Hämäläinen Satu, Solovieva Svetlana, Vehmas Tapio, Leino-Arjas Päivi, Hirvonen Ari
Finnish Institute of Occupational Health, Centre of Expertise for Health and Work Ability, Topeliuksenkatu 41 a A, FI-00250 Helsinki, Finland.
BMC Musculoskelet Disord. 2014 Sep 24;15:311. doi: 10.1186/1471-2474-15-311.
The development of osteoarthritis (OA) involves inflammation, but the evidence for participation of genes propagating or inhibiting inflammation in the OA process is inconsistent. We investigated the associations of common variants in the TNFα gene, and their interactions with other cytokine genes, with hand OA among Finnish women.
This cross-sectional study was based on bilateral hand radiographs of 542 female dentists and teachers which were classified according to the presence of OA (radiographic K-L score ≥ 2 in ≥ 3 joints) using reference images. The genotypes were determined by PCR-based methods. The degree of pairwise linkage disequilibrium (LD) and haplotypes were constructed and analyzed by the SNPStats software. The associations between four TNFα SNPs and hand OA were tested using logistic regression adjusting for age, occupation, and BMI, and fitting a log-additive model of inheritance. Gene-gene interactions of TNFα SNPs with IL4R and IL10 SNPs were examined by stratified logistic regression analyses. Possible interactions of the TNFα SNPs with variants in the previously reported IL1β and IL6 genes in influencing hand OA were also explored.
Two TNFα polymorphisms ("-1031" and "-863") were associated with hand OA (OR = 1.45, 95% CI 1.01-2.07 and 1.55, 1.06-2.25, respectively). These associations retained when adjusting further for IL1β "3954" and IL6 "174". The TNFα G-A-G haplotype was associated with an increased risk of hand OA (1.61, 1.10-2.37, p = 0.01). Interactions were observed between TNFα "-1031" and IL4R Ser503Pro, TNFα "-1031" and IL10 "-1082", and TNFα "-863" and IL10 "-1082" SNPs with regard to hand OA (p = 0.012, p = 0.0068, and p = 0.02, respectively). The carriage of the TNFα "-1031" minor allele doubled the risk (2.01, 1.26 - 3.22) only in women with the IL4R Ser/Ser genotype. Similarly, the TNFα "-1031" and "-863" minor alleles were associated with an increased risk of hand OA only in IL10 G/G or A/A homozygotes (2.54, 1.45-4.47 and 2.60, 1.46-4.62, respectively) but not in heterozygotes (G/A).
Our results suggest that the TNFα gene variants play a role in the etiology of hand OA. In addition, the findings are suggestive of a gene-gene interaction of the TNFα with IL4R and IL10 genes.
骨关节炎（OA）的发展涉及炎症，但在OA进程中，关于传播或抑制炎症的基因参与其中的证据并不一致。我们研究了芬兰女性中TNFα基因常见变异及其与其他细胞因子基因的相互作用与手部OA的关联。
这项横断面研究基于542名女牙医和女教师的双侧手部X光片，使用参考图像根据OA的存在情况（≥3个关节的放射学K-L评分≥2）进行分类。通过基于PCR的方法确定基因型。使用SNPStats软件构建并分析成对连锁不平衡（LD）程度和单倍型。使用逻辑回归对年龄、职业和BMI进行调整，并拟合遗传的对数加性模型，测试四个TNFα单核苷酸多态性（SNP）与手部OA之间的关联。通过分层逻辑回归分析检查TNFα SNP与IL4R和IL10 SNP之间的基因-基因相互作用。还探讨了TNFα SNP与先前报道的IL1β和IL6基因变异在影响手部OA方面可能的相互作用。
两个TNFα多态性（“-1031”和“-863”）与手部OA相关（OR分别为1.45，95%CI 1.01 - 2.07和1.55，1.06 - 2.25）。在进一步对IL1β“3954”和IL6“174”进行调整后，这些关联仍然存在。TNFα G-A-G单倍型与手部OA风险增加相关（1.61，1.10 - 2.37，p = 0.01）。在手部OA方面，观察到TNFα“-1031”与IL4R Ser503Pro、TNFα“-1031”与IL10“-1082”以及TNFα“-863”与IL10“-1082”SNP之间存在相互作用（p分别为0.012、0.0068和 p = 0.02）。仅在具有IL4R Ser/Ser基因型的女性中，TNFα“-1031”次要等位基因的携带使风险加倍（2.01，1.26 - 3.22）。同样，TNFα“-1031”和“-863”次要等位基因仅在IL10 G/G或A/A纯合子中与手部OA风险增加相关（分别为2.54，1.45 - 4.47和2.60，1.46 - 4.62），而在杂合子（G/A）中则不然。
我们的结果表明，TNFα基因变异在手部OA的病因中起作用。此外，研究结果提示TNFα与IL4R和IL10基因之间存在基因-基因相互作用。
