Background
Methods
Study subjects
Measurement of serum vitamin D levels
SNPs selection and genotyping
Statistical analysis
Results
Demographic and Clinical Characteristics of the Study Subjects
Characteristics | Total (n = 336) | Control group (n = 149) | NH group (n = 187) | χ2/t/Z | P-Value |
---|---|---|---|---|---|
Neonatal characteristics | |||||
Age, Median (IQR), day | 4.50 (6.98) | 6.00 ((8.00) | 4.00 (5.75) | -4.63 |
< 0.001
|
Gender | 2.99 | 0.084 | |||
Male, n (%) | 189 (56.25%) | 76 (51.01%) | 113 (60.43%) | ||
Female, n (%) | 147 (43.75%) | 73 (48.99%) | 74 (39.57%) | ||
Gestational age, Mean ± SD, day | 273.28 ± 9.20 | 274.74 ± 8.55 | 272.12 ± 9.55 | 2.61 |
0.009
|
Birth weight, Median (IQR), g | 3310.00 (607.50) | 3370.00 (620.00) | 3300.00 (610.00) | -1.34 | 0.179 |
Weight loss ≥ 10%, n (%) | 14 (4.17%) | 3 (2.01%) | 11 (5.88%) | 3.35 | 0.067 |
Breast feeding, n (%) | 87 (25.89%) | 41 (27.52%) | 46 (24.60%) | 0.368 | 0.544 |
Mild infection, n (%) | 224 (66.67%) | 108 (72.48%) | 116 (62.03%) | 4.08 |
0.043
|
Cephalohematoma, n (%) | 56 (16.67%) | 14 (9.40%) | 42 (22.46%) | 10.19 |
0.001
|
ABO incompatibility, n (%) | 66 (19.64%) | 29 (19.46%) | 37 (19.79%) | 0.01 | 0.941 |
Vitamin D, Median (IQR), ng/ml | 9.82(7.06) | 10.38(7.12) | 9.48(7.56) | -1.79 | 0.074 |
Vitamin D status | 4.55 | 0.103 | |||
Sufficiency, n (%) | 28 (8.33%) | 17 (11.41%) | 11 (5.88%) | ||
Insufficiency, n (%) | 37 (11.01%) | 19 (12.75%) | 18 (9.63%) | ||
Deficiency, n (%) | 271 (80.66%) | 113 (75.84%) | 158 (84.49%) | ||
Maternal characteristics | |||||
Age, Mean ± SD, years | 28.97 ± 4.23 | 28.63 ± 4.18 | 29.24 ± 4.27 | -1.31 | 0.190 |
Primigravida, n (%) | 200 (59.52%) | 89 (59.73%) | 111 (59.36%) | 0.01 | 0.945 |
Pregnancy Complications, n (%) | 184 (54.76%) | 79 (53.02%) | 105 (56.15%) | 0.33 | 0.567 |
Vitamin D deficiency and genotypes
Non-vitamin D deficiency (n = 65) | Vitamin D deficiency (n = 271) | Crude OR (95% CI) | P-Value | Adjusted OR (95% CI) | P-Value | |
---|---|---|---|---|---|---|
Control group | 36 (55.38%) | 113 (41.70%) | 1 | 1 | ||
NH group | 29 (44.62%) | 158 (58.30%) | 1.74 (1.01, 2.99) |
0.048
| 1.18 (0.65, 2.14) | 0.588 |
NADSYN1/DHCR7 rs12785878 | ||||||
GG | 17(26.15%) | 67 (24.72%) | 1 | 1 | ||
GT | 30 (46.15%) | 129 (47.60%) | 0.67 (0.39, 1.16) | 0.153 | 0.69 (0.39, 1.24) | 0.218 |
TT | 18 (27.70%) | 75 (27.68%) | 0.45 (0.25, 0.83) |
0.011
| 0.45 (0.23, 0.86) |
0.016
|
GC rs4588 | ||||||
CC | 38 (58.46%) | 120 (44.28%) | 1 | 1 | ||
CA | 22 (33.85%) | 117 (43.17%) | 0.77 (0.49, 1.22) | 0.261 | 0.79 (0.49, 1.30) | 0.359 |
AA | 5 (7.69%) | 34 (12.55%) | 1.31 (0.64, 2.72) | 0.460 | 1.22 (0.56, 2.65) | 0.620 |
GC rs7041 | ||||||
TT | 24 (36.92%) | 142 (52.40%) | 1 | 1 | ||
TG | 30 (46.16%) | 90 (33.21%) | 0.93 (0.58, 1.49) | 0.774 | 1.09 (0.65, 1.80) | 0.750 |
GG | 11 (16.92%) | 39 (14.39%) | 1.79 (0.92, 3.50) | 0.086 | 1.55 (0.76, 3.15) | 0.224 |
CYP2R1 rs12794714 | ||||||
CC | 29 (44.61%) | 108 (39.85%) | 1 | 1 | ||
CT | 28 (43.08%) | 113 (41.70%) | 0.99 (0.62, 1.59) | 0.979 | 0.97 (0.58, 1.61) | 0.902 |
TT | 8 (12.31%) | 50 (18.45%) | 1.06 (0.57, 1.97) | 0.855 | 1.14 (0.59, 2.23) | 0.692 |
CYP24A1 rs17216707 | ||||||
TT | 56 (86.15%) | 247 (91.14%) | 1 | 1 | ||
CT | 9 (13.85) | 24 (8.86%) | 1.25 (0.60, 2.61) | 0.547 | 1.19 (0.54, 2.61) | 0.665 |
CYP27B1 rs10877012 | ||||||
GG | 19 (29.23%) | 56 (20.66%) | 1 | 1 | ||
GT | 30 (46.15%) | 130 (47.97%) | 0.60 (0.34, 1.06) | 0.076 | 0.53 (0.29, 0.98) |
0.042
|
TT | 16 (24.62%) | 85 (31.37%) | 0.49 (0.26, 0.90) |
0.023
| 0.60 (0.31, 1.16) | 0.131 |
The correlation between genotype and NH
Control group (n = 149) | NH group (n = 187) |
P
H−W
| Crude OR (95% CI) | P-Value | Adjusted OR (95% CI) | P-Value | ||
---|---|---|---|---|---|---|---|---|
NADSYN1/DHCR7 rs12785878 | ||||||||
Genotype | GG | 29 (19.46%) | 55 (29.41%) | 0.806 | 1 | 1 | ||
GT | 70 (46.98%) | 89 (47.59%) | 0.67 (0.39, 1.16) | 0.153 | 0.69 (0.39, 1.24) | 0.218 | ||
TT | 50 (33.56%) | 43 (23.00%) | 0.45 (0.24, 0.83) |
0.011
| 0.45 (0.23, 0.86) |
0.016
| ||
Allele | G | 128 (42.95%) | 199 (53.21%) | 1 | 1 | |||
T | 170 (57.05%) | 175 (46.79%) | 0.66 (0.49, 0.90) |
0.008
| 0.66 (0.48, 0.92) |
0.013
| ||
Dominant model | GT + TT | 120 (80.54%) | 132 (70.59%) | 0.58 (0.35, 0.97) |
0.038
| 0.59 (0.34, 1.02) | 0.059 | |
GG | 29 (19.46%) | 55 (29.41%) | 1 | 1 | ||||
Recessive model | GG + GT | 99 (66.44%) | 144 (77.01%) | 0.77 (0.60, 0.98) |
0.032
| 0.76 (0.58, 0.98) |
0.036
| |
TT | 50 (33.56%) | 43 (22.99%) | 1 | 1 | ||||
GC rs4588 | ||||||||
Genotype | CC | 67 (44.97%) | 91 (48.66%) | 0.782 | 1 | 1 | ||
CA | 68 (45.64%) | 71 (37.97%) | 0.77 (0.49, 1.22) | 0.261 | 0.79 (0.49, 1.30) | 0.359 | ||
AA | 14 (9.839%) | 25 (13.37%) | 1.31(0.64, 2.72) | 0.460 | 1.22 (0.56, 2.65) | 0.620 | ||
Allele | C | 202 (67.79%) | 253 (67.65%) | 1 | 1 | |||
A | 96 (32.21%) | 121 (32.35%) | 1.00 (0.85, 1.18) | 0.970 | 0.99 (0.83, 1.18) | 0.950 | ||
Dominant model | CA + AA | 82 (55.03%) | 96 (51.33%) | 0.86 (0.56, 1.33) | 0.500 | 0.87 (0.55, 1.38) | 0.554 | |
CC | 67 (44.97%) | 91 (48.66%) | 1 | 1 | ||||
Recessive model | CC + CA | 135 (90.60%) | 162 (86.63%) | 1.22 (0.86, 1.73) | 0.261 | 1.16 (0.80, 1.69) | 0.423 | |
AA | 14 (9.40%) | 25 (13.37%) | 1 | 1 | ||||
GC rs7041 | ||||||||
Genotype | TT | 76 (51.00%) | 90 (48.13%) | 0.054 | 1 | 1 | ||
TG | 57 (38.26%) | 63 (33.69%) | 0.93 (0.58, 1.49) | 0.774 | 1.09 (0.65, 1.80) | 0.750 | ||
GG | 16 (10.74%) | 34 (18.18%) | 1.79 (0.92, 3.50) | 0.086 | 1.55 (0.76, 3.15) | 0.224 | ||
Allele | T | 209 (70.13%) | 243 (64.97%) | 1 | 1 | |||
G | 89 (29.87%) | 131 (35.03%) | 1.13 (0.96, 1.32) | 0.157 | 1.11 (0.94, 1.33) | 0.228 | ||
Dominant model | TG + GG | 73 (48.99%) | 97 (51.87%) | 1.12 (0.73, 1.73) | 0.600 | 1.20 (0.76, 1.91) | 0.438 | |
TT | 76 (51.01%) | 90 (48.13%) | 1 | 1 | ||||
Recessive model | TT + TG | 133 (89.26%) | 153 (81.82%) | 1.36 (0.99, 1.87) | 0.059 | 1.22 (0.87, 1.72) | 0.240 | |
GG | 16 (10.74%) | 34 (18.18%) | 1 | 1 | ||||
CYP2R1 rs12794714 | ||||||||
Genotype | CC | 61 (40.94%) | 76 (40.64%) | 0.343 | 1 | 1 | ||
CT | 63 (42.28%) | 78 (41.71%) | 0.99 (0.62, 1.59) | 0.979 | 0.97 (0.58, 1.61) | 0.902 | ||
TT | 25 (16.78%) | 33 (17.65%) | 1.06 (0.57, 1.97) | 0.855 | 1.14 (0.59, 2.23) | 0.692 | ||
Allele | C | 185 (62.08%) | 230 (61.50%) | 1 | 1 | |||
T | 113 (37.92%) | 144 (38.50%) | 1.01 (0.87, 1.18) | 0.877 | 1.03 (0.87, 1.21) | 0.755 | ||
Dominant model | CT + TT | 88 (59.06%) | 111 (59.36%) | 1.01 (0.65, 1.57) | 0.956 | 1.02 (0.64, 1.63) | 0.941 | |
CC | 61 (40.94%) | 76 (40.64%) | 1 | 1 | ||||
Recessive model | CC + CT | 124 (83.22%) | 154 (82.35%) | 1.03 (0.77, 1.37) | 0.834 | 1.08 (0.79, 1.47) | 0.634 | |
TT | 25 (16.78%) | 33 (17.65%) | 1 | 1 | ||||
CYP24A1 rs17216707 | ||||||||
Genotype | TT | 136 (91.28%) | 167 (89.30%) | 0.802 | 1 | 1 | ||
CT | 13 (8.72%) | 20 (10.70%) | 1.25 (0.60, 2.61) | 0.547 | 1.19 (0.54, 2.62) | 0.665 | ||
Allele | T | 285 (95.64%) | 354 (94.65%) | 1 | 1 | |||
C | 13 (4.36%) | 20 (5.35%) | 1.24 (0.61, 2.53) | 0.55 | 1.18 (0.55, 2.54) | 0.674 | ||
CYP27B1 rs10877012 | ||||||||
Genotype | GG | 25 (16.78%) | 50 (26.74%) | 0.880 | 1 | 1 | ||
GT | 73 (49.00%) | 87 (46.52%) | 0.60 (0.34, 1.06) | 0.076 | 0.53 (0.29, 0.98) |
0.042
| ||
TT | 51 (34.22%) | 50 (26.74%) | 0.49 (0.26, 0.91) |
0.024
| 0.60 (0.31, 1.16) | 0.131 | ||
Allele | G | 123 (41.28%) | 187 (50.00%) | 1 | 1 | |||
T | 175 (58.72%) | 187(50.00%) | 0.84 (0.72, 0.98) |
0.024
| 0.89 (0.75, 1.05) | 0.162 | ||
Dominant model | GT + TT | 124 (83.22%) | 137 (73.26%) | 0.55 (0.32, 0.95) |
0.031
| 0.56 (0.31, 0.99) |
0.045
| |
GG | 25 (16.78%) | 50 (26.74%) | 1 | 1 | ||||
Recessive model | GG + GT | 98 (65.77%) | 137 (73.26%) | 0.84 (0.66, 1.06) | 0.138 | 0.96 (0.74, 1.24) | 0.758 | |
TT | 51 (34.23%) | 50 (26.74%) | 1 | 1 |
Mild (n = 76) | Moderate (n = 93) | Severe (n = 18) | Crude OR (95% CI) | P-Value | Adjusted OR (95% CI) | P-Value | ||
---|---|---|---|---|---|---|---|---|
NADSYN1/DHCR7 rs12785878 | ||||||||
Genotype | GG | 15 (19.74%) | 33 (35.48%) | 7 (38.89%) | 1 | 1 | ||
GT | 45 (59.21%) | 37 (39.79%) | 7 (38.89%) | 2.47 (1.27, 4.79) |
0.008
| 2.43 (1.22, 4.86) |
0.012
| |
TT | 16 (21.05%) | 23 (24.73%) | 4 (22.22%) | 1.51 (0.69, 3.28) | 0.300 | 1.37 (0.61, 3.05) | 0.445 | |
Allele | G | 75 (49.34%) | 103 (55.38%) | 21 (58.33%) | 1 | 1 | ||
T | 77 (50.66%) | 83 (44.62%) | 15 (41.67%) | 1.29 (0.87, 1.91) | 0.201 | 1.23 (0.82, 1.85) | 0.312 | |
Dominant model | GT + TT | 61 (80.26%) | 60 (64.52%) | 11 (61.11%) | 2.09 (1.12, 3.88) |
0.020
| 1.97 (1.04, 3.73) |
0.037
|
GG | 15 (19.74%) | 33 (35.48%) | 7 (38.89%) | 1 | 1 | |||
Recessive model | GG + GT | 60 (78.95%) | 70 (75.27%) | 14 (77.78%) | 0.87 (0.45, 1.68) | 0.678 | 0.82 (0.41, 1.63) | 0.570 |
TT | 16 (21.05%) | 23 (24.73%) | 4 (22.22%) | 1 | 1 | |||
GC rs4588 | ||||||||
Genotype | CC | 40 (52.63%) | 45 (48.39%) | 6 (33.33%) | 1 | 1 | ||
CA | 26 (34.21%) | 37 (39.78%) | 8 (44.45%) | 0.71 (0.39, 1.29) | 0.257 | 0.71 (0.38, 1.33) | 0.291 | |
AA | 10 (13.16%) | 11 (11.83%) | 4 (22.22%) | 0.71 (0.30, 1.66) | 0.426 | 0.76 (0.31, 1.86) | 0.551 | |
Allele | C | 106 (69.74%) | 127 (68.28%) | 20 (55.56%) | 1 | 1 | ||
A | 46 (30.26%) | 59 (31.72%) | 16 (44.44%) | 0.78 (0.51, 1.18) | 0.240 | 0.81 (0.52, 1.24) | 0.330 | |
Dominant model | CA + AA | 36 (47.37%) | 48 (51.61%) | 12 (66.67%) | 0.71 (0.41, 1.23) | 0.220 | 0.73 (0.41, 1.29) | 0.277 |
CC | 40 (52.63%) | 45 (48.39%) | 6 (33.33%) | 1 | 1 | |||
Recessive model | CC + CA | 66 (86.84%) | 82 (88.17%) | 14 (77.78%) | 0.82 (0.36, 1.85) | 0.636 | 0.88 (0.38, 2.06) | 0.770 |
AA | 10 (13.16%) | 11 (11.83%) | 4 (22.22%) | 1 | 1 | |||
GC rs7041 | ||||||||
Genotype | TT | 41 (53.95%) | 38 (40.86%) | 11 (61.11%) | 1 | 1 | ||
TG | 26 (34.21%) | 32 (34.41%) | 5 (27.78%) | 0.95 (0.51, 1.76) | 0.863 | 0.85 (0.44, 1.63) | 0.619 | |
GG | 9 (11.84%) | 23 (24.73%) | 2 (11.11%) | 0.62 (0.29, 1.33) | 0.221 | 0.69 (0.31, 1.52) | 0.355 | |
Allele | T | 108 (71.05%) | 108 (58.06%) | 27 (75.00%) | 1 | 1 | ||
G | 44 (28.95%) | 78 (41.94%) | 9 (25.00%) | 0.77 (0.51, 1.16) | 0.205 | 0.79 (0.52, 1.21) | 0.285 | |
Dominant model | TG + GG | 35 (46.05%) | 55 (59.14%) | 7 (38.89%) | 0.81 (0.47, 1.41) | 0.460 | 0.78 (0.44, 1.39) | 0.406 |
TT | 41 (53.95%) | 38 (40.86%) | 11 (61.11%) | 1 | 1 | |||
Recessive model | TT + TG | 67 (88.16%) | 70 (75.27%) | 16 (88.89%) | 0.63 (0.31, 1.31) | 0.217 | 0.74 (0.35, 1.55) | 0.421 |
GG | 9 (11.84%) | 23 (24.73%) | 2 (11.11%) | 1 | 1 | |||
CYP2R1 rs12794714 | ||||||||
Genotype | CC | 35 (46.05%) | 35 (37.63%) | 6 (33.33%) | 1 | 1 | ||
CT | 31 (40.79%) | 37 (39.79%) | 10 (55.56%) | 0.72 (0.39, 1.33) | 0.298 | 0.81 (0.43, 1.56) | 0.535 | |
TT | 10 (13.16%) | 21 (22.58%) | 2 (11.11%) | 0.62 (0.28, 1.37) | 0.241 | 0.54 (0.24, 1.24) | 0.149 | |
Allele | C | 101 (66.45%) | 107 (57.53%) | 22 (61.11%) | 1 | 1 | ||
T | 51 (33.55%) | 79 (42.47%) | 14 (38.89%) | 0.750 (0.50, 1.12) | 0.162 | 0.72 (0.48, 1.10) | 0.128 | |
Dominant model | CT + TT | 41 (53.95%) | 58 (62.37%) | 12 (66.67%) | 0.69 (0.39, 1.21) | 0.198 | 0.72 (0.39, 1.30) | 0.271 |
CC | 35 (46.05%) | 35 (37.63%) | 6 (33.33%) | 1 | 1 | |||
Recessive model | CC + CT | 66 (86.84%) | 72 (77.42%) | 16 (88.89%) | 0.73 (0.35, 1.52) | 0.402 | 0.60 (0.28, 1.29) | 0.189 |
TT | 10 (13.16%) | 21 (22.58%) | 2 (11.11%) | 1 | 1 | |||
CYP24A1 rs17216707 | ||||||||
Genotype | TT | 70 (92.11%) | 83 (89.25%) | 14 (77.78%) | 1 | 1 | ||
CT | 6 (7.89%) | 10 (10.75%) | 4 (22.22%) | 0.50 (0.20, 1.24) | 0.134 | 0.53 (0.21, 1.35) | 0.183 | |
Allele | T | 146 (96.05%) | 176 (94.62%) | 32 (88.89%) | 1 | 1 | ||
C | 6 (3.95%) | 10 (5.38%) | 4 (11.11%) | 0.52 (0.22, 1.25) | 0.144 | 0.55 (0.22, 1.37) | 0.199 | |
CYP27B1 rs10877012 | ||||||||
Genotype | GG | 19 (25.00%) | 27 (29.03%) | 4 (22.22%) | 1 | 1 | ||
GT | 35 (46.05%) | 42 (45.16%) | 10 (55.56%) | 0.99 (0.51, 1.95) | 0.990 | 1.01 (0.50, 2.06) | 0.969 | |
TT | 22 (28.95%) | 24 (25.81%) | 4 (22.22%) | 1.22 (0.57, 2.60) | 0.605 | 1.18 (0.54, 2.60) | 0.677 | |
Allele | G | 73 (48.03%) | 96 (51.61%) | 18 (50.00%) | 1 | 1 | ||
T | 79 (51.97%) | 90 (48.39%) | 18 (50.00%) | 1.11 (0.75, 1.66) | 0.589 | 1.10 (0.73, 1.64) | 0.659 | |
Dominant model | GT + TT | 57 (75.00%) | 66 (70.97%) | 14 (77.78%) | 1.07 (0.58, 2.00) | 0.823 | 1.08 (0.56, 2.07) | 0.826 |
GG | 19 (25.00%) | 27 (29.03%) | 4 (22.22%) | 1 | 1 | |||
Recessive model | GG + GT | 54 (71.05%) | 69 (74.19%) | 14 (77.78%) | 1.22 (0.66, 2.29) | 0.526 | 1.17 (0.61, 2.25) | 0.632 |
TT | 22 (28.95%) | 24 (25.81%) | 4 (22.22%) | 1 | 1 |
Haplotype-based analysis results
Haplotype | NH group (freq) | Control group (freq) | Chi Square | P-Value | Non-vitamin D deficiency (freq) | Vitamin D deficiency (freq) | Chi Square | P-Value |
---|---|---|---|---|---|---|---|---|
CT | 0.368 | 0.400 | 0.709 | 0.3997 | 0.379 | 0.395 | 0.118 | 0.7315 |
CG | 0.308 | 0.278 | 0.737 | 0.3906 | 0.280 | 0.359 | 3.139 | 0.0765 |
AT | 0.282 | 0.301 | 0.317 | 0.5737 | 0.311 | 0.205 | 5.751 |
0.0165
|
AG | 0.042 | 0.021 | 2.374 | 0.1234 | 0.030 | 0.041 | 0.414 | 0.5199 |
SNP-SNP and SNP-vitamin D levels interaction models
Model | Training Bal. Acc. | Testing Bal. Acc. | CVC |
P
a
|
---|---|---|---|---|
Gene-gene interaction | ||||
rs10877012 | 0.5551 | 0.4886 | 5/10 | 0.623 |
rs12785878, rs10877012 | 0.6036 | 0.5376 | 10/10 | 0.623 |
rs12785878, rs10877012, rs12794714 | 0.6475 | 0.5210 | 6/10 | 0.0547 |