Multilocus Genetic Risk Scores for Skeletal Fluorosis: A Cross-Sectional, Case-Control Study in China

Background: Previous genetic studies have revealed several single nucleotide polymorphisms (SNPs) related to skeletal fluorosis. We set out to ascertain the genetic association with skeletal fluorosis and to obtain more precise risk predictions using a cross-sectional, case-control design.   Methods:  We tested six SNPs for association with skeletal fluorosis in a cross-sectional, case-control design including 1319 participants aged 16 years or older (312 participants with skeletal fluorosis and 1007 controls free of the disease) from three provinces of China (Inner Mongolia, Qinghai, Xinjiang). We modeled SNPs as a multilocus genetic risk scores and used logistic regression models to estimate the association of the genetic risk score with skeletal fluorosis. For further analyses we evaluated the potential value of the 5-SNP and 6-SNP genetic risk score in risk predictions for skeletal fluorosis.   Findings:  The genetic risk score including the five SNPs associated with skeletal fluorosis was associated with the risk of skeletal fluorosis (even after adjustment for sex, age, ethnicity, osteoarthritis, daily fluoride intake and urine fluoride in the model). Participants in the third quartile of the 5-SNP genetic risk score had a relative 2·73-times increased risk of skeletal fluorosis when compared with those in the bottom quartile (95% CI 1·23-6·97, p value for linear trend across the quartiles=0·021). The area under the receiver operating characteristic curve (AUC) estimates for skeletal fluorosis models with 5-SNP genetic risk score or 6-SNP genetic risk score, where sex, age, ethnicity, osteoarthritis, daily fluoride intake and urine fluoride were adjusted, were 0·769 (95% CI 0·740-0·798) and 0·771 (95% CI 0·742-0·800), respectively, and they were significantly higher than the estimates (0·761, 95% CI 0·732-0·791) from the model without any genetic risk score (p=0·049; p=0·034). Furthermore, the 5-SNP genetic risk score did have significant effects on the categorical and continuous net reclassification improvement and integrated discrimination index for skeletal fluorosis (5·21%, 95% CI 0·93%-9·49%, p=0·0171; 0·2474, 95% CI 0·1223-0·3724, p=0·0001; 0·0096, 95% CI 0·0038-0·0154, p=0·0012, for the three measures, respectively).   Interpretation: Using a genetic risk score design, we can ascertain the genetic association with skeletal fluorosis in our study population in China. Furthermore, more precise risk predictions for the disease can be obtained. Whether this panel of six SNPs has clinical use and general predictive performance remains to be defined.   Funding Statement: National Natural Science Foundation of China (No.81673110). Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: The study was conducted under the approval of the Ethical Review Board of Harbin Medical University (HMUIRB20120021). All participants provided written informed consent, and the guardians on behalf of the ethnicity provided written informed consent.