FROM PHENOTYPE TO GENOTYPE: DO COMT, MTHFR, BDNF, OPRM1, AND HTR2A POLYMORPHISMS CONTRIBUTE TO CHRONIC MUSCULOSKELETAL PAIN?

H. Demir Usan | Faculty of Medicine, Yuksek Ihtisas University, Ankara, Turkey

Background and Aims. This study sought to determine whether functional polymorphisms in COMT, MTHFR, BDNF, OPRM1, and HTR2A are differentially distributed across major chronic musculoskeletal pain phenotypes and whether they are associated with pain severity, fatigue, stress, and disease duration.
Methods. In this single-center retrospective observational study, the researchers included 19 adults with chronic musculoskeletal pain lasting more than 3 months. Primary diagnoses were fibromyalgia, myofascial pain syndrome, lumbar disc herniation, and arthritis-related pain. Clinical data (demographics, diagnosis, disease duration, VAS pain/fatigue/stress) were extracted from the records. Genomic DNA was isolated from buccal swabs and genotyped for COMT (rs4680, rs4633, rs4818, rs6269), MTHFR (rs1801133, rs1801131), BDNF rs6265, OPRM1 rs1799971, and HTR2A (rs6311). Nonparametric tests (Kruskal–Wallis, chi-square/Fisher's exact) were applied (p<0.05).
Results. Fibromyalgia (n=11) showed the greatest genetic heterogeneity, with COMT and MTHFR intermediate/low-activity genotypes and predominantly AA OPRM1 rs1799971. Myofascial pain syndrome (n=3) displayed a similar “nociplastic” profile with heterozygous COMT and MTHFR and OPRM1 AA. Arthritis and lumbar disc herniation were characterized by preserved MTHFR/BDFN patterns and higher frequencies of OPRM1 rs1799971 AG, suggesting a more nociceptive, opioid-modulated profile. OPRM1 rs1799971 distribution differed significantly across diagnoses (p=0.017), while no SNP showed significant associations with VAS pain, fatigue, or stress.
Conclusions. Diagnosis-specific genotype patterns, particularly for OPRM1 rs1799971, support biologically distinct nociplastic versus nociceptive profiles in chronic musculoskeletal pain. Although underpowered for definitive associations, this pilot study illustrates the potential of multimarker genetic panels for mechanism-oriented phenotyping and calls for larger, prospective, multi-omic studies to refine genotype-informed, personalized pain management.