Background/Purpose

Patients with rheumatoid arthritis (RA) have a higher prevalence of dyslipidemia than healthy individuals. Since RA is a chronic inflammatory disease, an inflammatory response may be partly involved in the pathogenesis of dyslipidemia. Recently, low-density lipoprotein (LDL) cholesterolemia has been reported to be a risk factor for radiographic progression of joint destruction. Several genetic risk loci for progression of joint destruction have been identified so far. However, the genetic predisposition factors have not yet been elucidated. The purpose of this study was to evaluate impact of genetic variants modulating serum LDL cholesterol (LDL-C) levels on progression of joint destruction in Japanese patients with RA. 

Methods

This study included 1,005 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 as 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. Thirteen single nucleotide polymorphisms (SNPs) in the 8 loci influencing serum LDL-C concentrations in the Japanese population were selected and genotyped in the DNA samples: rs611917, in SORT1; rs693, rs7575840, and rs515135, in APOB; rs3846662, in HMGCR; rs662799, in BUD13-APOA1-APOA5; rs838867, in SCARB1; rs1532624, and rs2303790, in CETP; rs688, and rs1433099, in LDLR; rs429358, and rs7412, in APOE-C1. Multivariate linear regression analyses were performed to examine the association of each SNP with radiographic progression of joint destruction in the first 5 years after onset of RA, calculated as SHS of hands at the 5-year disease duration. Adjustments were made for gender, age of onset, anti-citrullinated peptide status, and year of disease onset. All SHS were log-transformed to obtain a normal distribution. 

Results

Multivariate linear regression analyses revealed that the minor allele of rs662799 in BUD13-APOA1-APOA5 was associated with progression of joint destruction in the recessive model (P=0.04). However, the association could not reach the level of the significance after Bonferroni correction for multiple comparisons. The other SNPs showed no association (Table 1). 

Conclusion

We could not confirm the association between genes modulating serum LDL-C levels and progression of joint destruction in Japanese patients with RA. Our results indicated that rs662799 in BUD13-APOA1-APOA5 might be a risk factor for progression of joint destruction, but further studies would be required to confirm the association. 

Table 1 Multivariate linear regression analyses of each SNP associated with progression of joint destruction

Gene	SNP	Allele (minor/major)	MAF	Risk allele	Tested model	β	P value
SORT1	rs611917	G/A	0.07	A	additive dominant recessive	-0.01 0.02 -0.01	0.79 0.65 0.69
APOB	rs693	A/G	0.04	A	additive dominant recessive	0.02 0.02 -0.04	0.60 0.52 0.36
	rs7575840	T/G	0.08	T	additive dominant recessive	0.03 0.03 0.01	0.37 0.39 0.65
	rs515135	T/C	0.10	T	additive dominant recessive	0.02 0.02 0.01	0.57 0.59 0.77
HMGCR	rs3846662	A/G	0.48	G	additive dominant recessive	0.00 0.02 -0.01	0.93 0.59 0.71
BUD13-APOA1-APOA5	rs662799	G/A	0.34	G	additive dominant recessive	0.05 0.07 -0.00	0.14 0.04 0.95
SCARB1	rs838867	G/A	0.46	A	additive dominant recessive	0.03 -0.01 0.05	0.32 0.88 0.10
CETP	rs1532624	T/G	0.30	G	additive dominant recessive	-0.01 0.00 -0.01	0.86 0.96 0.80
	rs2303790	G/A	0.03	A	additive dominant recessive	-0.04 0.02 -0.05	0.23 0.43 0.16
LDLR	rs688	T/C	0.12	T	additive dominant recessive	-0.06 -0.06 -0.04	0.05 0.08 0.16
	rs1433099	T/C	0.29	C	additive dominant recessive	-0.03 -0.05 -0.01	0.40 0.11 0.85
APOE-C1	rs429358	C/T	0.10	C	additive dominant recessive	-0.03 -0.03 -0.02	0.30 0.36 0.43
	rs7412	T/C	0.04	T	additive dominant recessive	0.03 -0.03 0.04	0.33 0.14 0.17

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/impact-of-genes-modulating-serum-low-density-lipoprotein-cholesterol-levels-on-progression-of-joint-destruction-in-japanese-patients-with-rheumatoid-arthritis/