Frequencies of the LILRA3 6.7-kb Deletion Are Highly Differentiated Among Han Chinese Subpopulations and Involved in Ankylosing Spondylitis Predisposition

Abstract

Introduction: Leukocyte immunoglobulin-like receptor A3 (LILRA3) belongs to the LILR family with unique feature of a 6.7-kb deletion variation among individuals. Frequencies of the 6.7-kb deletion vary widely across populations, but so far it has not been carefully investigated among Han Chinese subpopulations. Furthermore, we previously identified the non-deleted (functional) LILRA3 as a novel genetic risk for multiple autoimmune diseases. The current study aimed to investigate (i) whether frequencies of the LILRA3 6.7-kb deletion differ within Han Chinese subpopulations and (ii) whether the functional LILRA3 is a novel genetic risk for ankylosing spondylitis (AS).Methods: The LILRA3 6.7-kb deletion was genotyped in two independent cohorts, including 1,567 subjects from Shenzhen Hospital and 2,507 subjects from People’s Hospital of Peking University. Frequencies of the 6.7-kb deletion were first investigated in combined healthy cohort according to the Chinese administrative district divisions. Association analyses were performed on whole dataset and subsets according to the geographic regions. Impact of the functional LILRA3 on AS disease activity was evaluated.Results: Frequencies of LILRA3 6.7-kb deletion were highly differentiated within Han Chinese subpopulations, being gradually decreased from Northeast (80.6%) to South (47.4%). Functional LILRA3 seemed to be a strong genetic risk in susceptibility to AS under almost all the alternative genetic models, if the study subjects were not geographically stratified. However, stratification analysis revealed that the functional LILRA3 was consistently associated with AS susceptibility mainly in Northern Han subgroup under the alternative genetic models, but not in Central and Southern Hans. Functional LILRA3 conferred an increased disease activity in AS patients (P < 0.0001 both for CRP and ESR, and P = 0.003 for BASDAI).Conclusions: The present study is the first to report that the frequencies of LILRA3 6.7-kb deletion vary among Chinese Hans across geographic regions. The functional LILRA3 is associated with AS susceptibility mainly in Northern Han, but not in Central and Southern Han subgroups. Our finding provides new evidence that LILRA3 is a common genetic risk for multiple autoimmune diseases and highlights the genetic differentiation among different ethnicities, even within the subpopulations of an ethnic group.

Leukocyte Immunoglobulin-Like Receptor A3 (LILRA3): A Novel Marker for Lymphoma Development among Patients with Young Onset Sjogren’s Syndrome

“…Although the Caucasian pattern regarding the prevalence of LILRA3 gene was observed in the Greek cohort, the contribution of the wild rather than the deleted form of the LILRA3 gene seems to increase susceptibility to autoimmunity. Thus, in accord with our findings, the functional rather than the deleted variant has been linked to several autoimmune disorders in Asian populations such as RA [ 39 ], ankylosing spondylitis [ 40 ], SLE, and SS [ 20 ]. Moreover, in Chinese populations, it was the functional allele which was found to serve as risk factor for seropositive SS [ 20 ].…”

The Genomic Organization of the LILR Region Remained Largely Conserved Throughout Primate Evolution: Implications for Health And Disease

“…LILRA3 and LILRB3 are both identified as susceptibility genes in Takayasu’s arteritis ( 161 ). Furthermore, LILRA3 is associated with ankylosing spondylitis susceptibility in different cohorts, including Han Chinese subpopulations and a Polish population, underlying the genetic differences between different ethnicities ( 140 , 149 ). Associations involving disruptive gene expression are seldom reported.…”

Association of the Leukocyte Immunoglobulin‐like Receptor A3 Gene With Neutrophil Activation and Disease Susceptibility in Adult‐Onset Still’s Disease

“…It exhibits a 6.7-kb deletion polymorphism by removing the first 6 of a total of 7 exons, the Ig-like domains of the gene, which produces a nonfunctional putative truncated form (6). The deletion occurs at an extremely higher frequency in Northeastern Asian populations (56-84%) than in European populations (17%) or African populations (10%) (7), with a frequency of 70-90% previously reported in one Chinese population (8).…”

“…Functional LILRA3 has been reported to be associated with susceptibility to and disease severity of many autoimmune diseases, including rheumatoid arthritis (RA), systemic lupus erythematous (SLE), primary Sjögren's syndrome (primary SS), ankylosing spondylitis (AS), multiple sclerosis (MS), and Takayasu arteritis, among others (8)(9)(10)(11)(12)(13)(14). A higher frequency of functional LILRA3 has been observed in Chinese patients with RA, conferring greater risk for RA in male patients and a predisposition toward anti-citrullinated protein antibody-positive RA (10).…”

“…Moreover, functional LILRA3 is defined as a factor of disease susceptibility in SLE and primary SS, and levels of LIR-A3 in both serum and CD14+ monocytes were significantly increased in SLE and correlated with disease activity (11,14). In addition, functional LILRA3 appears to be a strong genetic risk factor for susceptibility to AS, mainly in the Northern Han subpopulation, and typically confers an increase in the severity of disease activity (8). However, the association between LILRA3 and AOSD has not yet been illustrated.…”