AbstractObjectiveTo examine the allelic diversity of structural, inflammatory, and matrix‐modifying gene candidates and their association with disc degeneration.MethodsSubjects were 588 men ages 35–70 years. We investigated associations of single‐nucleotide polymorphisms in AGC1 and in 12 collagen, 8 interleukin, and 4 matrix metalloproteinase genes with quantitative magnetic resonance imaging measurements of disc desiccation and disc bulging and height narrowing scores, after controlling for age and suspected risk factors. Analyses were performed using QTDT software.Pvalues were derived from 1,000 permutations, and empiricalPvalues for global significance also were applied.ResultsTwelve of the 99 variants in 25 selected candidate genes provided evidence of association (P< 0.05) with disc signal intensity in the upper and/or lower lumbar regions. Allelic variants of AGC1 (rs1042631;P= 0.001), COL1A1 (rs2075555;P= 0.005), COL9A1 (rs696990;P= 0.00008), and COL11A2 (rs2076311;P= 0.018) genes provided the most significant evidence of association with disc signal intensity. The same variants of AGC1 (P= 0.010) and COL9A1 (P= 0.014), as well as variants in the COL11A1 gene (rs1463035 [P= 0.004]; rs1337185 [P= 0.015]) were also associated with disc bulging, as was AGC1 with disc height narrowing (rs1516797;P= 0.005). In addition, 4 allelic variants in the immunologic candidate genes (rs2071375 in IL1A [P= 0.027]; rs1420100 in IL18RAP [P= 0.005]) were associated with disc signal intensity.ConclusionGenetic variants account for interindividual differences in disc matrix synthesis and degradation. The accuracy of the quantitative disc signal intensity measurements we used likely enhanced our ability to observe these associations. Our findings shed light on possible mechanisms of degeneration and support the view that disc degeneration is a polygenetic condition.