Genetic Risk Score May Predict Ankylosing Spondylitis Susceptibility

Predicting ankylosing spondylitis (AS) susceptibility based on all currently known single nucleotide polymorphisms (SNPs) was superior than human leukocyte antigen-B27 (HLA-B27) carrier state alone, according to a study published in The Journal of Rheumatology.

Researchers developed a weighted genetic risk score using AS associated SNPs and evaluated if this score is more predictive when combined with other variables using data from cohort 2 and 3 of the Nord-Trøndelag Health Study (HUNT). Participants completed surveys, interviews, medical examinations, blood draws, and genotyping. Diagnosis of AS was determined using the modified New York criteria. SNPs associated with AS were determined by using validated, large, case-controlled studies found on PubMed. Three final weighed genetic risk scores were developed using 110, 15, and 8 polymorphisms. HLA-B27 was not included in the weighted genetic risk score, but rather used as a separate variable.

Cohort 2 of the HUNT study included 39,782 participants, 142 of whom were diagnosed with AS, and cohort 3 included 9414 participants, 22 of whom were diagnosed with AS. The first model using the weighted genetic risk score containing 110 polymorphisms found a mean score of 14.6 for participants with AS and 14.26 for participants without, and was significantly associated with AS (odds ratio [OR], 1.7; 95% CI, 1.4-2.1; P <.001).

The fourth model combining the 110 polymorphism genetic risk score, HLA-B27, and adjusted for variables had the best discriminative ability (area under the curve [AUC] = 0.91; 95% CI, 0.89-0.94; P =.03) and an OR of 1.8 (95% CI, 1.4-2.1; P <.001). Results using the weighted genetic risk score using 15 and 8 polymorphisms did not improve results. Using the Hosmer-Lemeshow test, when sensitivity and specificity of 88% were used as the cutoff point for the AUC for the fourth model, the negative predictive value was 100% and the positive predicted value was 2.3% for AS.

Limitations of this study include the potential for false positive or false negative AS diagnosis due to diagnosing criteria, a possible selection bias, lack of further validation of results, and the inability to transfer these results to other population and ethnicities.

The researchers concluded, “high discriminatory ability was seen with HLA-B27 and even higher when a [weighted genetic risk score] based on most of the currently known risk SNPs for AS was also considered.”

Reference

Rostami S, Hoff M, Brown MA, et al. Prediction of ankylosing spondylitis in the population-based HUNT study by a genetic risk score combining 110 SNPs of genome-wide significance [published online April 1, 2019]. J Rheumatol. doi:10.3899/jrheum.181209