Abstract
Objective The genetic component of ankylosing spondylitis (AS) development is ~90%. Of the known heritability, ~20% is explained by HLA-B27, and 113 identified AS-associated SNPs account for ~7.4%. The objectives were to construct a weighted genetic risk score (wGRS) using currently known genome-wide susceptibility SNPs, and evaluate its predictive ability for AS in the Norwegian population-based Nord- Trøndelag Health Study (HUNT).
Methods AS cases (n=164) and controls (n=49,032) were from the second (1995- 1997) and third (2006-2008) waves of the HUNT study, to which the entire adult population of the northern region of Trøndelag was invited. A wGRS based on 110 SNPs weighted by published odds ratios for AS was constructed, representing each person’s carriage of all risk variants. Logistic regression models including the wGRS alone or in combination with HLA-B27 carrier state and other adjustment variables (gender, age, smoking, body mass index, and hypertension) were developed. Discrimination among models was compared using area-under-the-curve (AUC).
Results The wGRS was associated with AS (OR: 1.7; 95% CI: 1.4-2.1), but showed low discrimination (AUC: 0.62 (0.58-0.67)). HLA-B27 was significantly associated with AS (OR: 50(32-81), showing high discrimination (AUC: 0.88 (0.85-0.90)). Combining the wGRS and HLA-B27 improved prediction (AUC: 0.90 (0.87-0.92)), p<0.001 vs. wGRS alone, p<0.01 vs. HLA-B27 alone). Further inclusion of adjustment variables gave a small improvement (AUC: 0.91 (0.89-0.94), P=0.03).
Conclusion Prediction in a population-based setting based on all currently known AS susceptibility SNPs was better than HLA-B27 carrier state alone, although the improvement was small and of uncertain clinical value.
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