Autophagy-related gene LRRK2 is likely a susceptibility gene for systemic lupus erythematosus in northern Han Chinese

Abstract

Autophagy is associated with various immune diseases, including systemic lupus erythematosus (SLE). Seven variants within autophagy-related genes previously reported to show top association signals by genome-wide association studies in immune diseases were selected for analysis. Initially, 510 SLE patients (631 controls) were enrolled in the study. An additional independent cohort of 511 SLE patients (687 controls) was included for replication. Polymorphism rs2638272 in LRRK2 gene showed significant association with susceptibility to SLE (P = 1.14 × 10−2) within the initial patient population. This was independently replicated (second patient cohort), and was reinforced with combination (P = 2.82 × 10−3). By combining multiple layers of regulatory effects, rs1491941 in high linkage disequilibrium with rs2638272 (r2 = 0.99) was regarded to have the strongest function in LRRK2. The rs1491941 protective A-allele exhibited an increase of nuclear protein binding, and an increase in LRRK2 transcription compared with G-allele. Furthermore, we observed increased transcription levels of LRRK2 in peripheral blood mononuclear cells from SLE patients compared with controls. In conclusion, we have identified a novel genetic association between the autophagy-related LRRK2 gene and susceptibility to SLE. By integrating layers of functional data, we derived the beneficial effect of autophagy on the pathogenesis of SLE.

Autophagy and immunological aberrations in systemic lupus erythematosus

“…These data strongly supported the notion that autophagy plays an important role in the genetic etiology of SLE . Combining with further follow‐up studies, several variants locating in other autophagy‐related genes were observed to be associated with susceptibility to SLE, including ATG7 , IRGM , LRRK2 , MAP1LC3B, MTMR3 , and APOL1 (Table ) .…”

A Rare Variant (rs933717) at FBXO31‐MAP1LC3B in Chinese Is Associated With Systemic Lupus Erythematosus

“…Genetic data derived from GWAS and follow‐up studies indicated variants in genes related to autophagy, including ATG5 , ATG7 , IRGM , DRAM1 , CDKN1B , APOL1 , MTMR3 , CLEC16A , LRRK2 , and ATG16L2 , especially in Asian populations . Most of these genetic associations ( ATG5 , ATG7 , IRGM , MTMR3 , LRRK2 , and ATG16L2 ) could be replicated in our previous studies .…”

The Emerging Functions of LRRK2 and Rab GTPases in the Endolysosomal System

“…For example, LRRK2 has been shown to regulate the efficient clearance of certain pathogens, such as Listeria monocytogenes, Salmonella Typhimurium and Mycobacterium tuberculosis (Zhang et al, 2015;Liu et al, 2017;Hartlova et al, 2018;Shutinoski et al, 2019), which may be explained by the altered regulation of phagolysosomes by LRRK2 in the course of innate immune responses. The action of LRRK2 may also cover the adaptive immunity, because antigen presentation by macrophages or dendritic cells is mediated at least in part by the lysosome-related organelle called MHC class II compartment (MIIC), and LRRK2 has been identified as a risk gene for systemic lupus erythematosus (SLE), a representative autoimmune disorder (Zhang et al, 2017). Further studies will clarify the most important readout of LRRK2 function and dysfunction around endolysosomes, especially in vivo.…”

“…Some functional variants in LRRK2 gene influencing the disease risk are shared between Crohn's disease and PD (Hui et al, 2018). Another study has also pointed to a genetic association between LRRK2 and susceptibility to systemic lupus erythematosus (SLE) (Zhang et al, 2017). Consistently, LRRK2 is considered to be involved in a wide range of disorders affecting both brain and periphery.…”