Table 2.
Candidate genes significantly enriched in rare variants determining an alteration of protein sequence predicted to alter its function (likely pathogenic mutations) in NAFLD-HCC patients vs. healthy individuals (left panel).
| Gene | NAFLD-HCC (n = 72) | Controls (n = 513) | OR | (95% c.i.) | p value* | % carriers NAFLD-HCC | ExAC | OR (95% c.i.) | Adjusted p value** |
|---|---|---|---|---|---|---|---|---|---|
| Discovery cohort (Italy) | Replication vs. ExAC NFE | ||||||||
| RTEL1 | 9 | 9 | 7.9 | 2.7–23.5 | 7.8*10–5 | 12.5 | 2.1 | 5.9 (2.6–11.8) | 0.0003 |
| SQSTM1 | 3 | 1 | 22.0 | 1.7–1161 | 0.0065 | 4.2 | 0.7 | 5.8 (1.2–18.0) | 0.050 |
| TSC2 | 6 | 10 | 4.6 | 1.3–14.4 | 0.0083 | 8.3 | 3.1 | 2.7 (0.9–6.1) | 0.064 |
| APOB | 11 | 31 | 2.8 | 1.2–6.1 | 0.012 | 15.3 | 4.6 | 3.3 (1.6–6.2) | 0.005 |
| TERF2 | 3 | 3 | 7.4 | 1–55.6 | 0.027 | 4.2 | 0.2 | 17.4 (3.4–55.0) | 0.004 |
| SMAD4 | 2 | 1 | 14.5 | 1–859 | 0.041 | 2.8 | 0.4 | 7.4 (0.9–28.3) | 0.064 |
| Validation cohort (UK) | |||||||||
| STK11 | 2 | 1 | 14.9 | 1–884 | 0.039 | 2.9 | 0.3 | 8.4 (1.0–32) | 0.051 |
| MBOAT7 | 2 | 1 | 14.9 | 1–884 | 0.039 | 2.9 | 0.6 | 4.5 (0.5–17.1) | 0.076 |
| NF2 | 3 | 4 | 5.7 | 1–34.2 | 0.041 | 4.3 | 0.3 | 12.1 (2.4–37.2) | 0.009 |
| RB1 | 4 | 8 | 3.8 | 1–14.7 | 0.0201 | 5.7 | 1.0 | 5.9 (1.6–16) | 0.018 |
| Overall | |||||||||
| RTEL | 10 | 9 | 4.2 | 1.5–12 | 0.0026 | 7.0 | 2.1 | 3.3 (1.5–6.3) | 0.006 |
| RB1 | 7 | 8 | 3.3 | 1–10.5 | 0.026 | 4.9 | 1.0 | 5.1 (2.0–11) | 0.003 |
| TSC1 | 6 | 6 | 3.7 | 1–14.1 | 0.027 | 4.2 | 1.7 | 2.5 (0.9–5.6) | 0.077 |
| SMAD4 | 3 | 1 | 11.0 | 1–579 | 0.034 | 2.1 | 3.7 | 5.6 (1.1–17.2) | 0.054 |
| SQSTM1 | 3 | 1 | 11.0 | 1–579 | 0.034 | 2.1 | 0.7 | 3.0 (0.6–8.9) | 0.086 |
Significant associations were replicated against NFE individuals included in the ExAC project (n = 33370).
*Evaluated by Burden test. **Evaluated by Fisher’s test adjusted for multiple comparisons. RTEL1: regulator of telomere elongation helicase 1, SQSTM1: sequestosome-1 (p62), TSC2: tuberous sclerosis complex 2, APOB: apolipoprotein B, TERF2: telomere repeat binding factor 2, SMAD4: SMAD (suppressor of mothers against decapentaplegic) family member 4, STK11: serine/threonine kinase 11 (LKB1), MBOAT7: membrane bound O-acyltranferase domain containing 7, NF2: neurofibromin 2, RB1: retinoblastoma 1. Control group was defined as n = 404 NFE individuals form 1000 G project, n = 59 NAFLD patients with advanced fibrosis/cirrhosis, n = 50 local healthy individuals.