rs2032582

This pilot study investigated associations between genetic polymorphisms in transporter genes (SLC19A1, ABCC2, ABCB1, ABCC1, ABCC3, ABCG2) and clinical response to methotrexate (MTX) in 100 Chinese rheumatoid arthritis (RA) patients. Multiple SNPs showed significant associations with MTX response: SLC19A1 rs12659 and rs3788200 major alleles were associated with EULAR good/moderate response (RR=1.42-1.45, p=0.03-0.04); ABCC2 rs3740066 major allele was associated with DAS28-ESR low disease activity (RR=0.67, p=0.02). Haplotype analysis identified significant associations of SLC19A1 and ABCC2 haplotypes with clinical response outcomes.

This PhD thesis comprises multiple studies examining personalized treatment with psychiatric drugs through pharmacogenetics and therapeutic drug monitoring. Two key studies examined: (1) ABCB1 polymorphisms (rs1045642, rs2032582, rs4148739, rs2235040, rs2235015, rs2032583, rs28401781, rs9282564) in relation to antidepressant response in 152 Russian patients with moderate-to-severe depression over 4 weeks, finding rs2235040 and rs4148739 influenced timing of antidepressant response (early vs late). (2) ABCB1 polymorphisms and antipsychotic-induced hyperprolactinemia in Russian schizophrenia patients (N=186), revealing rs2032582 (G2677T) was protective against hyperprolactinemia in the risperidone/paliperidone subgroup. (3) CYP17 polymorphism (rs743572, T34C) and tardive dyskinesia in 146 patients, finding CYP17 CC genotype protective against tardive dyskinesia, though not mediated through DHEA(S) levels.

This dissertation examined pharmacogenetic associations with clozapine adverse effects in 237 Finnish schizophrenia patients. ADRA2A rs1800544 was associated with clozapine-induced sialorrhea (OR 2.13, 95% CI: 1.17-3.88, p=0.013). Eight HNMT SNPs in complete linkage disequilibrium (r²=1) were associated with sedation. CHRM3 rs685548 and weighted genetic risk scores from HTR4, HTR7, TPH1, CHRM2, ABCB1, and OPRM1 were associated with anticholinergic symptoms.

Case-control study of 1,000 Han Chinese individuals (450 epilepsy cases, 550 controls) examining associations between STX1B polymorphisms and epilepsy treatment response. The rs140820592 variant showed significant association with reduced epilepsy risk (OR=0.542, p=0.004) and drug-resistant epilepsy risk (OR=0.260, p=0.004), with eQTL analysis confirming rs140820592 regulates STX1B expression in brain tissues.

This case-control study of 283 SLE patients and 247 healthy controls in the Chinese Guangxi population found that MDR1 rs1128503 T allele and TT genotype were associated with increased systemic lupus erythematosus susceptibility (T allele: OR 1.36, 95% CI 1.07-1.74, P = 0.014; TT genotype: OR 1.77, 95% CI 1.08-2.88, P = 0.022), with stronger effects in older subjects (≥40 years). The rs1045642 polymorphism showed no significant associations with SLE risk.

This pharmacogenetic study of 54 Asian nasopharyngeal cancer patients examined how polymorphisms in CYP3A4, CYP3A5, ABCB1, ABCC2, ABCG2, and SLCO1B3 affect docetaxel pharmacokinetics and toxicity. Patients homozygous for the variant allele (GG) of SLCO1B3 rs11045585 had significantly higher AUC and lower clearance of docetaxel (P = 0.026 and P = 0.036, respectively). ABCB1 heterozygotes showed the highest decrease in nadir hemoglobin (P = 0.006). The study suggests functional polymorphisms in SLCO1B3 and ABCB1 cooperatively influence docetaxel disposition.

A candidate gene association study examining ABCB1 (MDR1) gene variants and corticosteroid dependence in 260 pediatric Crohn's disease patients. The rare C allele of rs2032583 conferred protection from corticosteroid dependency (OR=0.56, 95% CI: 0.34-0.95, P=0.029), with the heterozygous TC genotype also protective (OR=0.52, P=0.035). A three-marker haplotype was significantly associated with corticosteroid dependence after multiple comparison correction (P=0.004).

A candidate gene study of 34 patients with neuropathic pain found significant association between the serotonin receptor 2C gene (HTR2C rs6318 C allele) and pain relief during escitalopram treatment, with an odds ratio of 15.5 (p=0.014) in men and 10.6 (p=0.010) in combined analysis. Additional genes in the serotonergic pathway including HTR2A, SLC6A4 (5-HTTLPR), CYP2C19, and ABCB1 were also analyzed, with 5-HTTLPR showing a borderline association.

This systematic review of 98 studies examined biological predictors of clozapine response in treatment-resistant schizophrenia patients. Of 379 different gene variants investigated across 70 genetic studies, only three variants (DRD3 Ser9Gly rs6280, HTR2A His452Tyr, and GNB3 C825T) achieved independent replication. Non-genetic predictors included higher prefrontal cortical volumes and lower HVA:5-HIAA ratio in cerebrospinal fluid.

A population pharmacokinetics study of ciclosporin A (CsA) in 33 de novo kidney transplant recipients found that body weight explained 35% of variability in CsA clearance and prednisolone dose >20 mg/day explained 20% of within-patient variability. Genetic polymorphisms in ABCB1 (rs1128503, rs1045642, rs2032582), CYP3A4, CYP3A5, and PXR were not significantly associated with CsA pharmacokinetics after accounting for non-genetic covariates.

This case-control association study analyzed three ABCB1/MDR1 gene polymorphisms (rs1128503, rs2032582, rs1045642) in 95 Polish colorectal cancer patients to assess their role as prognostic factors. The T1236 allele (rs1128503) was significantly more frequent in early-stage tumors (T1/T2: 89.7%, M0: 81.6%, I/II: 82.7%) versus advanced-stage tumors (T3/T4: 68.2%, M1: 47.4%, III/IV: 65.1%, p=0.0021, HR=0.26, p=0.0424). The haplotype T1236-G2677-C3435 was detected only in less advanced tumors. Multivariate Cox regression identified T1236 allele as an independent protective prognostic factor for colorectal cancer survival.

This comprehensive review synthesizes genomic and pharmacogenomic research in schizophrenia, discussing over 200 candidate genes associated with psychotic disorders, genetic mechanisms including copy number variants and microRNA alterations, and pharmacogenomic factors affecting antipsychotic efficacy and safety. Key genes covered include dopamine receptors (DRD1-5), dysbindin (DTNBP1), DISC1, neurotrophic factors, and metabolic enzymes such as CYP2D6, CYP3A4, and COMT, with emphasis on genotype-phenotype correlations in antipsychotic response and side effects.

A systematic review of 98 studies investigating biological predictors of clozapine response in treatment-resistant schizophrenia. Of 70 genetic studies examining 379 variants, only three genetic variants have independently replicated findings: DRD3 Ser9Gly (rs6280), HTR2A His452Tyr, and GNB3 C825T (rs5442/rs5443). Non-genetic predictors include higher prefrontal cortical structural integrity and activity, and lower HVA:5-HIAA ratio in cerebrospinal fluid.

This case-control study of 270 pediatric Crohn's disease cases and 336 controls examined 14 tag-SNPs in the ABCB1/MDR1 gene for associations with disease susceptibility and phenotypes. While SNP rs17327442 showed nominal association with overall CD susceptibility (OR=0.72, P=0.04), this did not withstand multiple testing correction. Two SNPs (rs10248420, rs2032583) were significantly associated with colonic disease location (L2±L4), and five SNPs were nominally associated with noninflammatory disease phenotype. Haplotype analysis revealed specific haplotypes associated with colonic and noninflammatory CD phenotypes.

Case-control study of 310 Croatian IBD patients (199 CD, 109 UC) and 120 healthy controls investigating MDR1 (ABCB1) polymorphisms C3435T (rs1045642) and G2677T (rs2032582). The 3435TT genotype was associated with UC (p=0.02; OR 2.12, 95% CI 1.11-4.03), and carriers of the 3435T/2677T haplotype had increased UC risk (p=0.02; OR 1.55, 95% CI 1.06-2.28). Heterozygous C3435T carriers showed protective effect in CD (p=0.02; OR 0.58).

This pharmacogenetics study analyzed 28 SNPs in methotrexate (MTX) metabolism genes (SLC19A1/RFC1, ABCB1, FPGS, GGH) in two Spanish populations with rheumatoid arthritis (n=124 and n=194). Key findings: FPGS rs10987742 and rs10106 associated with MTX response (p=0.033, p=0.041); FPGS rs10106 also associated with MTX survival (p=0.005) and toxicity (p=0.021); ABCB1 rs868755, rs10280623, rs1858923 associated with toxicity (p=0.025, p=0.048, p=0.031). In the first study, MTHFR rs17421511 (p=0.024) and rs1476413 (p=0.0086) associated with response, DHFR rs1643650 (p=0.026) associated with response, ATIC rs16853826 associated with toxicity (p=0.039).

This pharmacogenetic study examined genetic variants in the folate metabolism and MTX transport pathways in rheumatoid arthritis patients receiving methotrexate monotherapy. Study 1 (n=124) identified rs17421511 and rs1476413 in MTHFR and rs1643650 in DHFR as significantly associated with MTX treatment response (p=0.024, p=0.0086, p=0.026 respectively), and rs16853826 and rs10197559 in ATIC as associated with toxicity (p=0.039). Study 2 (n=194) found rs10106 and rs10987742 in FPGS associated with response, and rs868755, rs10280623, rs1858923 in ABCB1 associated with toxicity, with rs10106 also associated with longer MTX monotherapy survival.

A case-control study of 146 Bulgarian colorectal cancer patients and 160 healthy controls found no significant association between MDR1/ABCB1 polymorphisms 2677G>T (rs2032582) and 3435C>T (rs1045642) and sporadic colorectal cancer risk. The 2677T allele frequency was 43.5% in patients vs 44.1% in controls, and the 3435T allele frequency was 48.3% vs 50.9% (both P > 0.05). No differences were observed in haplotype frequencies or in tumor vs normal tissue genotypes.

A case-control study of 365 UC and 331 CD patients versus 550 controls in a Spanish population found that the PXR gene locus (specifically a risk haplotype rs3814055*T//rs6784598*C//rs2276707*C) was significantly associated with extensive ulcerative colitis (OR=1.66, 95% CI 1.20-2.30, P=0.001). The study also identified an epistatic interaction between PXR -25385C/T and MDR1 rs3789243, where carriers of risk alleles at both loci showed increased susceptibility to extensive UC.

Population-based case-control study of 285 Russian colorectal cancer patients and 275 controls examining the association between MDR1/ABCB1 gene polymorphisms and cancer susceptibility. The study found a significant association between MDR1 genotypes (-129TT; 2677GG; 3435CC and -129TT; 2677TT; 3435TT) and colorectal cancer risk in lifelong non-smokers aged ≥63 years (OR=3.9, 95% CI: 2.0-7.7), with stronger effects for rectal cancer (OR=5.4) than colon cancer (OR=2.7). The association was dependent on smoking status and age, highlighting the interaction between genetic and lifestyle risk factors.

A meta-analysis of 52 case-control studies (15,789 cases and 20,274 controls) examining associations between MDR1 (ABCB1) polymorphisms and cancer risk. The 3435C>T polymorphism showed significant association with cancer (OR=1.286, 95% CI=1.123-1.474 for TT vs CC), particularly in acute lymphoblastic leukemia (ALL: OR=1.890) and Caucasian populations. The 2677G>T/A polymorphism was associated with increased cancer risk overall (OR=1.348) and especially in Asian populations (OR=1.642). The 1236C>T polymorphism showed no significant association with cancer risk.