rs4818

This international doctoral thesis examined gene-physical activity interactions in fibromyalgia through six studies analyzing 64 SNPs across 34 candidate genes in Spanish women. The case-control study (314 fibromyalgia cases vs. 112 controls) identified associations of rs841 (GCH1), rs1799971 (OPRM1), and rs2097903 (COMT) with fibromyalgia susceptibility (p=0.04, p=0.02, and p=0.04 respectively). Cross-sectional studies (n=274-276 fibromyalgia patients) found that SCN9A rs4453709 and other genetic polymorphisms interacted with physical activity to influence pain, fatigue, and resilience outcomes.

This review examines neurogenetic and neuropharmacological correlates of opioid use disorder (OUD) with emphasis on ancestry-specific genetic risk profiles. The paper identifies multiple genes involved in the reward pathway (DRD2, DRD3, DRD4, OPRM1, OPRK1, OPRD1, BDNF, NRXN3, COMT, SLC6A4, KCNC1, KCNG2) and their variants associated with OUD susceptibility and treatment response across different ethnic populations, highlighting critical research disparities where African Americans and Hispanics have been underrepresented in genetic association studies.

This nested case-control study of 361 women with advanced serous epithelial ovarian cancer (102 incomplete responders, 259 complete responders) identified germline STAT3 polymorphisms as predictors of unfavorable response to first-line platinum-based chemotherapy. The lead STAT3 SNP rs62075772 showed the strongest association with treatment resistance (OR 2.24, 95% CI 1.32-3.78, p=0.0027), and STAT3 was significantly associated at the gene level (p=0.006 by admixture maximum likelihood test).

This case-control study of 468 schizophrenia patients treated with clozapine (202 with metabolic syndrome, 266 without) examined associations between three COMT gene polymorphisms (rs4633, rs4680, rs4818) and metabolic parameters. The key finding was a significant association between rs4680 (the Val158Met variant) and elevated triglyceride (TG) levels (corrected P=0.024), particularly among female patients (P=0.009), suggesting a potential role for COMT variation in clozapine-associated metabolic syndrome.

A candidate gene association study in 100 Russian vitiligo patients and 100 controls identified a strong novel association between GSTP1 rs1138272 (Ala114Val, OR=13.03, Bonferroni-adjusted P=0.0015) and vitiligo susceptibility. Cumulative analysis of multiple xenobiotic metabolizing genes showed that carrying higher numbers of risk alleles was associated with increased vitiligo risk (9-16 vs 3-8 alleles: OR=2.79, P=0.00063), supporting a polygenic model for vitiligo involving detoxification pathway genes.

This population-based study of 3,904 subjects examined the interaction between COMT and TXNRD2 SNPs and temporomandibular disorder (TMD) pain, modified by depressive symptoms. Six SNPs from the first COMT/TXNRD2 haploblock showed significant interactions with depressive symptoms (smallest p-value: 2.7 × 10^-10), with opposite SNP effects between depressed and non-depressed individuals. In non-depressed subjects, rs5993882 (COMT) was most associated with TMD pain, while in depressed subjects, rs1544325 (COMT) and TXNRD2 SNPs were preferentially associated. The findings indicate that COMT polymorphisms affect pain perception through a mechanism significantly moderated by depressive symptoms.

Case-control study of 112 Brazilian fibromyalgia patients and 110 healthy controls examining COMT gene SNPs rs4680 and rs4818. The homozygous mutant genotype AA of rs4680 was present in 77.67% of patients vs 28.18% of controls (FIQ score 87.92 vs 15.56). The CC genotype of rs4818 was found in 73.21% of patients vs 39.09% of controls (FIQ score 86.14 vs 13.13). Both SNPs showed significant association with fibromyalgia and elevated pain sensitivity (p < 0.001).

Case-control study of 604 Han Chinese examining associations between two COMT gene polymorphisms (rs740603 and rs4818) and schizophrenia. Found no significant association with schizophrenia susceptibility, but rs740603 and the rs740603(G)-rs4818(G) haplotype were associated with negative symptoms severity, particularly in females (p=0.025 for rs740603; p=0.021 for haplotype in females).

This review examines polymorphisms in six genes (SCN9A, KCNS1, GCH1, COMT, OPRM1, OPRK1) involved in nociception and their associations with chronic post-surgical pain (CPSP). Key findings include rs4680 in COMT associated with higher pain risk (OR 3.42 in knee replacement patients), rs734784 in KCNS1 explaining ~5% of pain variance in lumbar discectomy patients, and rs6746030 in SCN9A conferring increased pain sensitivity. The paper reviews conflicting evidence across multiple surgical populations and discusses potential clinical applications of genetic testing for CPSP risk stratification.

This comprehensive review examines the genomics of schizophrenia and pharmacogenomics of antipsychotic drugs, synthesizing evidence on over 200 genes associated with psychotic disorders. The authors discuss five categories of genes relevant to antipsychotic response: disease-associated genes, mechanism-of-action genes, drug metabolism genes (particularly CYP2D6, CYP2C19, CYP2C9, CYP3A4), drug transporter genes, and pleiotropic genes. The review details pharmacogenomic profiles of 20+ antipsychotic drugs and demonstrates significant ethnic and interindividual variation in drug metabolism phenotypes, with examples including CYP2D6 extensive metabolizers (55.71% of population), intermediate metabolizers (34.7%), poor metabolizers (2.28%), and ultra-rapid metabolizers (7.31%).

This case-control association study of 931 Caucasian schizophrenia patients (270 with treatment-resistant schizophrenia [TRS], 661 non-TRS) examined COMT rs4680 (Val158Met) and rs4818 polymorphisms for sex-specific associations with treatment resistance. In females with TRS, the COMT rs4680 AA genotype was nominally more frequent than G carriers (p=0.033), and the COMT rs4818 CC genotype was significantly more frequent than G carriers (p=0.014). The high-activity G-G/G-G haplotype was protective against TRS in females (p=0.009, OR=2.10 for non-carriers vs GG carriers), but no associations were found in males. Results suggest estrogen-modulated, sex-specific effects of COMT variants on antipsychotic treatment response.

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.

This population-based study of 4,470 breast cancer cases from the SEARCH cohort examined associations between germline polymorphisms in 6 steroid hormone metabolism genes (COMT, CYP19A1, ESR1, PGR, SULT1E1, STS) and survival after breast cancer diagnosis. A COMT polymorphism (rs4818) showed significant association with survival in a dominant model (HR=0.80, 95% CI: 0.69-0.95, p=0.009), though this was only marginally significant after permutation adjustment (p=0.047). No significant associations were found in the other genes studied.

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.

Association study of COMT haplotypes in 435 adult ADHD patients and 383 controls reveals that the high-activity COMT haplotype (tagged by rs6269) is associated with increased hyperactivity/impulsivity scores (P=0.01). All four COMT SNPs (rs6269, rs4633, rs4818, rs4680) showed a trend toward association with the hyperactivity/impulsivity dimension (peak P=0.007 for rs6269), suggesting COMT haplotype variation has stronger effects on ADHD symptom severity than the Val158Met polymorphism alone.

Literature review of 77 publications examining the effects of genes COMT, MAO-A, MAO-B, DAT, DRD2, VMAT2, TPH2, and SNCA on Parkinson's disease neuropsychiatric symptoms and therapy response. Key polymorphisms include rs1800497 (DRD2) associated with impulse control disorders, rs6269/rs4633/rs4818/rs4680 (COMT) with cognitive decline, and rs1352250/rs6582078 (TPH2) with impulse control. The review identifies genetic predictors for early complications (cognitive decline, depression, psychosis, impulse control disorders) and therapy optimization, relevant for patient selection for deep brain stimulation.

This case-control study examined COMT gene polymorphisms in 150 endometrial cancer patients and 165 controls, identifying that the COMT codon 62 T/T genotype (rs4633) is associated with increased endometrial cancer risk (OR=2.39, 95% CI: 1.31-4.37, P=0.004). The protective C-G haplotype of codons 62 and 158 was significantly more frequent in controls (P<0.0001), and immunohistochemistry showed that polymorphic variants led to lower COMT protein expression in cancer tissues.

This paper demonstrates the application of ion-pair reversed-phase HPLC-electrospray ionization time-of-flight mass spectrometry (ICEMS) for haplotyping five SNPs (rs769223, rs4818, rs4986871, rs8192488, rs4680) in exon 4 of the human COMT gene. Using two differently sized PCR amplicons analyzed simultaneously, the authors genotyped 101 Austrian individuals and obtained haplotype frequency distributions for reference in future association studies. Two previously unknown polymorphic sites within the COMT gene were also detected and characterized.

Population genetics study of OPRM1 and COMT gene variants in the Chaco province of Argentina. Genotyped 11 SNPs in 54 individuals from Misión Nueva Pompeya and compared with published data from Resistencia (n=109) and Wichí native communities (n=27). Found significant population differentiation at Fst values ranging from 1.507% to 2.744% between populations, with notable variation in pain-related and dopaminergic genes that could inform personalized pain management strategies.

This functional study examined differential allele expression of COMT polymorphisms using an RT-coupled 5' nuclease assay in human lymphoblasts and brain tissue. The Met158 allele (rs4680) showed consistent 65-77% higher mRNA expression than Val158 across both tissue types (29/29 lymphoblasts and 39/39 brain samples). Val158 was less expressed despite being associated with higher enzyme activity, demonstrating opposing effects on mRNA expression versus protein activity that together result in ~30% lower enzyme activity with the Met158 allele.

This doctoral thesis conducted multiple candidate gene association studies in 274-426 southern Spanish women with fibromyalgia to investigate gene-physical activity/sedentary behavior interactions with pain, fatigue, and resilience. Study III identified rs841 (GCH1) GG genotype (OR=0.61, p=0.04) and rs2097903 (COMT) AT/TT genotypes (OR=1.66, p=0.04) associated with fibromyalgia susceptibility, and confirmed rs1799971 (OPRM1) GG genotype (OR=0.58, p=0.02) confers genetic risk. Study IV found rs6311/rs6313 (HTR2A) polymorphisms individually associated with algometer pain score, and gene-sedentary behavior interactions involving rs4680/rs165599 (COMT), rs1383914 (ADRA1A), rs12994338/rs4453709 (SCN9A), and rs6860 (CHMP1A) significantly associated with pain outcomes. SCN9A emerged as most robust gene for fibromyalgia phenotype.