Abstract: Epistatic Interactions Between HLA-DRB1 and Interleukin 4, But Not Interferon-g, Increase Susceptibility to Giant Cell Arteritis

Epistatic Interactions Between HLA-DRB1 and Interleukin 4, But Not Interferon-g, Increase Susceptibility to Giant Cell Arteritis

MAHSA M. AMOLI, MIGUEL A. GONZALEZ-GAY, ELEFTHERIA ZEGGINI, FIONA SALWAY, CARLOS GARCIA-PORRUA, and WILLIAM E.R. OLLIER

ABSTRACT.

Objective. To assess the roles of the interleukin 4 (IL-4) and interferon-g (IFN-g) gene polymorphisms in a series of patients with biopsy-proven giant cell arteritis (GCA).

Methods. Eighty-two patients with biopsy-proven GCA and 102 ethnically matched controls from the Lugo region (Northwest Spain) were studied. The following single nucleotide polymorphisms (SNP) were assessed: IL-4 (SNP1: rs2070874, SNP2: rs2227284, SNP3: rs2227282, SNP4: rs2243266, and SNP5: rs2243267) and IFN-g (SNP1: rs1861494, SNP2: rs1861493, and SNP3: rs2069718).

Results. Significant differences in allele and genotype frequencies were observed for the IL-4 SNP between HLA-DRB1*04 negative patients and controls. Epistatic interaction between SNP2 (rs2227284) with HLA-DRB1 showed a significant interaction (p = 0.001) and carriage of the SNP2*T allele in the absence of HLA-DRB1*04 resulted in a 4-fold risk of developing GCA (OR 4.2, 95% CI 1.1–15.6). Also, a significant increase in the frequency of the T-T-C-A-C IL-4 haplotype was observed in HLA-DRB1*04 negative GCA patients compared to the controls (p = 0.02; OR 2.0, 95% CI 1.0–3.9). Similar distributions of allele and genotype frequencies were observed for the IFN-g polymorphisms in both GCA patients and controls.

Conclusion. Our results suggest an association with IL-4 gene polymorphism that is dependent on HLA-DRB1 genotype in GCA susceptible individuals. These data indicate an interaction between HLA-DRB1 and IL-4 that contributes to pronounced disease susceptibility. (J Rheumatol 2004;31:2413-7)

Key Indexing Terms:

GIANT CELL (TEMPORAL) ARTERITIS
SINGLE NUCLEOTIDE POLYMORPHISM
INTERLEUKIN 4
INTERFERON-g
HLA-DRB1*04
DISEASE SUSCEPTIBILITY

From the Centre for Integrated Genomic Medical Research, School of Epidemiology and Health Sciences, University of Manchester, Manchester, United Kingdom; and the Division of Rheumatology, Hospital Xeral-Calde, Lugo, Spain.

M.M. Amoli, MD, PhD; E. Zeggini, PhD; F. Salway, MPhil; W.E.R. Ollier, PhD, FRCPath, Centre for Integrated Genomic Medical Research, School of Epidemiology and Health Sciences, University of Manchester; M.A. Gonzalez-Gay, MD, PhD; C. Garcia-Porrua, MD, PhD, Rheumatology Division, Hospital Xeral-Calde.

Address reprint requests to Dr. M.A. Gonzalez-Gay, Rheumatology Division, Hospital Xeral-Calde, c/ Dr. Ochoa s/n, 27004 Lugo, Spain. E-mail: miguelaggay@hotmail.com

Submitted April 1, 2004; revision accepted July 15, 2004.