Association of IL-6 174G/C (rs1800795) and 572C/G (rs1800796) polymorphisms with risk of osteoporosis: a meta-analysis

Osteoporosis, one of the most common disorder, which is characterized by low bone mineral density (BMD) and degradation of bone microstructure, leading to an increased risk of fractures [1]. According to WHO standard, osteoporosis was defined as bone mineral density below 2.5 standard deviation of the average level of healthy adults. With the extension of human lifespan, more and more elderly people suffer from osteoporosis. Approximately 1.5 million new cases of osteoporotic fractures were reported every year worldwide, placing a huge financial burden on patient families [2]. It has become a public health problem in the world.

Several factors contribute to the pathogenesis of osteoporosis, such as exercise, age, sex, diet etc. [3]. In addition, genes and gene polymorphisms may also play an important role in osteoporosis predisposition [4]. Such as, In a study of familial diseases, bone mineral density was found to be highly heritables: 60–90% of BMD in the population is genetically determined [5]. Many genes were thought to be linked to osteoporosis and bone density. Those genes include estrogen receptor (ESR), calcitonin receptor (CTR), vitamin D receptor (VDR) and interleukin 6 (IL-6), etc. [6‐8]. However, these risk genes can only explain part of the heritability of osteoporosis, and more variants have yet to be identified.

IL-6 gene is a multifunctional cytokine, located on human chromosome 7p21, which can stimulate the formation and absorption of bone cells [9‐11]. Clinical studies had shown that the expression of IL-6 mRNA in bone explants of patients with osteoporotic vertebral fractures is enhanced [12]. Furthermore, some studies had found that IL-6 and other inflammatory cytokines can potentially up regulate the expression of RANKL on osteoblasts, accelerate the signal transduction of RANKL, and directly lead to bone destruction [13]. Recently, it has been discovered that functional polymorphisms of the IL-6 promoter,such as the C allele of the G-174C polymorphism, were associated with reduced promoter activity and plasma IL-6 levels, leading to reduced bone density [14‐16]. Since Nordstrom first reported the link between IL-6 and susceptibility to osteoporosis [8], many related studies had also been published, but their results were conflicting. Such as, research by Ji Y F et al. revealed that G allele of rs1800796 was associated with increased risk of osteoporosis, while IL-6 174G/C was not significantly associated with osteoporosis [17]. However, the study of Magana et al. suggested that the increase of BMD is related to IL-6 174G/C, but not rs1800796 [18]. We consider that it may be related to the size of the sample size, the quality of the study, and whether the study conform to HWE. In view of this, we performed a meta-analysis in the hope of providing more reliable results for this association.

With the increasing aging of society, osteoporosis is becoming a serious social health problem, and have caused severe physical, psychological and economic burden to patients. Several factors contribute to the pathogenesis of osteoporosis. Among them, genetic factors play an important role in the histogenesis and development of osteoporosis [4]. Identification of potential pathogenic genes and their polymorphisms enables us to predict disease risk and take corresponding preventive measures. Interleukin-6 is one of the candidate genes due to it can potentially up regulate the expression of RANKL on osteoblasts, accelerate the signal transduction of RANKL, and directly lead to bone destruction [13]. There are some studies trying to figure out the association between IL-6 gene polymorphism and osteoporosis risk, while these results acquired were conflicting. The limited sample size of a single study is considered as one of the reasons. To overcome this shortcoming, meta-analysis is a competent alternative [37].

A total of 9 studies involving 1891 osteoporosis patients and 2027 healthy controls were included in the current meta-analysis, of which 8 studies evaluated the association between IL-6 174G/C polymorphism and osteoporosis, 3 studies related to IL-6 572C/G (rs1800796). Overall, We observed the higher osteoporosis risk in IL-6 572C/G additive, dominant and recessive model. However, the IL-6 572C/G C allele was associated with reduced osteoporosis risk. For IL-6 174G/C, the pooled odds rations indicate it was insignificantly associated with risk of developing osteoporosis in four genetic model comparisons. Furthermore, the current meta-analysis were performed by applying different genetic models, at the cost of multiple comparisons, in which case, the pooled P-value must be adjusted [37]. In the Venice criteria, statistical power and I² were important indicator [38]. Hence, the false-positive report probabilities (FPRP) test [28] and the Venice criteria [29] were used to evaluate the credibility of statistically significant associations. Finally, we identified “less credible positive results” in IL-6 572C/G recessive and additive model. Heterogeneity was also observed in IL-6 174G/C allele model and IL-6 572C/G dominant model. We explore the source of heterogeneity using meta regression analysis. The results suggested that menopause was the source of heterogeneity. In addition, in molecular epidemiological studies, small sample studies are more likely to generate random errors and biases, and are more likely to produce false positive results [29]. Positive research results are more likely to be published, which can lead to publication bias. As shown in Fig. 6 in the current meta-analysis, the slight asymmetry of the funnel plot is caused by the study of small samples. However, due to the limited number of studies on IL-6 572C/G and osteoporosis risk, Begg’s funnel plot was not performed to explored publication bias.

It is worth noting that two previous meta-analyses of IL-6 174G/C and steoporosis risk have been published [39, 40]. Ni Y et al’s meta-analysis included 4 articles including 800 case groups and 900 control groups, and the results showed that the IL-6 CC genotype was significantly associated with a reduced risk for osteoporosis [39]. The examination of 12 studies by Fajar et al. indicated that 174G/C C allele and CC genotype may significant decreased osteoporosis risk [40]. However, when we carefully examined these two meta-analyses, we found that 6 articles [41‐46] were incorrectly included in the study of Fajar et al. Such as Garnero et al. explored the relationship between IL-6 and BMD in premenopausal and postmenopausal healthy people. There was no osteoporosis in the case group [41]. Similarly, the case group in the Lee j et al. study was adolescents with idiopathic scoliosis [45], and Korvala et al. studied stress fractures in military personnel, not osteoporotic or osteoporotic fracture [44]. The other three studies did not provide detailed case and control genotype data [42‐44]. So the results are not credible. In the meta-analysis of Ni Y et al., we found that the quality of the literature was not evaluated, no statistical power was calculated, and p-value was not adjusted after multiple comparisons. In order to overcome these shortcomings, the current meta-analysis was performed.

In conclusion, IL-6 572C/G GG genotype may be associated with increased risk of osteoporosis. The question of whether and how rs1800795 affect osteoporosis in postmenopausal women requires further investigation.