Association between acromegaly and a single nucleotide polymorphism (rs2854744) in the IGFBP3 gene

With a prevalence of 14–22%, pituitary adenoma is one of the most common intracranial neoplasms. An increasing number of pituitary surgeries are performed in our hospital. Somatotroph adenomas, which constitute the commonly diagnosed secreting adenomas (10–15%), are the most frequent causes of acromegaly [1]. However, acromegaly is a relatively rare disease. It is attributable to excessive levels of growth hormone (GH) and secondary elevation of insulin-like growth factor 1 (IGF-1) levels, which lead to somatic overgrowth, multiple comorbidities and an increased risk of death [2].

Excessive secretion of GH causes an overproduction of IGF-1 in the liver and other systemic tissues. A majority of circulating IGF-1 is bound to IGF-specific binding proteins (IGFBPs). There are six types of IGFBPs (IGFBP1~ IGFBP6). IGFBP3 is the major subtype that transports more than 75% of serum IGF. IGFBP3 modulates the bioavailability of IGF by increasing its half-life and modifying its biological activities on target tissues [3]. IGFBP3 not only inhibits the effect of IGF-1 by blocking the binding of IGF-1 to its receptor but also enhances the action of IGF-1 and, consequently, stimulates cell growth by protecting IGF-1 from degradation under some conditions [4]. The determination of IGFBP3 circulating levels and gene polymorphisms is useful for the assessment of growth disorders and various kinds of cancer [5‐8].

The SNP rs2854744 at the − 202 site of the IGFBP3 gene, which is located at chromosome 7p, has been reported to be correlated with the circulating levels of IGFBP3 in both in vitro and in vivo studies [9]. Several studies have shown an association between the IGFBP3–202 A/C polymorphism and both the clinical features and therapeutic responses of acromegaly patients [10‐12]. To our knowledge, there has been only one small-scale study that reported a difference in the genotype-specific distribution of IGFBP3 between acromegaly patients and controls. However, they did not study the association of the SNP with acromegaly susceptibility [10]. Pituitary adenomas can be classified into various subtypes according to multiple clinical and imaging characteristics. Therefore, we aimed to examine the correlation of IGFBP3 genetic polymorphisms at the -202 site with the susceptibility to acromegaly and its different subtypes in the Han Chinese population.

In this acromegaly case-control study, we compared the rs2854744 genotype frequency in 102 acromegalic patients and 143 control group patients. In addition, we evaluated the association of the common polymorphism of IGFBP3 with the susceptibility to acromegaly, as well as with the susceptibility in subgroups of acromegaly. We found that IGFBP3 genetic variants were significantly correlated with an altered risk of acromegaly and that allele C of rs2854744 was strongly correlated with a decreased risk of acromegaly in the Han Chinese population.

IGFBP3 is the major transport protein for IGF-1, with IGFBP3 modulating the half-life and biological activities of IGF-1. Some cell culture studies have shown that IGFBP3 plays a vital role in cell survival or apoptosis in various microenvironments; meanwhile, several clinical studies have indicated that variations in IGFBP3 levels are associated with an altered risk for certain common cancers [14]. More than half of the changes in IGFBP3 levels were identified to be genetically determined by the gene polymorphism at the − 202 locus of IGFBP3 [9]. Therefore, we attempted to identify whether polymorphic variation at the − 202 site constitutes a risk factor for acromegaly, an important type of pituitary tumour disorder.

The rs2854744 polymorphism is situated 202 base pairs (bp) upstream of the transcription start site of IGFBP3 and has been reported to control promoter activity. The A allele has been proven to be correlated with higher promoter activity. The AA genotype was associated with higher IGFBP-3 circulating levels, which have been previously shown to be associated with a decreased risk of most cancers [15, 16]. This is because IGFBP3 commonly displays growth inhibition and pro-apoptosis properties, and IGFBP3 has been recognized as an inhibitor of IGF activity by blocking the binding of IGF to its receptor. In our study, we found that the AA genotype showed a tendency for an association with higher IGFBP3 serum levels, although the difference was not statistically significant (P = 0.331), which may be explained by the small sample size. At first, we hypothesized that the AA genotype at the − 202 site of the IGFBP-3 gene might be associated with a decreased risk of acromegaly. However, our results showed that the C allele was actually correlated with a decreased acromegaly risk. Using the A allele as a reference, the OR for the C allele was 0.594 (95% CI 0.388–0.909). The multivariate analysis showed that this association was still significant after adjusting for age, sex, and smoking and drinking status. This may be because IGFBP3 has been identified as being able to enhance the activity of IGF by protecting IGF from degradation under certain circumstances [17, 18]. In addition, IGFBP3 is capable of acting via an IGF-independent mechanism to promote cell growth and survival, such as by binding the 78 kDa glucose-regulated protein (GRP78), by inducing autography, and by promoting non-homologous end-joining (NHEJ) repair during genotoxic stress [14]. These results might explain why the acromegaly risk was decreased with the C allele in the current study.

Additionally, the varying allele frequencies among different ethnicities, geographies and populations may yield conflicting results regarding IGFBP3 polymorphisms and cancer risk. A large-scale urinary bladder cancer study based on a multiethnic population residing in Germany and Hungary demonstrated that the C allele (55%) was slightly more frequent than the A allele (45%) at the − 202 site of the IGFBP-3 gene [19], which was significantly different from our participants’ allele distributions. However, a cancer study involving Korean and Japanese [20] adults indicated that the A allele (65–80%) was appreciably more frequent than the C allele (20–35%) and that the C allele was correlated with a reduced non-small cell lung cancer risk [21]. The genotypic distribution and study results of the Asian population were similar to those of our population.

Furthermore, our results showed that the association between the C allele of rs2854744 and a decreased risk of acromegaly was more significant in females, those with large tumours and those treated with monotherapy. IGFBP3 levels have been reported to be correlated with the stage and prognosis of cancer [6, 22, 23]. Several studies have found that some SNPs have different effects on cancer susceptibility between genders [24, 25]. We analysed genetic polymorphism and acromegaly risk in different subgroups. The results of our study were in some accordance with the results of the previously mentioned studies.

Our study had a few advantages. First, this was one of the first acromegaly case-control studies examining the relationship between the IGFBP3 -202A/C polymorphism and acromegaly risk. Second, we conducted an analysis of subgroups according to sex, treatment method and adenoma size, since pituitary adenomas possess diverse clinical manifestations, and the IGFBP3 gene may be associated with a specific subtype.

However, several limitations existed in the present study. First, we only selected acromegaly inpatients confirmed by postoperative pathology from Beijing Tiantan Hospital, which might have led to a selection bias. Second, as the groups with a CC genotype had fewer participants, comparisons with the AA group had limited statistical significance. Third, we did not perform functional research to confirm our findings.

In summary, this was the first study that explored the relationship between the IGFBP3 -202A/C polymorphism and a predisposition to acromegaly in a Chinese population. Our findings revealed that IGFBP3 genetic variants are associated with acromegaly risk. The C allele of rs2854744 was associated with a decreased risk of acromegaly. As mentioned above, more studies that include functional research and that focus on other populations are needed to confirm and further characterize the association.