Table 1.
Stepwise Cox Proportional Hazards Analysis for 1142 β-Thalassemia Individuals in Cohort C
| Ameliorating alleles | p | Hazard Ratio | 95% CI |
|---|---|---|---|
| KLF1 mutations | 2.294 × 10−7 | 0.219 | 0.123-0.389 |
| HBB mutations (β+) | 3.286 × 10−48 | 0.379 | 0.333-0.432 |
| HBG1: rs368698783 (A) | 3.029 × 10−14 | 0.552 | 0.473-0.643 |
| HBS1L-MYB: rs9399137 (C) | 1.175 × 10−10 | 0.710 | 0.640-0.788 |
| HBA mutations | 1.875 × 10−10 | 0.713 | 0.643-0.791 |
| BCL11A: rs4671393 (A) | 1.830 × 10−5 | 0.806 | 0.730-0.889 |
A backward stepwise Cox proportional hazards model in 1,142 β-thalassemia individuals in cohort C was conducted to evaluate the associations between putative ameliorating alleles and the age at first transfusion. The covariates were classified based on the number of copies of putative modifying allele. Motif-disrupting SNP rs368698783 alone with ten known modifiers (HBB mutations, HBA mutations, KLF1 mutations, HBS1L-MYB: rs9399137, rs4895441, rs9402686, rs1427407; BCL11A: rs4671393, rs11886868, and rs766432) were included in the analysis. The discriminative ability of the model was high (Harrell’s concordance index = 0.708, R2 = 0.274). The performance of the model was measured by Harrell’s concordance index by using the Hmisc and rms package in R version 3.3.1.
HBB genotype categories are defined as (β0): NM_000518(HBB_v001): c.126_129delCTTT, NM_000518(HBB_v001): c.52A>T, NM_000518(HBB_v001): c.316-197C>T, NM_000518(HBB_v001): c.216_217insA, NM_000518(HBB_v001): c.92+1G>T, NM_000518(HBB_v001): c.130G>T, NM_000518(HBB_v001):c.84_85insC, NM_000518(HBB_v001):c.91A>G, NM_000518(HBB_v001):c.45_46insC, NM_000518(HBB_v001):c.165_177delTATGGGCAACCCT, NM_000518(HBB_v001):c.315+1G>A, NM_000518(HBB_v001):c.287_288insA, NM_000518(HBB_v001):c.113G>A, NM_000518(HBB_v001):c.93-1G>C;
(β+): NM_000518(HBB_v001): c.-78A>G, NM_000518(HBB_v001): c.79G>A, NM_000518(HBB_v001): c.-79A>G, NM_000518(HBB_v001): c.315+5G>C, NM_000518(HBB_v001): c.-140C>T, NM_000518(HBB_v001): c.-81A>C, NM_000518(HBB_v001): c.92+5G>C.
HBA genotype categories are defined as (-α): NG_000006.1: g.34247_38050del, NC_000016.9: g.219817_(223755_224074)del; (–): NG_000006.1: g.26264_45564del19301, NG_000006.1: g.10664_44164del33501; (αTα): NM_000517.4(HBA2_v001): c.427T>C, NM_000517.4(HBA2_v001): c.369C>G, NM_000517.4(HBA2_v001):c.377T>C.