Promoter polymorphisms in the chitinase 3-like 1 gene influence the serum concentration of YKL-40 in Danish patients with rheumatoid arthritis and in healthy subjects

Kaspar R Nielsen,Soeren Lundbye-Christensen,Sophine B Krintel,Rudi Steffensen,Mette Nyegaard,Merete L Hetland,Hans E Johnsen,John Baech,Martin Boegsted,Julia S Johansen

doi:10.1186/ar3391

Abstract

IntroductionThe present study investigates the association between single nucleotide polymorphisms (SNPs) in the chitinase 3-like 1 (CHI3L1) gene and serum concentrations of YKL-40 in Danish patients with rheumatoid arthritis (RA) and healthy controls as well as the association with RA in the Danish population. The CHI3L1 gene is located on chromosome 1q32.1 and encodes the YKL-40 glycoprotein. YKL-40 concentrations are elevated in the serum of patients with RA compared to healthy subjects, and YKL-40 has been suggested to be an auto-antigen and may play a role in development of RA and in inflammation.MethodsEight SNPs in the CHI3L1 gene and promotor were genotyped in 308 patients with RA and 605 controls (healthy blood donors) using TaqMan allele discrimination assays. Serum concentrations of YKL-40 were determined by an enzyme-linked immunosorbent assay (ELISA).ResultsWe found significant association between the serum concentrations of YKL-40 and polymorphism in the CHI3L1 gene among both patients with RA and controls. The g.-131(C > G) polymorphism (rs4950928) was most strongly associated with age adjusted serum concentrations of YKL-40 in patients with RA (P < 2.4e-8) and controls (P < 2.2e-16). No significant allelic- or genotypic association with RA was found in this Danish cohort.ConclusionsWe suggest that the g.-131(C > G) promoter polymorphism has a substantial impact on serum concentrations of YKL-40 in patients with RA and healthy subjects. However, the polymorphism does not seem to confer risk to RA itself. The effect of CHI3L1 polymorphism on clinical outcome or the response to treatment in patients with RA remains to be investigated.

Highlights

The present study investigates the association between single nucleotide polymorphisms (SNPs) in the chitinase 3-like 1 (CHI3L1) gene and serum concentrations of YKL-40 in Danish patients with rheumatoid arthritis (RA) and healthy controls as well as the association with RA in the Danish population
A high serum concentration of YKL-40 is emerging as a new biomarker of severe disease activity and poor prognosis in patients with diseases characterized by inflammation and ongoing tissue remodelling such as RA, inflammatory bowel disease, asthma and cancer [8,10,16,17,18,19,20,21,22,23,24,25,26]
An apparent increase in serum YKL-40 with age was found for the older patients in the case group

Summary

Introduction

The present study investigates the association between single nucleotide polymorphisms (SNPs) in the chitinase 3-like 1 (CHI3L1) gene and serum concentrations of YKL-40 in Danish patients with rheumatoid arthritis (RA) and healthy controls as well as the association with RA in the Danish population. YKL-40 concentrations are elevated in the serum of patients with RA compared to healthy subjects, and YKL-40 has been suggested to be an auto-antigen and may play a role in development of RA and in inflammation. A high serum concentration of YKL-40 is emerging as a new biomarker of severe disease activity and poor prognosis in patients with diseases characterized by inflammation and ongoing tissue remodelling such as RA, inflammatory bowel disease, asthma and cancer [8,10,16,17,18,19,20,21,22,23,24,25,26]. Two recent studies have explored the effect of YKL-40 as a stimulator of angiogenesis in tumours, suggesting that anti-YKL-40 antibodies could have a place in cancer treatment [33,34]

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