, kg/m2 | 29.9 (4.5) | 32.3 (5.4) | 55.3 (1.5) | 29.3 (3.8) | 31.2 (4.1) | 28.2 (3.2) | <0.001 | 29.4 (3.9) | <0.001 | <0.001 | <0.001 |
| <25 | 852 (2%) | 185 (5%) | 0 (0%) | 262 (0%) | 7 (0%) | 60 (1%) | <0.001 | 1,174 (1%) | <0.001 | <0.001 | <0.001 |
| 25–30 | 24,979 (59%) | 1,345 (34%) | 0 (0%) | 92,030 (67%) | 1,885 (46%) | 6,670 (79%) | 123,679 (66%) | ||||
| ≥30 | 16,262 (39%) | 2,469 (62%) | 19 (100%) | 44,747 (33%) | 2,245 (54%) | 1,722 (20%) | 62,750 (33%) | ||||
| Waist circumference, cm | 97.4 (12.2) | 106.1 (13.4) | 135.2 (11.4) | 94.8 (10.7) | 102.3 (11.1) | 88.5 (9.9) | <0.001 | 95.1 (11.2) | <0.001 | <0.001 | <0.001 |
| Significant alcohol intake (n)1 | 8446 (20%) | 753 (19%) | 0 (0%) | 28560 (21%) | 1255 (30%) | 1693 (20%) | <0.001 | 38699 (21%) | <0.001 | <0.001 | <0.001 |
| Liver imaging | |||||||||||
| PDFF, % | 3.8 (2.4–7.1) | 7.7 (3.9–13.5) | − | 3.9 (2.5–7.1) | 9.7 (4.7–16.4) | 2.6 (1.9–4) | <0.001 | 3.8 (2.4–6.9) | <0.001 | <0.001 | 0.316 |
| PDFF NA, n (%) | 40,706 (97%) | 3,918 (98%) | 19 (100%) | 131,782 (96%) | 3,975 (96%) | 8,109 (96%) | <0.001 | 180,616 (96%) | <0.001 | 1 | <0.001 |
| Steatosis by PDFF>5.5%, n (%) | 453 (33%) | 53 (65%) | − | 1,773 (34%) | 109 (67%) | 61 (18%) | <0.001 | 2,287 (33%) | <0.001 | <0.001 | 1 |
| cT1, msec | 709 (675–746) | 757 (704–786) | − | 705 (672–742) | 745 (697.5–785.2) | 691 (662–728) | <0.001 | 705 (672–742) | <0.001 | <0.001 | 1 |
| cT1 NA, n (%) | 41,215 (98%) | 3,950 (99%) | 19 (100%) | 133,606 (97%) | 4,037 (98%) | 8,217 (97%) | <0.001 | 183,057 (98%) | <0.001 | 1 | <0.001 |
| MASH by PDFF>5.5% and cT1>800 msec, n (%) | 58 (5%) | 11 (19%) | − | 220 (5%) | 18 (15%) | 13 (4%) | <0.001 | 291 (5%) | <0.001 | <0.001 | 1 |
| Glycolipid profile | |||||||||||
| Glucose, mg/dL | 95.7 (23.7) | 166.6 (76.1) | 93.2 (22.8) | 90.6 (14) | 95.1 (22.8) | 87.1 (14.4) | <0.001 | 91.6 (16.9) | <0.001 | <0.001 | <0.001 |
| HbA1c, % | 5.5 (5.2–5.8) | 7.7 (6.6–8.7) | 5.6 (5.4–5.7) | 5.4 (5.2–5.6) | 5.4 (5.2–5.7) | 5.1 (4.9–5.3) | <0.001 | 5.4 (5.2–5.6) | <0.001 | <0.001 | <0.001 |
| Total cholesterol, mmol/L | 4.6 (0.6) | 4.7 (1) | 4.6 (0.5) | 6.3 (0.9) | 5.9 (1) | 4.7 (0.5) | <0.001 | 5.9 (1.1) | <0.001 | 1 | <0.001 |
| LDL cholesterol, mmol/L | 2.7 (0.4) | 2.8 (0.7) | 2.9 (0.4) | 4.1 (0.7) | 3.8 (0.8) | 2.8 (0.3) | <0.001 | 3.7 (0.9) | <0.001 | 0.004 | <0.001 |
| HDL cholesterol, mmol/L | 1.4 (0.4) | 1.1 (0.3) | 1.1 (0.2) | 1.4 (0.3) | 1.2 (0.3) | 1.4 (0.3) | <0.001 | 1.4 (0.3) | <0.001 | <0.001 | <0.001 |
| Triglycerides, mmol/L | 1.5 (1.1–2) | 3.1 (2.1–4.5) | 1.6 (1.2–1.9) | 1.8 (1.3–2.5) | 2.2 (1.6–3.2) | 1 (0.8–1.4) | <0.001 | 1.7 (1.2–2.3) | <0.001 | <0.001 | <0.001 |
| Liver function tests | |||||||||||
| ALT, U/L | 21.9 (17–28.7) | 35.4 (26–47.8) | 23 (16.9–27.4) | 21.7 (16.7–29) | 73.6 (65.1–86.3) | 16.5 (12.9–22.1) | <0.001 | 21.5 (16.5–28.7) | <0.001 | <0.001 | <0.001 |
| AST, U/L | 25 (21.5–29.3) | 29.4 (23.6–37.8) | 23.3 (20.8–25.9) | 24.5 (21.2–28.7) | 47.6 (39.6–59.2) | 21.2 (18.4–25.1) | <0.001 | 24.5 (21.1–28.7) | <0.001 | <0.001 | <0.001 |
| ALP, U/L | 81.9 (69.1–97.2) | 88.5 (73.7–105.4) | 85.6 (76.5–106.3) | 82.3 (69.5–97.4) | 87.2 (72.5–105.9) | 70.8 (60–83.6) | <0.001 | 81.7 (68.9–96.8) | <0.001 | <0.001 | 0.59 |
| GGT, U/L | 28.6 (20.4–42.5) | 47.7 (32.6–74.5) | 26.6 (22.1–46.5) | 29 (20.5–43.8) | 70.7 (47–116.7) | 19 (14.5–26.9) | <0.001 | 28.3 (20.1–42.8) | <0.001 | <0.001 | <0.001 |
| Bilirubin, mg/dL | 0.5 (0.3) | 0.5 (0.2) | 0.4 (0.1) | 0.5 (0.2) | 0.6 (0.3) | 0.5 (0.3) | <0.001 | 0.5 (0.2) | 0.016 | <0.001 | <0.001 |
| Albumin, g/dL | 4.5 (0.3) | 4.5 (0.3) | 4.2 (0.2) | 4.5 (0.3) | 4.6 (0.3) | 4.5 (0.3) | <0.001 | 4.5 (0.3) | 1 | <0.001 | <0.001 |
| Platelets, 10e3/uL | 246 (59.3) | 248.4 (62.9) | 288.6 (69.2) | 257.8 (58.1) | 245.6 (56.6) | 256.4 (57.6) | <0.001 | 255.1 (58.5) | <0.001 | <0.001 | 0.728 |
| Comorbidities | |||||||||||
| Hypertension, n (%) | 21,060 (50%) | 2,642 (66%) | 9 (47%) | 35,734 (26%) | 1,360 (33%) | 833 (10%) | <0.001 | 57,636 (31%) | <0.001 | 0.01 | <0.001 |
| Dyslipidemia, n (%) | 20,783 (49%) | 2,816 (70%) | 5 (26%) | 14,784 (11%) | 698 (17%) | 351 (4%) | <0.001 | 35,923 (19%) | <0.001 | <0.001 | <0.001 |
| Type 2 diabetes, n (%) | 6,165 (15%) | 2,974 (74%) | 5 (26%) | 2,048 (1%) | 215 (5%) | 127 (2%) | <0.001 | 8,345 (4%) | <0.001 | 0.074 | <0.001 |
| Genetic variants | |||||||||||
| PNPLA3 rs738409 C>G, n (%) | 25,995 (62%) | 2,371 (59%) | 7 (37%) | 85,196 (62%) | 1,981 (48%) | 5,258 (62%) | <0.001 | 116,456 (62%) | <0.001 | <0.001 | <0.001 |
| CC | 14,104 (34%) | 1,389 (35%) | 11 (58%) | 45,655 (33%) | 1,708 (41%) | 2,806 (33%) | 62,576 (33%) | ||||
| CG | 1,959 (5%) | 237 (6%) | 1 (5%) | 6,060 (4%) | 446 (11%) | 381 (5%) | 8,401 (4%) | ||||
| GG | |||||||||||
| TM6SF2 rs58542926 C>T, n (%) | 35,098 (84%) | 3,370 (84%) | 18 (95%) | 117,961 (86%) | 3,285 (80%) | 7,039 (83%) | <0.001 | 160,116 (86%) | 0.191 | <0.001 | <0.001 |
| CC | 6,465 (15%) | 591 (15%) | 1 (5%) | 18,292 (13%) | 798 (19%) | 1,315 (16%) | 26,073 (14%) | ||||
| CT | 424 (1%) | 28 (1%) | 0 (0%) | 453 (0%) | 46 (1%) | 78 (1%) | 955 (1%) | ||||
| TT | |||||||||||
| MBOAT7 rs641738 C>T, n (%) | 13,130 (31%) | 1,274 (32%) | 6 (32%) | 42,546 (31%) | 1,163 (28%) | 2,638 (31%) | 0.002 | 58,320 (31%) | 1 | <0.001 | 0.003 |
| CC | 20,675 (50%) | 1,911 (48%) | 10 (53%) | 66,996 (49%) | 2,059 (50%) | 4,171 (50%) | 91,852 (49%) | ||||
| CT | 7,927 (19%) | 781 (20%) | 3 (16%) | 26,357 (19%) | 875 (21%) | 1,585 (19%) | 35,872 (19%) | ||||
| TT | |||||||||||
| GCKR rs1260326 C>T, n (%) | 16,111 (38%) | 1,468 (37%) | 8 (42%) | 49,948 (37%) | 1,412 (34%) | 3,294 (39%) | <0.001 | 69,361 (37%) | 1 | 0.002 | 0.162 |
| CC | 19,764 (47%) | 1,898 (48%) | 8 (42%) | 65,287 (48%) | 2,034 (49%) | 3,933 (47%) | 88,992 (48%) | ||||
| CT | 6,045 (14%) | 619 (16%) | 3 (16%) | 21,221 (16%) | 673 (16%) | 1,191 (14%) | 28,460 (15%) | ||||
| TT | |||||||||||
| PRS–HFC | 0.193 (0.126–0.394) | 0.256 (0.126–0.394) | 0.329 (0.128–0.394) | 0.193 (0.126–0.394) | 0.331 (0.128–0.459) | 0.193 (0.126–0.394) | <0.001 | 0.193 (0.126–0.394) | <0.001 | <0.001 | <0.001 |
| PRS–HFC cut–offs, n (%) | 2,633 (6%) | 228 (6%) | 2 (11%) | 8,355 (6%) | 156 (4%) | 514 (6%) | <0.001 | 11,504 (6%) | <0.001 | <0.001 | <0.001 |
| <10° percentile | 34,948 (83%) | 3,301 (83%) | 15 (79%) | 116,290 (85%) | 3,158 (76%) | 7,040 (83%) | 158,293 (84%) | ||||
| 10°–90° percentile | 4,512 (11%) | 470 (12%) | 2 (11%) | 12,394 (9%) | 823 (20%) | 898 (11%) | 17,806 (9%) | ||||
| >90° percentile | |||||||||||
| Cardiovascular events | |||||||||||
| CLD, n (%) | 5,647 (13.416%) | 875 (21.88%) | 1 (5.263%) | 13,642 (9.955%) | 394 (9.524%) | 162 (1.917%) | <0.001 | 19,452 (10.369%) | <0.001 | 0.238 | <0.001 |
| Follow–up, years | 13.1 (12.2–14) | 13 (11–13.9) | 14 (13.2–14.3) | 13.3 (12.4–14) | 13.4 (12.5–14.2) | 13.5 (12.7–14.1) | <0.001 | 13.4 (12.7–14.1) | <0.001 | <0.001 | <0.001 |
| Participant characteristics across the clusters in the prospective UK Biobank cohort for type 2 diabetes outcome (n=196,791) (C) | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Cluster 1 | Cluster 2 | Cluster 3 | Cluster 4 | Cluster 5 | Cluster 6 | Adj-p | CTRL Cluster | Adj-p 2 vs CTRL | Adj-p 5 vs CTRL | Adj-p 2 vs 5 | |
| N | 45,021 | 942 | 15 | 138,365 | 4,017 | 8,431 | − | 191,832 | − | − | − |
| Clinical data | |||||||||||
| Age, years | 60.9 (6.1) | 59.5 (6.8) | 44.9 (3.3) | 56.6 (7.6) | 51.6 (7.7) | 43.2 (2.2) | <0.001 | 57 (7.9) | <0.001 | <0.001 | <0.001 |
| Women, n (%) | 18,476 (41%) | 151 (16%) | 13 (87%) | 71,711 (52%) | 1,004 (25%) | 5,555 (66%) | <0.001 | 95,755 (50%) | <0.001 | <0.001 | <0.001 |
| BMI, kg/m2 | 29.8 (4.1) | 31.3 (4.4) | 55.5 (1.6) | 29.3 (3.7) | 31 (4) | 28.2 (3.2) | <0.001 | 29.4 (3.8) | <0.001 | <0.001 | 0.274 |
| <25 | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | <0.001 | 0 (0%) | <0.001 | <0.001 | 0.895 |
| 25−30 | 28,290 (63%) | 427 (45%) | 0 (0%) | 93,366 (67%) | 1,899 (47%) | 6,708 (80%) | 128,364 (67%) | ||||
| ≥30 | 16,731 (37%) | 515 (55%) | 15 (100%) | 44,999 (33%) | 2,118 (53%) | 1,723 (20%) | 63,468 (33%) | ||||
| Waist circumference, cm | 97.3 (11.5) | 104.9 (11.2) | 136.2 (14.2) | 94.8 (10.7) | 101.9 (10.9) | 88.6 (9.8) | <0.001 | 95.1 (11) | <0.001 | <0.001 | <0.001 |
| Significant alcohol intake (n)1 | 9126 (20%) | 295 (31%) | 0 (0%) | 28884 (21%) | 1224 (30%) | 1695 (20%) | < 0.001 | 39705 (21%) | < 0.001 | < 0.001 | 1 |
| Liver imaging | |||||||||||
| PDFF, % | 3.7 (2.4−6.4) | 7.6 (5.9−11.9) | − | 3.9 (2.5−7.1) | 9.5 (4.8−16.5) | 2.6 (1.9−4) | 1 | 3.8 (2.4−6.8) | 0.003 | <0.001 | 1 |
| PDFF NA, n (%) | 43,594 (97%) | 923 (98%) | 15 (100%) | 133,080 (96%) | 3,857 (96%) | 8,089 (96%) | <0.001 | 184,778 (96%) | 0.016 | 0.929 | 0.008 |
| Steatosis by PDFF>5.5%, n (%) | 433 (30%) | 15 (79%) | − | 1,772 (34%) | 108 (68%) | 61 (18%) | <0.001 | 2,266 (32%) | <0.001 | <0.001 | 1 |
| cT1, msec | 708 (675−746) | 762.3 (758−803.5) | − | 705 (672−742) | 746 (699−786) | 693 (662−728.5) | 1 | 705 (672−742) | 0.002 | <0.001 | 0.367 |
| cT1 NA, n (%) | 44,118 (98%) | 932 (99%) | 15 (100%) | 134,916 (98%) | 3916 (97%) | 8,196 (97%) | <0.001 | 187,245 (98%) | 0.015 | 1 | 0.014 |
| MASH by PDFF>5.5% and cT1>800 msec, n (%) | 58 (5%) | 3 (27%) | − | 217 (5%) | 18 (15%) | 13 (4%) | <0.001 | 288 (5%) | 0.035 | <0.001 | 1 |
| Glycolipid profile | |||||||||||
| Glucose, mg/dL | 91.1 (12.6) | 97.4 (18.9) | 86 (10.6) | 89.9 (11.5) | 91.9 (14.8) | 86.6 (10.2) | <0.001 | 90.1 (11.7) | <0.001 | <0.001 | <0.001 |
| HbA1c, % | 5.4 (5.2−5.7) | 5.7 (5.5−6) | 5.4 (5.2−5.6) | 5.4 (5.2−5.6) | 5.4 (5.2−5.6) | 5.1 (4.9−5.3) | <0.001 | 5.4 (5.2−5.6) | <0.001 | <0.001 | <0.001 |
| Total cholesterol, mmol/L | 4.6 (0.6) | 5 (0.7) | 4.7 (0.5) | 6.3 (0.9) | 5.9 (1) | 4.7 (0.5) | <0.001 | 5.8 (1.1) | <0.001 | 1 | <0.001 |
| LDL cholesterol, mmol/L | 2.7 (0.4) | 2.9 (0.5) | 3 (0.3) | 4.1 (0.7) | 3.8 (0.8) | 2.8 (0.3) | <0.001 | 3.7 (0.9) | <0.001 | <0.001 | <0.001 |
| HDL cholesterol, mmol/L | 1.3 (0.4) | 1 (0.2) | 1.2 (0.2) | 1.4 (0.3) | 1.2 (0.3) | 1.4 (0.3) | <0.001 | 1.4 (0.3) | <0.001 | <0.001 | <0.001 |
| Triglycerides, mmol/L | 1.5 (1.1−2) | 5.4 (4.5−6.1) | 1.4 (1.2−1.9) | 1.8 (1.3−2.5) | 2.2 (1.6−3.2) | 1 (0.8−1.4) | <0.001 | 1.7 (1.2−2.3) | <0.001 | <0.001 | <0.001 |
| Liver function tests | |||||||||||
| ALT, U/L | 22 (17.1−28.8) | 41.1 (31.7−51.7) | 22 (16.9−24.1) | 21.7 (16.6−29) | 73.2 (65−85.5) | 16.5 (12.9−22.1) | <0.001 | 21.5 (16.5−28.7) | <0.001 | <0.001 | <0.001 |
| AST, U/L | 25.4 (21.9−29.8) | 33.8 (28.3−40.6) | 23.3 (20.6−24.9) | 24.6 (21.2−28.7) | 47.4 (39.6−58.9) | 21.2 (18.4−25.1) | <0.001 | 24.6 (21.2−28.9) | <0.001 | <0.001 | <0.001 |
| ALP, U/L | 82 (69.2−97.3) | 86.2 (72.5−101.5) | 99.1 (77.7−107.7) | 82.3 (69.5−97.3) | 87.1 (72.4−105.7) | 70.9 (60−83.7) | <0.001 | 81.7 (68.9−96.8) | <0.001 | <0.001 | 0.141 |
| GGT, U/L | 29.1 (20.8−43.6) | 55.9 (39.2−85.8) | 24.2 (20.2−34.1) | 29 (20.5−43.8) | 69.8 (46.4−115.1) | 19 (14.5−27.1) | <0.001 | 28.5 (20.2−43.1) | <0.001 | <0.001 | <0.001 |
| Bilirubin, mg/dL | 0.5 (0.3) | 0.5 (0.3) | 0.4 (0.1) | 0.5 (0.2) | 0.6 (0.3) | 0.5 (0.3) | <0.001 | 0.5 (0.2) | 1 | <0.001 | <0.001 |
| Albumin, g/dL | 4.5 (0.3) | 4.6 (0.3) | 4.1 (0.2) | 4.5 (0.3) | 4.6 (0.3) | 4.5 (0.3) | <0.001 | 4.5 (0.3) | <0.001 | <0.001 | <0.001 |
| Platelets, 10e3/uL | 243.6 (58.9) | 238.5 (56.9) | 290.2 (67.4) | 257.7 (58) | 245.6 (56.5) | 256.4 (57.6) | <0.001 | 254.4 (58.5) | <0.001 | <0.001 | 0.005 |
| Comorbidities | |||||||||||
| Hypertension, n (%) | 24,433 (54%) | 578 (61%) | 8 (53%) | 36,937 (27%) | 1,343 (33%) | 855 (10%) | <0.001 | 62233 (32%) | <0.001 | 0.553 | <0.001 |
| Dyslipidemia, n (%) | 23,912 (53%) | 553 (59%) | 3 (20%) | 15,744 (11%) | 701 (17%) | 363 (4%) | <0.001 | 40022 (21%) | <0.001 | <0.001 | <0.001 |
| Genetic variants | |||||||||||
| PNPLA3 rs738409 C>G, n (%) | 27,892 (62%) | 586 (62%) | 6 (40%) | 86,045 (62%) | 1,923 (48%) | 5,255 (62%) | <0.001 | 119,198 (62%) | 1 | <0.001 | <0.001 |
| CC | 15,001 (33%) | 307 (33%) | 8 (53%) | 46,075 (33%) | 1,655 (41%) | 2,790 (33%) | 63,874 (33%) | ||||
| CG | 2,088 (5%) | 48 (5%) | 1 (7%) | 6,115 (4%) | 437 (11%) | 380 (5%) | 8,584 (4%) | ||||
| GG | |||||||||||
| TM6SF2 rs58542926 C>T, n (%) | 37,710 (84%) | 820 (88%) | 14 (93%) | 119,152 (86%) | 3,190 (80%) | 7,024 (83%) | <0.001 | 163,900 (86%) | 0.706 | <0.001 | <0.001 |
| CC | 6,795 (15%) | 114 (12%) | 1 (7%) | 18,414 (13%) | 774 (19%) | 1,310 (16%) | 26,520 (14%) | ||||
| CT | 414 (1%) | 3 (0%) | 0 (0%) | 459 (0%) | 46 (1%) | 78 (1%) | 951 (0%) | ||||
| TT | |||||||||||
| MBOAT7 rs641738 C>T, n (%) | 14,088 (32%) | 300 (32%) | 5 (33%) | 43,002 (31%) | 1,101 (28%) | 2,639 (32%) | <0.001 | 59,734 (31%) | 1 | <0.001 | 0.073 |
| CC | 22,080 (49%) | 459 (49%) | 7 (47%) | 67,621 (49%) | 2,021 (51%) | 4,164 (50%) | 93,872 (49%) | ||||
| CT | 8,467 (19%) | 179 (19%) | 3 (20%) | 26,588 (19%) | 852 (21%) | 1,569 (19%) | 36,627 (19%) | ||||
| TT | |||||||||||
| GCKR rs1260326 C>T, n (%) | 16,955 (38%) | 270 (29%) | 6 (40%) | 50,225 (36%) | 1,363 (34%) | 3,290 (39%) | <0.001 | 70,476 (37%) | <0.001 | 0.003 | 0.004 |
| CC | 21,242 (47%) | 480 (51%) | 6 (40%) | 66,043 (48%) | 1,981 (50%) | 3,926 (47%) | 91,217 (48%) | ||||
| CT | 6,655 (15%) | 189 (20%) | 3 (20%) | 21,508 (16%) | 655 (16%) | 1,181 (14%) | 29,347 (15%) | ||||
| TT | |||||||||||
| PRS−HFC2 | 0.193 (0.126−0.394) | 0.193 (0.128−0.394) | 0.329 (0.128−0.426) | 0.193 (0.126−0.394) | 0.331 (0.128−0.459) | 0.193 (0.126−0.394) | <0.001 | 0.193 (0.126−0.394) | 0.949 | <0.001 | <0.001 |
| PRS−HFC cut−offs, n (%) | 2,809 (6%) | 39 (4%) | 2 (13%) | 8,428 (6%) | 146 (4%) | 513 (6%) | <0.001 | 11,752 (6%) | 0.097 | <0.001 | <0.001 |
| <10° percentile | 37,507 (83%) | 818 (87%) | 11 (73%) | 117,435 (85%) | 3,066 (76%) | 7,023 (83%) | 161,976 (84%) | ||||
| 10–90° percentile | 4,705 (10%) | 85 (9%) | 2 (13%) | 12,502 (9%) | 805 (20%) | 895 (11%) | 18,104 (9%) | ||||
| >90° percentile | |||||||||||
| Diabetes events | |||||||||||
| Type 2 diabetes, n (%) | 2,934 (6.517%) | 257 (27.282%) | 1 (6.667%) | 4,939 (3.57%) | 375 (9.335%) | 57 (0.676%) | <0.001 | 7,931 (4.134%) | <0.001 | <0.001 | <0.001 |
| Follow-up, years | 13.2 (12.3–14) | 12.8 (9.5–13.9) | 13.9 (12.8–14.4) | 13.4 (12.6–14.1) | 13.4 (12.5–14.2) | 13.5 (12.8–14.2) | <0.001 | 13.3 (12.6–14.1) | <0.001 | 0.339 | <0.001 |
Continuous variables are shown as mean (SD) or median (IQR) as appropriate. Categorical variables are shown as frequency (percentage).
Cluster control group is defined as cluster 1 + 3 + 4 + 6. Clusters were compared using Kruskal-Wallis test, Chi-squared test, or Fisher’s exact test, as appropriate.The adjusted P value is reported for comparisons across the three clusters, as well as for post hoc comparisons between cluster 2 versus CTRL, cluster 5 versus CTRL, and cluster 2 versus cluster 5. Differences were considered statistically significant when p-value(s) adjusted for multiple comparisons using Bonferroni correction were less than 0.05. For variables statistically significant, post-hoc analysis was performed comparing pairwise MASH-enriched clusters (2 and 5) and the combined non-enriched MASH clusters (1, 3, 4, and 6) using the Dunn test, Chi-squared test, or Fisher’s exact test, as appropriate, with Bonferroni adjustment.
1: Significant alcohol intake was defined as a daily consumption above 20 g in women and 30 g in men.
2:PRS + Polygenic Risk Score was calculated with the formula: prs=0.266∗PNPLA3_012 + 0.274∗TMS6F2_012 + 0.065∗GCKR_012 + 0.063∗MBOAT7_012
ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; eGFR, estimates of glomerular filtration rate; GCKR, glucokinase regulator; GGT, gamma-glutamyltransferase; HbA1c, hemoglobin A1c; HDL, high-density lipoprotein; HOMA2-B, homeostasis model assessment 2 estimates of beta-cell function; HOMA2-IR, homeostasis model assessment 2 estimates of insulin-resistance; LDL, low-density lipoprotein; MBOAT7, membrane-bound O-acyltransferase domain-containing 7; PNPLA3, patatin-like phospholipase domain-containing 3; PRS-HFC, polygenic risk score of hepatic fat content; TM6SF2, transmembrane 6 superfamily member, Adj-p, adjusted-p.