THU0002 Estrogen-Related Polymorphisms and Risk of Rheumatoid Arthritis: A Multicenter Study
Authors: L. Canet, R. Cáliz, C.B. Lupiañez, H. Canhão, I. Filipescu, A. Escudero, J. Segura-Catena, M.J. Soto-Pino, M. Ά. Ferrer, E. Pérez-Pampin, A. González-Utrilla, M. Ά. Lόpez-Nevot, E. Collantes, J.E. Fonseca, J. Sainz
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background</h3> Rheumatoid Arthritis (RA) is a chronic autoimmune disease with higher prevalence and worse prognosis in women than men. <h3>Objectives</h3> We aimed to determine whether 48 single nucleotide polymorphisms (SNPs) within steroid hormone signaling (<i>ESR1</i>, <i>ESR2</i>, <i>PGR</i>, <i>NR1I2</i>, and <i>SHBG</i>), phase I- and II-metabolizing enzyme (<i>HSD17B1</i>, <i>CYP1A1</i>, <i>CYP17A1</i>, <i>CYP1A2</i>, <i>CYP1B1</i>, <i>CYP2C9</i>, <i>CYP2C19</i>, <i>CYP3A4</i> and <i>GSTP1</i>) and hormone transporter (<i>ABCB1</i>) genes influence on the risk of developing RA and whether genotyping of these variants might help to predict disease risk. <h3>Methods</h3> The study population included 1357 RA patients and 1219 controls. Logistic regression analyses were performed to determine associations and to predict disease risk. <h3>Results</h3> We found that carriers of the <i>CYP2C19</i><sub>rs4244285A</sub> allele and <i>CYP3A4</i><sub>rs11773597C/C</sub> genotype had a significantly increased risk of RA (<i>P</i>=0.019 and <i>P</i>=0.0048) whereas carriers of the <i>CYP2C9</i><sub>rs1057910C</sub> and <i>ESR2</i><sub>rs4986938G</sub> alleles showed a reduced risk of developing the disease (<i>P</i>=0.036 and <i>P</i>=0.0026). In addition, when a log-additive model was assumed, we observed a significant association for the <i>CYP2C19</i><sub>rs4244285</sub>, <i>CYP3A4</i><sub>rs2740574</sub> and <i>ESR2</i><sub>rs4986938</sub> SNPs suggesting an allele-dosage effect of these variants to modulate the risk of RA (<i>P</i>=0.0076, <i>P</i>=0.044 and <i>P</i>=0.0004). Interestingly, a gender-stratified analysis also revealed that women carrying the <i>CYP17A1</i><sub>rs743572G/G</sub> genotype or the <i>PGR</i><sub>rs518162A</sub> allele showed an increased risk of RA (<i>P</i>=0.026 and <i>P</i>=0.032) whereas an opposite but not significant effect was observed in men (<i>P</i><sub>interaction</sub>=0.02 and 0.025, respectively). Furthermore, a rheumatoid factor (RF)-stratified analysis showed that seropositive patients carrying the <i>SULT1A1</i><sub>rs9282861A</sub> allele had a substantially increased risk of developing RA (<i>P</i>=0.0088) whereas no effect was observed in seronegative patients (<i>P</i>=0.56). Importantly, after correction for multiple testing (<i>P</i>=0.0010), the association of the <i>ESR2</i><sub>rs4986938</sub> SNP with a reduced risk of RA remained statistically significant (<i>P</i>=0.0004) whereas the overall association of <i>CYP2C19</i><sub>rs4244285</sub> and <i>CYP3A4</i><sub>rs2740574</sub> or <i>SULT1A1</i><sub>rs9282861</sub> in seropositive patients reached marginal significance (<i>P</i>=0.0076, <i>P</i>=0.0048 and <i>P</i>=0.0088). Finally, a predictive analysis showed that a model including 3 genetic variants significantly associated with RA had a higher prediction capacity than a model including a similar number of non-significant SNPs (AUROC=0.562 vs. AUROC=0.513; -2log likehood ratio test <i>P</i>=4.24E-07). The predictive analysis showed that the <i>ESR2</i><sub>rs4986938</sub> SNP had the highest predictive capacity (<i>P</i>=0.00015), which along with a previous study demonstrating its correlation with <i>ESR2</i> mRNA expression suggest a key role of this variant in the modulation of RA risk. <h3>Conclusions</h3> These findings suggest that SNPs within estrogen-related genes may play a role in modulating susceptibility to RA and can be used to improve the prediction of disease risk. <h3>Disclosure of Interest</h3> None declared