Tumor Biol. DOI 10.1007/s13277-014-1900-6
RESEARCH ARTICLE
Association between IRS-1 Gly972Arg polymorphism and colorectal cancer risk Peng Li & Lingjun Wang & Lihua Liu & Hong Jiang & Chong Ma & Tao Hao
Received: 17 February 2014 / Accepted: 26 March 2014 # International Society of Oncology and BioMarkers (ISOBM) 2014
Abstract In order to make a comprehensive assessment of the potential association between one genetic variant in the insulin receptor substrate 1 (IRS-1) gene, rs1801278, and colorectal cancer (CRC) risk, we conducted a meta-analysis of four epidemiological studies, which included 3,708 CRC cases and 4,176 controls. The data showed that rs1801278 polymorphism was not associated with increased CRC risk in the overall population. When stratifying by the race, the results showed that the rs1801278 polymorphism was associated with increased CRC risk under dominant model in mixed populations. Based on this meta-analysis, we conclude that the IRS-1 rs1801278 polymorphism might be a risk factor for CRC development in mixed populations. Further studies, either with larger sample size or involving other single nucleotide polymorphisms (SNPs) and haplotypes of the IRS-1 gene, are necessary to clarify the contribution of IRS-1 rs1801278 in colorectal carcinogenesis.
Keywords IRS-1 . Polymorphism . Colorectal cancer . Meta-analysis
P. Li (*) : H. Jiang : C. Ma : T. Hao Department of Anus & Intestine Surgery, Binzhou Medical University Hospital, 661 Huangheer Road, Binzhou 256603, Shandong, China e-mail: [email protected] L. Wang Boxing County People’s Hospital, Binzhou, Shandong, China L. Liu Department of Emergency, Binzhou People’s Hospital, Binzhou, Shandong, China
Introduction Colorectal cancer (CRC) remains a major public health problem in the world and is the third most common cancer in males and the second in females, with 26,470 deaths in males and 25,220 deaths in females expected to occur in 2012 in the USA [1]. It is widely accepted that cancer-associated inflammation promotes tumor growth and progression by inducing gene mutations, inhibiting apoptosis, and stimulating angiogenesis and cell proliferation [2, 3]. Presently, cancer is a major public health problem worldwide. It is a complex disease resulting from genetics, environmental factors, and their interactions [4–7]. Epidemiological studies have indicated that traditional risk factors including diet rich in fat, less physical activity, smoking, and alcohol consumption contributed to the susceptibility to cancer [4]. As is known, comparing with the traditional factors, genetic variants are not associated with potential confounders, can be measured objectively and precisely, and they may act as a lifelong marker of diseases [5–7]. Single nucleotide polymorphisms are the most common sources of human genetic variation, and they may contribute to an individual’s susceptibility to cancer [5–7]. Then, investigating the effects of genetic variants on cancer risk may help better understand the association between genetic variants and cancer risk. Insulin receptor substrate (IRS) proteins are critical to signal transduction in insulin target tissues [8]. The binding of insulin to its receptor induces the phosphorylation of the cytosolic substrates IRS-1 and IRS-2 [9]. Nevertheless, the biokinetic response of IRS-1 and IRS-2 to tyrosine protein kinases depends upon the binding specificity and affinity of the tyrosine phosphorylation sites within the IRS, which can be altered by mutated amino acid polymorphisms within the phosphotyrosine-binding domain [10]. Among these identified tyrosine phosphorylation sites [9, 10], mutations of rs1801278 have revealed different levels of reduction in
Tumor Biol.
phosphatidylinositol 3-kinase (PI 3-kinase) activity [10]. The impaired insulin-signaling pathway for PI 3-kinase activity plays a role in the development of insulin resistance [10–12]. Recently, rs1801278 polymorphism in the IRS-1 gene has been found to be involved in the pathogenesis of CRC. However, the results from different laboratories are conflicting. With the aim of providing a more precise estimation of the potential associations of the rs1801278 polymorphism with CRC risk, we performed a meta-analysis of the candidate eligible studies.
the presence or absence of heterogeneity, respectively. Subgroup analyses were performed by ethnicity. Sensitivity analysis was performed by excluding the studies where the Hardy–Weinberg equilibrium of the genotypes in controls was unknown. Begg’s funnel plot, a scatter plot of effect against a measure of study size, was generated as a visual aid to detect bias or systematic heterogeneity. Publication bias was assessed by Begg’s test and Egger’s test. Data analyses were performed using Review Manager 5.0 and Stata version 11.
Results Materials and methods Literature search PubMed and Embase were searched for eligible articles. The search strategy to identify all potential studies involved use of combinations of the following keywords: “IRS-1” and “variant or variation or polymorphism” and “CRC”. The reference lists of retrieved reviews and articles were hand-searched. The publication language was restricted to English. If more than one article was published using the same study population, only the study with largest sample size was selected. The literature search was updated on October 26, 2013. Inclusion criteria and data extraction Included studies should meet the following inclusion criteria: (1) using a case–control design, (2) evaluating the association between IRS-1 rs1801278 polymorphism and CRC risk, and (3) providing an odds ratio (OR) with 95 % confidence interval (CI) or sufficient data for the calculation of OR with 95 % CI. The following information was extracted from each study: (1) name of the first author, (2) year of publication, (3) country of origin, (4) ethnicity, (5) sample size of cases and controls, and (6) OR with 95 % CI under an additive models. Two authors independently assessed the articles for compliance with the inclusion criteria, and disagreement was followed by discussion until consensus was reached.
The detailed characteristics of the included studies are listed in Table 1. A total of 3,708 cases and 4,176 controls were identified for the data analysis [13–16]. The overall result showed that IRS-1 polymorphism was not significantly associated with an increased risk of CRC, with no evidence of between-study heterogeneity. In the stratified analysis, the data showed that rs1801278 polymorphism was associated with increased CRC risk under dominant model in mixed populations. The detailed data were shown in Table 2. Sensitivity analysis In order to compare the difference and evaluate the sensitivity of the meta-analyses, we conducted one-way sensitivity analysis to evaluate the stability of the meta-analysis. The statistical significance of the results was not altered when any single study was omitted. Hence, results of the sensitivity analysis suggest that the data in this meta-analysis are relatively stable. Publication bias Begg’s funnel plot and Egger’s test were performed to assess the publication bias. The shape of funnel plots did not reveal any evidence of obvious asymmetry in all comparisons in overall population, and the Egger’s test was used to provide statistical evidence of funnel plot. The results did not show any evidence of publication bias in all comparisons.
Statistical analysis The association between IRS-1 polymorphism and CRC risk was assessed by calculating pooled OR and 95 % CI. The pooled OR and its 95 % CI were performed for an additive model (AA vs GG), a recessive model (AA vs GA+GG), a dominant model (AA+GA vs GG), and an allelic model (A allele vs G allele). The significance of the pooled OR was determined by a Z test (p
RESEARCH ARTICLE
Association between IRS-1 Gly972Arg polymorphism and colorectal cancer risk Peng Li & Lingjun Wang & Lihua Liu & Hong Jiang & Chong Ma & Tao Hao
Received: 17 February 2014 / Accepted: 26 March 2014 # International Society of Oncology and BioMarkers (ISOBM) 2014
Abstract In order to make a comprehensive assessment of the potential association between one genetic variant in the insulin receptor substrate 1 (IRS-1) gene, rs1801278, and colorectal cancer (CRC) risk, we conducted a meta-analysis of four epidemiological studies, which included 3,708 CRC cases and 4,176 controls. The data showed that rs1801278 polymorphism was not associated with increased CRC risk in the overall population. When stratifying by the race, the results showed that the rs1801278 polymorphism was associated with increased CRC risk under dominant model in mixed populations. Based on this meta-analysis, we conclude that the IRS-1 rs1801278 polymorphism might be a risk factor for CRC development in mixed populations. Further studies, either with larger sample size or involving other single nucleotide polymorphisms (SNPs) and haplotypes of the IRS-1 gene, are necessary to clarify the contribution of IRS-1 rs1801278 in colorectal carcinogenesis.
Keywords IRS-1 . Polymorphism . Colorectal cancer . Meta-analysis
P. Li (*) : H. Jiang : C. Ma : T. Hao Department of Anus & Intestine Surgery, Binzhou Medical University Hospital, 661 Huangheer Road, Binzhou 256603, Shandong, China e-mail: [email protected] L. Wang Boxing County People’s Hospital, Binzhou, Shandong, China L. Liu Department of Emergency, Binzhou People’s Hospital, Binzhou, Shandong, China
Introduction Colorectal cancer (CRC) remains a major public health problem in the world and is the third most common cancer in males and the second in females, with 26,470 deaths in males and 25,220 deaths in females expected to occur in 2012 in the USA [1]. It is widely accepted that cancer-associated inflammation promotes tumor growth and progression by inducing gene mutations, inhibiting apoptosis, and stimulating angiogenesis and cell proliferation [2, 3]. Presently, cancer is a major public health problem worldwide. It is a complex disease resulting from genetics, environmental factors, and their interactions [4–7]. Epidemiological studies have indicated that traditional risk factors including diet rich in fat, less physical activity, smoking, and alcohol consumption contributed to the susceptibility to cancer [4]. As is known, comparing with the traditional factors, genetic variants are not associated with potential confounders, can be measured objectively and precisely, and they may act as a lifelong marker of diseases [5–7]. Single nucleotide polymorphisms are the most common sources of human genetic variation, and they may contribute to an individual’s susceptibility to cancer [5–7]. Then, investigating the effects of genetic variants on cancer risk may help better understand the association between genetic variants and cancer risk. Insulin receptor substrate (IRS) proteins are critical to signal transduction in insulin target tissues [8]. The binding of insulin to its receptor induces the phosphorylation of the cytosolic substrates IRS-1 and IRS-2 [9]. Nevertheless, the biokinetic response of IRS-1 and IRS-2 to tyrosine protein kinases depends upon the binding specificity and affinity of the tyrosine phosphorylation sites within the IRS, which can be altered by mutated amino acid polymorphisms within the phosphotyrosine-binding domain [10]. Among these identified tyrosine phosphorylation sites [9, 10], mutations of rs1801278 have revealed different levels of reduction in
Tumor Biol.
phosphatidylinositol 3-kinase (PI 3-kinase) activity [10]. The impaired insulin-signaling pathway for PI 3-kinase activity plays a role in the development of insulin resistance [10–12]. Recently, rs1801278 polymorphism in the IRS-1 gene has been found to be involved in the pathogenesis of CRC. However, the results from different laboratories are conflicting. With the aim of providing a more precise estimation of the potential associations of the rs1801278 polymorphism with CRC risk, we performed a meta-analysis of the candidate eligible studies.
the presence or absence of heterogeneity, respectively. Subgroup analyses were performed by ethnicity. Sensitivity analysis was performed by excluding the studies where the Hardy–Weinberg equilibrium of the genotypes in controls was unknown. Begg’s funnel plot, a scatter plot of effect against a measure of study size, was generated as a visual aid to detect bias or systematic heterogeneity. Publication bias was assessed by Begg’s test and Egger’s test. Data analyses were performed using Review Manager 5.0 and Stata version 11.
Results Materials and methods Literature search PubMed and Embase were searched for eligible articles. The search strategy to identify all potential studies involved use of combinations of the following keywords: “IRS-1” and “variant or variation or polymorphism” and “CRC”. The reference lists of retrieved reviews and articles were hand-searched. The publication language was restricted to English. If more than one article was published using the same study population, only the study with largest sample size was selected. The literature search was updated on October 26, 2013. Inclusion criteria and data extraction Included studies should meet the following inclusion criteria: (1) using a case–control design, (2) evaluating the association between IRS-1 rs1801278 polymorphism and CRC risk, and (3) providing an odds ratio (OR) with 95 % confidence interval (CI) or sufficient data for the calculation of OR with 95 % CI. The following information was extracted from each study: (1) name of the first author, (2) year of publication, (3) country of origin, (4) ethnicity, (5) sample size of cases and controls, and (6) OR with 95 % CI under an additive models. Two authors independently assessed the articles for compliance with the inclusion criteria, and disagreement was followed by discussion until consensus was reached.
The detailed characteristics of the included studies are listed in Table 1. A total of 3,708 cases and 4,176 controls were identified for the data analysis [13–16]. The overall result showed that IRS-1 polymorphism was not significantly associated with an increased risk of CRC, with no evidence of between-study heterogeneity. In the stratified analysis, the data showed that rs1801278 polymorphism was associated with increased CRC risk under dominant model in mixed populations. The detailed data were shown in Table 2. Sensitivity analysis In order to compare the difference and evaluate the sensitivity of the meta-analyses, we conducted one-way sensitivity analysis to evaluate the stability of the meta-analysis. The statistical significance of the results was not altered when any single study was omitted. Hence, results of the sensitivity analysis suggest that the data in this meta-analysis are relatively stable. Publication bias Begg’s funnel plot and Egger’s test were performed to assess the publication bias. The shape of funnel plots did not reveal any evidence of obvious asymmetry in all comparisons in overall population, and the Egger’s test was used to provide statistical evidence of funnel plot. The results did not show any evidence of publication bias in all comparisons.
Statistical analysis The association between IRS-1 polymorphism and CRC risk was assessed by calculating pooled OR and 95 % CI. The pooled OR and its 95 % CI were performed for an additive model (AA vs GG), a recessive model (AA vs GA+GG), a dominant model (AA+GA vs GG), and an allelic model (A allele vs G allele). The significance of the pooled OR was determined by a Z test (p
