OPG/RANK/RANKL Single-Nucleotide Polymorphisms in Rheumatoid Arthritis: Associations with Disease Susceptibility, Bone Mineral Density, and Clinical Manifestations in a Chinese Han Population.

Abstract

Objective: The osteoprotegerin (OPG)/receptor activator of nuclear factor-κB (RANK)/receptor activator of nuclear factor-κB ligand (RANKL) system plays a pivotal role in the balance between osteoblasts and osteoclasts and is closely related to the pathogenesis of rheumatoid arthritis (RA). The present study aimed to clarify the associations of OPG/RANK/RANKL gene single-nucleotide polymorphisms (SNPs) with disease susceptibility, bone mineral density (BMD), and clinical manifestations in RA patients.

Methods: A case-control study including 319 RA patients and 330 healthy controls was conducted. All subjects were genotyped for rs4355801 and rs1023968 in OPG, rs10805033 in RANK, and rs9533155 and rs875625 in RANKL. BMD and clinical manifestations were recorded.

Results: An association was found between OPG rs4355801 and risk of RA. In recessive models, the GG genotype of rs4355801 was associated with an increased risk of RA compared with the AA/AG genotypes (OR=1.679, 95% CI: 1.062-2.655, p=0.025). A correlation between RANKL rs9533155 and BMD was found in RA patients. Patients with the GG genotype (n=108) in RANKL rs9533155 had the more decreased BMD values at lumbar level 2 (t=3.424, p=0.009), lumbar level 3 (t=3.171, p=0.019), lumbar level 4 (t=4.187, p=0.001), and total lumbar levels 2-4 (t=2.989, p=0.021) compared with CC+GC genotypes. No associations were found between the OPG, RANK, and RANKL SNPs and clinical manifestations of RA (all p>0.05). Logistic regression analysis indicated that older age (OR=1.057, 95% CI: 1.017-1.099, p=0.005), higher HAQ (OR=2.786, 95% CI: 1.329-5.841, p=0.007), and GG genotype of rs9533155 (OR=3.242, 95% CI: 1.254-8.376, p=0.015) were risk factors of lumbar osteoporosis onset in RA patients.

Conclusion: In summary, OPG rs4355801 is associated with susceptibility to RA and RANKL rs9533155 GG genotype potentially contributes to decreased BMD in RA. Studies with larger sample sizes are needed to confirm the present findings.