Background/Purpose:

The disease severity of rheumatoid arthritis (RA) is objectively measured by radiographic joint destruction, which is reflective of the cumulative burden of inflammation. Recently, the heritability has been proven to be partly involved in progression of joint destruction in RA, and several genetic variants and gene-gene interactions have been reported to be associated with progression of joint destruction in European multi-cohort studies. However, the presence of genetic heterogeneity in RA susceptibility genes has been demonstrated in many population-based studies, and the genetic predisposition factors for progression of joint destruction remain to be poorly understood in Asian patients with RA. The purpose of this study was to identify genetic variants associated with progression of joint destruction in Japanese patients with RA. 

Methods:

This study included 865 Japanese patients with RA for whom Sharp/van der Heijde scores (SHS) of hands were available at a disease duration of 5 years. DNA samples of the subjects were obtained from the Institute of Rheumatology Rheumatoid Arthritis cohort study (IORRA) DNA collection. All of the patients who donated DNA samples consented to participate in this study in accordance with the process approved by the Tokyo Women’s Medical University Genome Ethics Committee, and satisfied the American College of Rheumatology 1987 revised criteria for the classification of RA. Nine of the single nucleotide polymorphisms (SNPs) reported in European multi-cohort studies were selected and genotyped in the DNA samples: rs6821171, and rs1521761 which is in absolute linkage disequilibrium (r²=1) with rs7667746, in interleukin15 (IL15); rs8192916, in granzyme B (GZMB); rs1896368, rs1896367, rs1528873, and rs10762715, in Dickkopf-1 (Dkk-1); rs4792909, and rs6503475, in sclerostin (Sost). SNP genotyping was performed by using the TaqMan fluorogenic 5’ nuclease assay (Applied Biosystems, Tokyo, Japan). Univariate linear regression analyses were performed to examine the association of each SNP and several combinations of SNPs with progression of joint destruction in the first 5 years after onset of RA, calculated as SHS of hands at the 5-year disease duration. All SHS were log-transformed to obtain a normal distribution. 

Results:

Univariate linear regression analyses revealed that all of the SNPs and combinations of SNPs tested in this study were not associated with progression of joint destruction (Table 1). 

Conclusion:

Genetic variants in IL15, GZMB, Dkk-1, and Sostwere not associated with progression of joint destruction in Japanese patients with RA. These results indicate the presence of genetic heterogeneity in risk loci of progression of joint destruction in RA between Caucasian and Asian patients. The heritability of the rate of joint destruction might be different among ethnic populations. 

Table 1

Gene	SNP	Allele (minor/major)	MAF	Tested model	β	P value
L15	rs6821171	C/A	0.30	additive recessive	-0.05 -0.13	0.48 0.36
	rs1521761	T/A	0.15	additive recessive	-0.10 -0.13	0.21 0.36
GZMB	rs8192916	A/G	0.45	additive recessive	-0.01 0.05	0.91 0.65
Dkk-1	rs1896368	A/G	0.42	additive recessive	0.07 0.12	0.21 0.16
	rs1896367	A/G	0.30	additive recessive	-0.11 -0.13	0.09 0.31
	rs1528873	C/A	0.22	additive recessive	-0.07 -0.02	0.28 0.90
Dkk-1 Sost	rs1528873 rs6503475	C/A G/A	0.22 0.45	additive	-0.02	0.59
	rs10762715 rs4792909	T/C T/G	0.22 0.40	additive	0.01	0.78
	rs10762715 rs6503475	T/C G/A	0.22 0.45	additive	0.02	0.59

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/genetic-association-on-disease-severity-in-rheumatoid-arthritis-a-validation-study-in-japanese-patients/