A common variant of leucine-rich repeat-containing 16A (LRRC16A) gene is associated with gout susceptibility

Abstract

Gout is a common disease resulting from hyperuricemia which causes acute arthritis. Recently, genome-wide association studies revealed an association between serum uric acid levels and a common variant of leucine-rich repeat-containing 16A (LRRC16A) gene. However, it remains to be clarified whether LRRC16A contributes to the susceptibility to gout. In this study, we investigated the relationship between rs742132 in LRRC16A and gout. A total of 545 Japanese male gout cases and 1,115 male individuals as a control group were genotyped. rs742132 A/A genotype significantly increased the risk of gout, conferring an odds ratio of 1.30 (95 % CI 1.05–1.60; p = 0.015). LRRC16A encodes a protein called capping protein ARP2/3 and myosin-I linker (CARMIL), which serves as an inhibitor of the actin capping protein (CP). CP is an essential element of the actin cytoskeleton, which binds to the barbed end of the actin filament and regulates its polymerization. In the apical membrane of proximal tubular cells in the human kidney, the urate-transporting multimolecular complex (urate transportsome) is proposed to consist of several urate transporters and scaffolding proteins, which interact with the actin cytoskeleton. Thus, if there is a CARMIL dysfunction and regulatory disability in actin polymerization, urate transportsome may be unable to operate appropriately. We have shown for the first time that CARMIL/LRRC16A was associated with gout, which could be due to urate transportsome failure.Electronic supplementary materialThe online version of this article (doi:10.1007/s13577-013-0081-8) contains supplementary material, which is available to authorized users.

Common Variant of PDZK1, Adaptor Protein Gene of Urate Transporters, is Not Associated with Gout

“…This may be partly because of the difference of the investigated population and/or because of the limited sample (2043 individuals). Our result with patients with gout does not deny the presence of urate transportsome involving PDZK1 because the association between rs12129861 and SUA 1,10 , as well as the molecular interaction among PDZK1 and urate transporters 6,7,8,9 , has already been reported. Nevertheless, the advantage of our study is the quality of the cases: all of the patients with gout who participated in our study were diagnosed by Figure 1.…”

“…Previous genetic studies have revealed that gout and serum uric acid (SUA) levels have associations with various genes such as ATP-binding cassette transporter, subfamily G, member 2 (ABCG2/BCRP) 1,2,3 , glucose transporter 9 (GLUT9/SLC2A9) 1 , organic anion transporter 4 (OAT4/SLC22A11) 1,4 , monocarboxylate transporter 9 (MCT9/SLC16A9) 1,5 , and leukine-rich repeat-containing 16 A (LRRC16A/CARMIL) 1,6 .…”

“…PDZ domain containing 1 (PDZK1, also known as NHERF3) plays a pivotal role as a scaffolding protein that forms urate transportsome 6,7,8,9 with URAT1, ABCG2, and OAT4 (Figure 1). A single-nucleotide polymorphism (SNP), rs12129861, was first reported to have an association between PDZK1 gene and SUA 1 , which was confirmed by a replication study 10 .…”

“…Similar to another scaffolding protein Na + /H + exchanger regulatory factor 1 (NHERF1), PDZK1 is one of the key molecules for urate transportsome 6,7,8 , and is known to bind urate transporters at its PDZ domains and to mediate the subcellular localization of those proteins (Figure 1). In addition, our previous study indicated that LRRC16A, which was reported to have an association with SUA 1 , has an association with gout susceptibility attributable to the transportsome failure 6 . PDZK1 is, therefore, thought to play a role in urate transport through this stabilization and/or anchoring effect of urate transporters 7,8 .…”

Common Variants of cGKII/PRKG2 Are Not Associated with Gout Susceptibility

“…Several genes associated with gout and serum uric acid (SUA) levels have been reported, including ATP-binding cassette transporter, subfamily G, member 2 (ABCG2/BCRP) 1,2,3,4,5 , glucose transporter 9 (GLUT9/SLC2A9) 6,7,8 , monocarboxylate transporter 9 (MCT9/SLC16A9) 9,10 , and leucine-rich repeat-containing 16 A (LRRC16A/CARMIL) 9,11 .…”