Table 2.
Overview of pharmacogenetic investigations and results.
| Reference | Sample tissue | Approach | Method | Gene(s) investigated | Genetic variants investigated | Pharmacogenetic outcomes | |
|---|---|---|---|---|---|---|---|
| Antidepressants | Corti et al. (2019) | Maternal blood and neonatal cord blood samples at birth | Candidate genes | Real-time PCR | CYP2D6, CYP2C19, CYP2B6, CYP3A4, and CYP3A5 | CYP2D6: CYP2D6*3, CYP2D6*4, CYP2D6*5, CYP2D6*6, rs1080985 and gene duplication; CYP2C19: CYP2C19*2, CYP2C19*3, and CYP2C19*17; CYP2B6: CYP2B6*6; CYP3A4: CYP3A4*22; CYP3A5: CYP3A5*3 | • No interaction between the investigated genes and antidepressant exposure on the phenotypic outcomes (p > 0.05) |
| Ackerman et al. (2017) | Neonatal blood samples | Whole-exome | Whole-exome sequencing | Genes exhibiting de novo LGD mutations [4,234 genes with de novo mutations identified in Iossifov et al. (2014)] | De novo LGD mutations (nonsense, splice site, and frame-shift) | Upon antidepressant exposure: • Children with ASD and LGD mutations had increased ADOS-evaluated ASD severity [F(1, 2542) = 4.882; p = 0.027] • Children with ASD and LGD mutations had higher ADI-R verbal communication score [F(1, 2397) = 4.554; p = 0.033] |
|
| Daud et al. (2017) | Self-sampled buccal cells (swabs) from mother and neonatal | Candidate genes | PCR | CYP1A2, CYP2C9, CYP2C19, CYP2D6, ABCB1, SLC6A4, HTR1A, HTR1B, HTR2A, and HTR3B | 53 variants in the 10 genes investigateda | • No interaction found between the investigated genes and antidepressant exposure on the risk of congenital heart anomalies (p > 0.05) | |
| Nembhard et al. (2017) | Self-sampled buccal cells (swabs) from parents and child | Candidate genes | Microarray | 60 genesb | 872 variants in the 60 genes investigated | Upon SSRI exposure: • Increased risk of congenital heart anomalies found if mothers exhibited SHMT rs9909104 AA/AG (p = 4.24 × 10−4), BHMT rs492842 AG/GG (p = 1.23 × 10−3), BHMT rs542852 AG/GG (p = 2.64 × 10−3), or MGST1 rs2075237 CC/AC (p = 6.97 × 10−4)c • Increased risk of congenital heart anomalies found if infants exhibited MGMT rs11511217 GG/AG (p = 5.67 × 10−04), GSTP1 rs7941395 GG/AG (p = 1.33 × 10−3); MGST1 rs7294985 GG/AG (p = 9.94 × 10−4), MTHFS rs1243847 AA/AC (p = 2.44 × 10−04), TRDMT1 rs66022178 AC/CC (p = 3.48 × 10−3), or GNMT rs11752813 CG/CC (p = 3.71 × 10−3)d • Increased risk of obstructive heart defects found if mothers exhibited TRDMT1 rs2038576 AG/GG (p = 3.39 × 10−5) or TRDMT1 rs2273735 AG/GG (p = 2.33 × 10−4)e • Increased risk of obstructive heart defects found if infants exhibited TRDMT1 rs10795459 AA/AG (p = 2.41 × 10−4), TRDMT1 rs17464824 CC (p = 6.57 × 10−4), and TRDMT1 rs10904893 GG (p = 7. 4 7 × 10−4)f |
|
| Weikum et al. (2013) | Neonatal whole blood samples | Candidate gene | PCR | SLC6A4 | SLC6A4 long and short alleles | • Upon SSRI exposure, children homozygous for the long allele (ll) of SLC6A4 had accuracy in the Hearts and Flowers task inversely related to the current severity of maternal depression (β = −0.092; 95% CI−0.171 – −0.014; χ2=5.29; p = 0.021) | |
| Brummelte et al. (2013) | Maternal blood and cord blood samples | Candidate gene | PCR | SLC6A4 | SLC6A4 long and short alleles | • Upon SRI exposure, mothers homozygous for the long allele (ll) of SLC6A4 had greater expression of the 310 kDa reelin band (p = 0.007) | |
| Oberlander et al. (2010) | Maternal blood and cord blood samples | Candidate gene | PCR | SLC6A4 | SLC6A4 long and short alleles | • No association of child or maternal SLC6A4 genotypes with child behavior upon SSRI exposure | |
| Hilli et al. (2009) | Neonatal blood samples | Candidate genes | Real-time PCR | SLC6A4, HTR1A, COMT, MAO-A, CYP2C19, and CYP2D6 | SLC6A4: 5-HTTLPR and 5-HTTVNTR; HTR1A: rs6295 and rs6313; COMT: rs4680; MAO-A: uVNTR (3, 3.5, 4, and 5 copies); CYP2C19: CYP2C19*2; CYP2D6: CYP2D6*3 and CYP2D6*4 | Upon SSRI exposure: • Children with the MAO-A genotype 4/4 copies exhibited higher serotonergic symptom scores (p = 0.024) and cord blood dihydroxyphenylglycol concentrations (p = 0.0054) • Children with COMT rs4680 GG/GA had higher cord blood prolactin concentrations (p = 0.044) • CYP2D6*3 or *4 heterozygous children had higher fluoxetine concentrations (p = 0.033) and active moieties (fluoxetine and norfluoxetine concentrations; p = 0.019) in blood |
|
| Oberlander et al. (2008) | Maternal blood and cord blood samples | Candidate gene | PCR | SLC6A4 | SLC6A4 long and short alleles | Upon SSRI exposure: • SLC6A4 heterozygous neonates had lower birth weight (F = 7.45; p = 0.008; η2 = 0.19) and increased risk of experiencing respiratory distress (p = 0.013) • Neonates homozygous for the long SLC6A4 allele had increased risk of rapid breathing (p = 0.018), respiratory distress (p = 0.043), and jitteriness (p = 0.014) • Neonates homozygous for the SLC6A4 short allele had higher birth weight (F = 4.50; p = 0.037; η2 = 0.29), lower 5-min Apgar (p < 0.001), increased jitteriness (p = 0.026), and abnormal tone (p = 0.017) |
|
| Antiepileptic drugs | Jose et al. (2014) | Peripheral blood samples | Candidate genes | PCR and RFLP | ABCB1, MTHFR, CYP2C9, and CYP2C19 | ABCB1: rs3213619, rs2214102, rs1202168, rs1128503, rs1922242, rs2032582, and rs1045642; MTHFR: rs1801133 and rs1801131; CYP2C9: CYP2C9*2 and CYP2C9*3; CYP2C19: CYP2C19*2 and CYP2C19*3 | Upon AED exposure: • Mothers of children with congenital anomalies had an increased frequency of ABCB1 rs1202168 CC (p = 0.0032) and the poor metabolizer CYP2C19*2 OR = 1.639 (95% CI 1.150–2.335; p = 0.007) and *2*2 genotypes (p = 0.005) • Strong association between maternal ABCB1 GCT haplotype (rs2214102 G allele, rs1202168 C allele, rs1128503 T allele) and development of congenital anomalies (p = 2.18 × 10−5) |
| Azzato et al. (2010) | Maternal blood samples collected 8 weeks before birth, at birth, and 6 weeks after birth | Candidate genes | PCR | CYP2C9 and EPHX1 | CYP2C9: CYP2C9*2 and CYP2C9*3; EPHX1: rs1051740 and rs2234922 | Upon phenytoin exposure: • Craniofacial anomalies were associated with maternal EPHX1 rs1051740 allele C (OR = 2.43; 95% CI 1.16–5.10; p = 0.018) and rs2234922 allele G (OR = 2.33; 95% CI 1.09–5.00; p = 0.030) • Maternal EPHX1 C/G haplotype (rs1051740/rs2234922) was associated with a risk of cranio-facial anomalies (OR = 6.55; 95% CI 1.37–31.20; p = 0.018), whereas the EPHX1 T/A haplotype protected against craniofacial anomalies (OR = 0.29; 95% CI 0.12–0.68; p = 0.0042) |
|
| Dean et al. (2007) | Parental and neonatal blood or buccal samples | Candidate genes | PCR and RFLP | MTHFR, SHMT1, MTR, and MTRR | MTHFR: rs1801133 and rs1801131; SHMT: rs1979277; MTR: rs1805087; MTRR: rs1801394 | Upon AED exposure: • Maternal MTHFR rs1801133 TT was associated with increased risk of congenital anomalies (RR = 4.09; 95% CI 1.06–15.83; p = 0.041) and fetal anticonvulsant syndrome (RR = 3.1; 95% CI 1.09–8.81; p = 0.033) compared to the other genotypes • Children with MTR rs1805087 GA/GG genotypes had increased risk of neurodevelopmental delays (OR = 1.76; 95% CI 1.03–3.03; p = 0.028) and fetal anticonvulsant syndrome (OR = 1.85; 95% CI 1.13–3.02; p = 0.0089) compared to the healthy blood donor controls |
|
| Kini et al. (2007) | Maternal and neonatal buccal samples | Candidate gene | PCR and RFLP | MTHFR | rs1801133 | • Upon valproic acid exposure (monotherapy or polytherapy), a significantly increased risk of major malformations was associated with the MTHFR rs1801133 CT/TT genotypes compared to controls (non-exposed) CT/TT (OR = 7.79; 95% CI 1.45–41.9; p-value not reported) | |
| Dean et al. (1999) | Parental and neonatal peripheral blood samples | Candidate gene | PCR and RFLP | MTHFR | rs1801133 | • Mothers of children with fetal anticonvulsant syndrome exposed to AEDs had a higher frequency of MTHFR rs1801133 T allele (p < 0.01) and TT genotype (p < 0.02) compared to mothers of children not exposed to AEDs | |
| Glucocorticoids | Van Der Voorn et al. (2015) | Child blood samples | Candidate gene | Genotyping by MS | NR3C1 and NR3C2 | NR3C1: rs6190 and rs6195; NR3C2: rs2070951 and rs5522 | Upon betamethasone exposure: • Children carrying NR3C1 rs6195 variant had a decreased linguistic capacity (p = 0.04), ability for logical reasoning (p = 0.01), and parent-reported other problems (p = 0.03) • Children with NR3C2 rs2070951 GG had decreased ability for spatial visualization (p = 0.02) and reduced self-reported thought problems (p = 0.02) • Children with NR3C2 rs2070951 CC had more parent-reported aggressive behavior (p = 0.01) • Children carrying NR3C2 rs5522 had a decreased ability for logical reasoning (p = 0.04) |
| Haas et al. (2013) | Maternal whole blood or saliva samples and neonatal cord blood or saliva samples | Candidate gene | SNP array, Real-time PCR, and Sanger sequencing | CYP3A4, CYP3A5, CYP3A7, SULT, ABCB1, NR3C1, and associated pathway genesg | 73 SNPsg | Upon betamethasone exposure: • Increased risk of bronchopulmonary dysplasia was associated with mothers carrying the minor allele of CYP3A7 rs113874418 (p = 0.006), CRHR1 Chr. 17-43895531 (p = 0.006). or CYP3A7*1E rs28451617 (OR = 4.97; 95% CI 1.12–22.05; p = 0.02), and with child NR3C1 rs41423247 (OR = 2.56; 95% CI 1.11–5.95; p = 0.02) and IPO13 rs4448553 (OR = 0.01; 95% CI 0.00–0.92; p = 0.04) • The need for respiratory support was associated with child ABCB1 rs1128503 (OR = 2.23; 95% CI 1.05–4.74; p = 0.03) • The need for surfactant was associated with mothers carrying IPO13 rs2428953 (OR = 13.8; 95 % CI 1.80–105.5; p = 0.01) or IPO13 rs2486014 (OR = 35.5; 95% CI 1.71–736.6; p = 0.02) • The need for surfactant replacement therapy was associated with child OLR1 rs3736233 (OR = 0.35; 95% CI 0.17–0.71; p = 0.003) |
|
| Oretti et al. (2009) | Cord blood samples | Candidate gene | PCR and RFLP | ABCB1, NR3C1, and GST | ABCB1: rs1045642, rs2032582, and rs1128503; NR3C1: rs41423247, rs6195, rs6189, and rs6190; GSTP1: rs1695; deletions in GSTM1 and GSTT1 | • Upon betamethasone exposure, children with respiratory distress syndrome had an increased frequency of the GSTP1 rs1695 AA genotype (OR = 3.758; 95% CI 1.16–12.17; p = 0.032) | |
| Bertalan et al. (2008) | Neonatal whole blood or placental blood samples | Candidate gene | PCR and RFLP | NR3C1 | rs41423247, rs6195, rs6189, and rs6190 | • No interaction found between the investigated gene and dexamethasone exposure on the phenotypic outcomes (p > 0.05) | |
| Thalidomide | Kowalski et al. (2020) | Neonatal saliva samples | Candidate gene | Targeted next generation sequencing | CRBN, CUL4A, DDB1, IKZF1, and IKZF3 | 145 variants found across the 5 genes | • Among individuals with thalidomide embryopathy, a higher frequency of CRBN rs1045433 G was found in individuals with pre-axial limb anomalies (p = 0.004) |
| Gomes et al. (2019) | Neonatal saliva samples | Candidate gene | Targeted next generation sequencing | ESCO2, TBX5, and SALL4 | 38 variants found across the 3 genes | • No interaction found between the investigated genes and thalidomide exposure on the susceptibility to thalidomide embryopathy (p > 0.05) | |
| Gomes et al. (2018) | Neonatal saliva samples | Candidate gene | Real-time PCR | FGF8, FGF10, BMP4, SHH, TP53, TP63, and TP73 | FGF8: rs1348870; FGF10: rs900379; SHH: rs28936675; BMP4: rs17563; TP53: rs1042522; TP63: rs17506395; TP73: rs2273953 | • No interaction found between the investigated genes and thalidomide exposure on the susceptibility to thalidomide embryopathy (p > 0.05) | |
| Kowalski et al. (2017) | Neonatal saliva samples | Candidate gene | Real-time PCR | NOS2, PTGS2, and VEGFA | NOS2: rs2297518; PTGS2: rs689465 and rs689466; VEGFA: rs3025039, rs1570360, rs2010963, and rs699947 | • No interaction found between the investigated genes and thalidomide exposure on the susceptibility to thalidomide embryopathy (p > 0.05) | |
| Kowalski et al. (2016) | Neonatal saliva samples | Candidate gene | Real-time PCR and Sanger sequencing | NOS3 | rs2070744, rs1799983, and rs61722009 | • Individuals with thalidomide embryopathy had a higher frequency of NOS3 C/4b haplotype (rs2070744/rs61722009) compared to the control group; the risk of thalidomide embryopathy due to the presence of this haplotype had an OR of 2.57 (95% CI: 1.20–5.80; p = 0.018) | |
| Vianna et al. (2016) | Neonatal saliva samples | Candidate gene | Sanger sequencing | CRBN (exons 9–11) | 8 non-exonic variants were found | • Among individuals with thalidomide embryopathy, a higher frequency of CRBN rs1620675 CC (100%) was found in individuals with neurological anomalies (n = 5) compared to individuals without these anomalies (p = 0.004) | |
| Vianna et al. (2013) | Neonatal saliva samples | Candidate gene | Real-time PCR | NOS3 | rs2070744 and rs1799983 | • Individuals with thalidomide embryopathy had a higher frequency of NOS3
rs2070744 C allele (p = 0.009) and CC genotype (p = 0.031) compared to the control group • The control group (with no presumed exposure and no congenital anomalies) had a higher frequency of NOS3 haplotype T/G (rs2070744/rs1799983; p = 0.004) |
|
| Other medications | Bustos et al. (2017) | Maternal blood samples | Candidate gene | Real-time PCR | CYP3A4, CYP3A5, and NR3C3 | CYP3A4: rs35599367, rs2242480, and rs2740574; CYP3A5: rs776746; NR3C3: rs578029, rs471767, rs666553, rs503362 rs500760 | • No interaction found between the investigated genes and 7-alpha hydroxyprogesterone caproate exposure on 17-alpha hydroxyprogesterone caproate plasma concentrations or spontaneous preterm births (p > 0.05) |
| Van Der Zanden et al. (2012) | Child blood samples | Candidate gene | Real-time PCR | SRD5A2, ESR1, ESR2, and ATF3 | SRD5A2: rs523349; ESR1: rs6932902; ESR2: rs2987983; ATF3: rs11119982 | • Upon estrogen exposure, the risk of hypospadias was significantly associated with the presence of SRD5A2 rs523349 CG (RR = 2.7; 95% CI 1.0–7.4) or GG genotypes (RR = 2.9; 95% CI 1.0–8.3) in the affected individuals (p < 0.001) | |
| Perzanowski et al. (2010) | Maternal and neonatal peripheral blood samples | Candidate gene | Real-time PCR and PCR | GSTP1, GSTT2, GSTT1, and GSTM1 | GSTP1: rs1695; GSTT2: rs2719; GSTT1 and GSTM1 gene deletion | Upon acetaminophen exposure: • Children with GSTP1 rs1695 AG/GG genotypes had increased risk of current wheeze (RR = 2.08; 95% CI 1.34–3.23; p = 0.001) and seroatopy at 5 years (RR = 1.96; 95% CI 1.36–2.84; p < 0.001) • There was evidence of effect modification in the presence of at least one allele of GSTT1 in seroatopy (RERI = 0.98; 95% CI 0.50–1.5; p < 0.001) |
|
| Shaheen et al. (2010) | Maternal whole blood or saliva samples | Candidate gene | Real-time PCR | NRF2, GSTP1, GSTT1, and GSTM1 | NRF2: rs6706649; GSTP1: rs1695; GSTT1 and GSTM1 gene deletion | Upon acetaminophen exposure in early pregnancy: • Mothers with NRF2 rs6706649 TC/TT genotypes had increased risk of having children with asthma (OR = 1.73; 95% CI 1.22–2.45; p = 0.002) and wheezing (OR = 1.53; 95% CI 1.06–2.20; p = 0.024) • Mothers with at least on allele of GSTT1 (OR = 1.24; 95% CI 1.02–1.50; p = 0.03) or two copies of alleles of GSTM1 (OR = 1.96; 95% CI 1.09–3.51; p = 0.03) had increased risk of having children with asthma Upon acetaminophen exposure in late pregnancy: • Mothers with NRF2 rs6706649 TC/TT genotypes had increased risk of having children with asthma (OR = 1.63; 95% CI 1.13–2.37; p = 0.009) • Mothers with at least on allele of GSTT1 had increased risk of having children with asthma (OR = 1.39; 95% CI 1.14–1.70; p = 0.001) and wheezing (OR = 1.27; 95% CI 1.03–1.56; p = 0.03), and mothers with at least one allele of GSTM1 had increased risk of having children with asthma (OR = 1.41; 95% CI 1.02–1.95; p = 0.04) or wheezing (OR = 1.60; 95% CI 1.15–2.24; p = 0.006) |
The bolded values in the tables indicate the significant genes and genotypes discovered in each study.
a
CYP1A2: rs2069521, rs2069526, rs4646425, rs4646427, rs2472304, rs2470890; CYP2C9: rs1799853, rs1057910, rs56165452, rs9332131, rs28371686, rs7900194, rs28371685, rs72558187, rs72558190; CYP2C19: rs4244285, rs4986893, rs28399504, rs56337013, rs72552267, rs72558186, rs41291556, rs17884712, rs6413438, rs12248560; CYP2D6: rs16947, rs35742686, rs5030867, rs5030656, rs1065852, rs5030863, rs5030862; ABCB1: rs1128503, rs2032582, rs1045642, rs2235040, rs4148739, rs1882478, rs9282564, rs10256836; SLC6A4: rs4795541, rs57098334; HTR1A: rs1364043, rs6295; HTR1B: rs6296, rs6298; HTR2A: rs7997012, rs6313, rs6314, rs1928040, rs6311; HTR3B: rs1176744, rs3831455;
b
Genes not reported;
c
Mothers: SHMT rs9909104, AG RR = 2.43 (1.46–4.03) or GG RR = 5.90 (2.13–16.24); BHMT rs492842, AG RR = 2.15 (1.33–3.46) or GG RR = 4.62 (1.77–11.97); BHMT rs542852, AG RR = 2.06 (1.26–3.34); MGST1 rs2075237, CC RR = 7.95 (2.50–25.40) or AC RR = 2.82 (1.58–5.04);
d
Children: MGMT rs11511217, AG RR = 2.41 (1.45–4.01); GSTP1 rs7941395, GG RR = 4.71 (1.90–11.63) or AG RR = 2.17 (1.38–3.41); MGST1 rs7294985, GG RR = 6.10 (0.10–17.72) or AG RR = 2.47 (1.45–4.21); MTHFS rs1243847, AA RR = 6.76 (2.56–17.89) or AC RR = 2.60 (1.60–4.23); TRDMT1 rs66022178, AC RR = 1.79 (1.14–2.80) or CC RR = 3.2 (1.30–7.84); GNMT rs11752813, CG RR = 1.80 (1.15–2.80) or CC RR = 3.24 (1.32–7.84);
e
Mothers: TRDMT rs2038576, AG RR = 4.64 (2.20–9.77) or GG RR = 21.53 (4.84–95.45); TRDMT rs2273735, AG RR = 3.20 (1.67–6.10) or GG RR = 10.24 (2.79–37.21);
f
Children: TRDMT1 rs10795459, AA RR = 9.00 (2.66–30.36) or AG RR = 3.0 (1.63–5.51); TRDMT1 rs17464824, CC RR = 6.81 (2.07–22.56) or AC RR = 2.61 (1.44–4.75); TRDMT1 rs10904893, GG RR = 6.97 (2.13–22.47) or AG RR = 2.64 (1.46–4.74);
g
ABCB1: rs1128503, rs2032582, rs1045642; ADCY9: rs2230739; CRH: rs12721511; CRHR1: rs1876828, rs242941; CYP3A4: rs4987159; CYP3A5*3: rs776746; CYP3A7: rs2687133; CYP3A7*2: rs2257401; GLCCI1: rs37973; IPO13: rs7412307, rs2301992, rs2301993, rs2428953, rs4448553, rs2486014, rs2240447, rs1990150, rs6671164, rs1636879; NR3C1: rs41423247; OLR1: rs3736233; STIP1/FERMT3: rs2236647; SULT1A2: rs1136703; TBX21: rs2240017; TRAPPC5/FCER2: rs28364072; CRHR1: rs4564621, rs2316763, Chr. 17- 43895531, rs242939, rs2316764, rs4277389, rs6658607; Chr. 17- 43895671, rs80249281, rs11316767, rs116593005, rs149144271, rs8077279, rs16940655; CYP3A7: rs45496695, rs45446698, rs113874418, rs11568826, rs45467892, rs45575938, rs45494802, rs11568824; CYP3A7*1B: rs45465393; CYP3A7*1C: rs11568825; CYP3A7*1D: rs55798860; CYP3A7*1E: rs28451617; NR3C1: rs6189, rs6190, rs72542738, rs72481829, rs61759025, rs79138720, rs6192, rs72558023, rs72542745, rs72558022, rs13306589, rs56149945, rs1800445; CYP3A4*1B: rs2740574; CYP3A5*6: rs10264272; CYP3A5*7: rs41303343; SULT1A1*2: rs9282861; SULT1A1: rs3760091, rs750155. AED, anti-epileptic drug; ASD, autism spectrum disorder; ADI-R, Autism Diagnostic Interview-revised; ADOS, autism diagnostic observation schedule; CI, confidence interval; LGD, likely gene-disruptive; MS, mass spectrometry; OR, odds ratio; PCR, polymerase chain reaction; RERI, relative excess risk due to interaction; RFLP, restriction fragment length polymorphism; RR, risk ratio; SNP, single nucleotide polymorphism; SRI, serotonin reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor.