Arthritis Genetics: Polygenic Inheritance, Not Simple Autosomal or Sex-Linked

Arthritis is not a single-gene disorder. It is a polygenic (multifactorial) condition resulting from the interplay of multiple genetic variants and environmental factors.

Genetic Architecture

• GWAS findings: >100 loci associated with rheumatoid arthritis (RA); HLA-DRB1 shared epitope alleles (strongest). Osteoarthritis (OA): >100 loci (e.g., GDF5, COL2A1). Ankylosing spondylitis: HLA-B27 (major), ERAP1, IL23R.
• Heritability estimates: RA ~60%, AS ~90%, OA ~40–65%.
• Polygenic risk scores (PRS) aggregate thousands of SNPs to estimate susceptibility.

Environmental Triggers

• Smoking (RA, especially ACPA+)
• Obesity (OA, RA)
• Microbiome (gut, oral)
• Infections (EBV, periodontal pathogens)
• Occupational joint loading (OA)
• Vitamin D deficiency

Gene-Environment Interaction

Example: HLA-DRB1 SE alleles + smoking → 20–40× increased RA risk (synergistic).

Clinical Implication

• No single genetic test diagnoses or predicts arthritis.
• Family history informs risk but is not deterministic.
• Precision medicine: genetic markers may guide biologic selection (e.g., HLA-DRB1 for rituximab response).

Arthritis etiology is complex; reduction to simple Mendelian patterns is inaccurate.