Contribution of Functional LILRA3, but Not Nonfunctional LILRA3, to Sex Bias in Susceptibility and Severity of Anti–Citrullinated Protein Antibody–Positive Rheumatoid Arthritis. Issue 4 (April 2014)

• Record Type: Journal Article
• Authors: Du, Yan; Cui, Yong; Liu, Xia; Hu, Fanlei; Yang, Yue; Wu, Xinyu; Liu, Xu; Ma, Xiaoxu; Zuo, Xianbo; Sheng, Yujun; Liu, Xiangyuan; Xu, Jianhua; Zhu, Ping; Sun, Lingyun; Hong, Nan; Zhang, Xuejun; Guo, Jianping; Li, Zhanguo
• Is Part Of: Arthritis & rheumatology. Volume 66:Issue 4(2014)
• Page Start: 822
• Page End: 830
• Publication Date: 2014-04
• Subjects: Arthritis -- Periodicals; Rheumatism -- Periodicals; 616.72
• DOI: 10.1002/art.38308
• Languages: English
• ISSNs: 2326-5191

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="art38308-sec-0001" sec-type="section"> <title>Objective</title> <p>Leukocyte immunoglobulin‐like receptor A3 belongs to a family of receptors with inhibitory or activating functions. Since Caucasian individuals lacking <italic>LILRA3</italic> have been found to be susceptible to multiple sclerosis and Sjögren's syndrome, we undertook this study to examine whether <italic>LILRA3</italic> deletion is a novel genetic risk factor for rheumatoid arthritis (RA) (another autoimmune disease), whether there are sex‐specific effects, and whether <italic>LILRA3</italic> influences the subtype and severity of RA.</p> </sec> <sec id="art38308-sec-0002" sec-type="section"> <title>Methods</title> <p>The <italic>LILRA3</italic> deletion and its tagging single‐nucleotide polymorphism rs103294 were genotyped in a Northern Han Chinese cohort (N‐Han) (1, 618 cases and 1, 658 controls) and a Southern Han Chinese cohort (S‐Han) (575 cases and 549 controls). Association analyses were performed on the complete data set and subsets. The effect of the nondeleted (functional) <italic>LILRA3</italic> allele on radiographic severity and <italic>LILRA3</italic> expression was evaluated.</p> </sec> <sec id="art38308-sec-0003" sec-type="section"> <title>Results</title> <p>In the N‐Han discovery cohort, we unexpectedly observed a higher frequency of the functional <italic>LILRA3</italic> in RA patients compared with healthy individuals (10.1% versus 6.3%; <italic>P =</italic> 4.01 × 10<sup>−5</sup>, odds ratio [OR] 1.92). The association was replicated in the S‐Han cohort and confirmed by meta‐analysis (<italic>P</italic> = 5.63 × 10<sup>−6</sup>, OR 1.83). Functional <italic>LILRA3</italic> conferred greater risk for RA in males (<italic>P</italic> = 1.09 × 10<sup>−6</sup>, OR 4.47), and was specifically associated with anti–citrullinated protein antibody (ACPA)–positive RA (<italic>P =</italic> 3.05 × 10<sup>−4</sup>, OR 1.75). Furthermore, functional <italic>LILRA3</italic> was associated with higher radiographic scores in ACPA‐positive patients with early RA (<italic>P</italic> = 9.70 × 10<sup>−3</sup>) and higher <italic>LILRA3</italic> messenger RNA levels (<italic>P</italic> = 3.31 × 10<sup>−8</sup>).</p> </sec> <sec id="art38308-sec-0004" sec-type="section"> <title>Conclusion</title> <p>Our study provides the first evidence that functional <italic>LILRA3</italic> is a novel genetic risk factor for RA, especially in males. It appears to highly predispose to ACPA‐positive RA and confers an increased risk of disease severity in patients with early RA.</p> </sec> </abstract>