Association Between the Interleukin-1β Gene ( IL1B ) C−511T Polymorphism and the Risk of Diabetic Nephropathy in Type 2 Diabetes: A Candidate

Abstract

Variants of the interleukin-1β gene (IL1B) are implicated in the development of diabetic nephropathy (DN). The present candidate–gene association study was conducted to investigate the association between the IL1B C−511T variant and the risk of DN in a Caucasian population. The study population consisted of 173 cases (patients with type 2 diabetes mellitus [DM] and DN) and 186 controls (patients with DM free of DN). Genotyping was performed by polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP). The PCR product was a 304-bp long DNA fragment of the IL1B gene promoter region, extending from position −702 to −398 and including the polymorphic AvaI site (at position −511). The magnitude of the overall association was tested using the generalized odds ratio (OR_G) metric, a genetic model-free approach. The ORs (adjusted for effect modifiers) of the additive and co-dominant models were also estimated. The mode of inheritance was assessed using the degree of dominance index (h). There was a significant difference in the genotype distribution between the group of cases with DN compared with diseased controls free of DN (p=0.014). Analysis produced a significant OR_G (OR_G=1.74, 95% confidence interval [CI]=1.20–2.52), indicating that the risk of DN is significantly associated with the mutational load. The risk of developing DN is significantly enhanced in IL1B T allele carriers (dominant model, p=0.005) and in homozygotes (additive model, p=0.018) respectively. However, the recessive model for T allele (p=0.097) and the co-dominant model (p=0.085) produced non-significant results. Considering that the additive model was significant (OR=2.53, 95% CI=1.20–5.36) and the co-dominant is non-significant (OR=1.53, 95% CI=0.97–2.40), the mode of inheritance is complete “additiveness,” with the degree of dominance being h=0. The findings provided evidence that the IL1B C−511T variant might be associated with development of DN.

Introduction

In industrialized countries, diabetic nephropathy (DN) has become the most frequent cause of end-stage renal disease requiring chronic renal replacement therapy (CDC 2005; Van Dijk et al., 2005; Foley and Collins, 2009). In the last decade great effort has been put forward to unravel pathogenesis of nephropathy, observed in about 30% of all patients with diabetes (Freedman et al., 2006). Strong evidence is accumulating for the involvement of genetic factors (Conway and Maxwell, 2009). The main arguments in favor of the genetic background theory derive from epidemiologic studies showing (i) a non-linear increase of affected diabetic patients over time with a peak incidence after ∼15 years of diabetes duration and (ii) a significant familiar clustering of DN in diabetes mellitus type 2 (DM) and in different populations (Quinn et al., 1996; Strojek et al., 1997; The Diabetes Control and Complications Trial Research Group, 1997). Furthermore, (iii) in family-based linkage studies certain genomic regions have been mapped that predispose to the development of DN (Thomas et al., 2012). However, a single pathogenetically relevant gene has not been identified yet (Freedman et al., 2007). It is therefore postulated that further investigation of genetic susceptibility to DN will be needed.

Interleukin-1 (IL-1), an inflammatory cytokine mainly produced by monocytes/macrophages, has been shown to modulate mesangial cell proliferation and extracellular matrix production (Liu et al., 1996; Loughrey et al., 1998; Huang and Siragy, 2009). In addition, mesangial cells produce IL-1, which acts as an autocrine growth factor, that is, inducing mesangial cell proliferation (Lovett et al., 1986). In the pathogenesis of DN these pathological alterations are common hallmarks that encompass thickening of basal membranes and accumulation of extracellular matrix components (Gruden et al., 2005; Braun et al., 2009; Chiarelli et al., 2009). Therefore, it may be readily hypothesized that allelic variations of the IL-1 cluster genes contribute to the development of DN. The IL-1β gene (IL1B; MIM 147720) is located on chromosome 2 (2q14) (Nicklin et al., 1994) in the same proximity with the other IL-1 gene family members (2q14–q21) (Steinkasserer et al., 1992; Nicklin et al., 2002). Several polymorphisms have been identified in the IL1B gene, including rs16944 a single base variation (C/T) at position −511 in the promoter region (di Giovine et al., 1992). Lee et al. (2004) showed a positive association between rs16944 and DN in a Korean population. Thus, our motivation was to replicate the findings of Lee et al. (2004) in a Caucasian population. Note that rs16944 has been shown to modify IL-1β levels both in vitro and in vivo (Pociot et al., 1992; Hall et al., 2004; Rogus et al., 2008). However, no other variants within the IL1B gene have shown significant association with DN in any population so far.

In the present candidate–gene study we tested the hypothesis of association between the C−511T polymorphism of the IL1B and DN in a homogeneous population of Caucasian origin (Germans). The study consisted of a group of patients with DM and DN (DM+DN) and diabetic controls matched for the disease (DM) duration without signs of diabetic sequelae affecting the kidneys (DM−DN).

Materials and Methods

Participants

The sample collection for the case–control study was conducted at the University Hospital of Aachen, Germany. The local ethical committee approved the study protocol and all participants signed an informed consent before enrollment. The study population consisted of 173 unrelated patients with type 2 diabetes mellitus (DM) and DN (cases; DM+DN) and 186 unrelated patients with DM free of DN (controls; DM−DN). All participants were Caucasians and in particular, German citizens of no migrant background. They resided during the study in the same region in Germany (North Rhine-Westphalia). They were recruited between October 2005 and June 2006 among patients attending the outpatient clinic for Internal Medicine (Nephrology and Clinical Immunology) at the University Hospital of Aachen, and local practitioners with specialization in diabetes care and nephrology. For the evaluation, patients with DM+DN (cases; n=173) were matched according to the duration of the type 2 diabetes to patients with DM−DN (diseased controls; n=186).

Diagnosis of type 2 diabetes was confirmed according to the American Diabetes Association (ADA) criteria of 2003 (Genuth et al., 2003). Diabetes type 2 with nephropathy was diagnosed on the basis of a persistent albuminuria, (urinary albumin excretion >300 mg/24 h; >200 μg/min; representing overt glomerular proteinuria) with or without elevated serum creatinine levels (reference range <1.3 mg/dL for males, <1.1 mg/dL for females) and in the absence of clinical evidence of non-diabetic renal disease. Patients with microalbuminuria, that is, urinary albumin excretion 30–300 mg/24 h (20–200 μg/min), were excluded. Although, microalbuminuria may be an early finding in DN it is not invariably equivalent to it and may also be due to hypertensive nephropathy in a considerable share of patients. Patients with type 2 diabetes were classified free of DN if their albumin excretion rate were <20 mg/24 h (<15 μg/min) and serum creatinine concentrations were within normal range in at least two examinations.

Each subject underwent a standardized physical examination and provided past medical history regarding diagnosis, treatment, and complications of diabetes mellitus as well as co-diseases. The presence of hypertension was not an exclusion criterion. Variables known to be associated with raised urinary albumin concentration including hypertension, cardiovascular disease, and glycosylated hemoglobin (HbA_1c) were registered. Blood sample to determine renal function parameters (serum creatinine and urea) and for DNA extraction was taken from each individual.

Genotyping

DNA was extracted from peripheral blood leukocytes by standard methodologies using a commercially available kit from Qiagen (Hilden, Germany). Genomic DNA was resuspended in 10 mM Tris-HCl, 1 mM ethylenediaminetetraacetic acid, pH 8.0, and the concentration was measured by spectrophotometry.

Genotyping was performed by polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP). To avoid confounding, all laboratory personnel were blinded for case–control status of the samples.

On restriction enzyme analysis of the human IL1B genomic clone the polymorphic AvaI site has been localized in the promoter region at position −511 of the IL1B. It represents a transition of cytosine (C) to thymine (T), which abolishes the AvaI recognition site in the mutant form (di Giovine et al., 1992).

For PCR amplification a forward primer (5′-TGGCATTGATCCAACTGGCTCCTGGTTCATC-3′) and a reverse primer (5′-GTTTAGGAATCTGTCTTGTGGTTTCCCACTT-3′) were applied. The PCR product was a 304-bp long DNA fragment of the IL1B gene promoter region, extending from position −702 to −398 and including the polymorphic AvaI site (at position −511). The PCR started with an initial denaturation (at 95°C for 10 min), followed by 38 cycles of amplification consisting of denaturation at 94°C for 45 s, annealing at 56°C for 45 s, extension at 72°C for 45 s, and ended with 7 min at 72°C. The PCR products were then digested by the addition of AvaI restriction enzyme (3 U) in restriction buffer and separated by electrophoresis on a 2% agarose gel. The AvaI RFLP was detected by ethidium bromide staining (di Giovine et al., 1992). Obtaining a set of bands, 190 and 114 bp, corresponded to the C allele (i.e., AvaI⁺ allele) and obtaining a single 304 bp band corresponded to the T allele (i.e., AvaI⁻ allele). Duplicate genotyping was applied in all samples and concordance was achieved for all samples.

Statistical methods

For inter-group comparisons of continuous and categorical variables, that is, patients with DM+DN versus patients with DM−DN, the Mann–Whitney U test and the chi-squared test were applied, respectively. The association between genotype distribution and clinical status was tested using the chi-squared test. The additive, recessive, dominant, and co-dominant models of the cases were examined using a logistic model. The associations were expressed in terms of odds ratios (ORs) [unadjusted and adjusted for by sex, age, and body mass index (BMI; kg/m²), existence of hypertension, and glycosylated hemoglobin levels (HbA_1c; %)] with the corresponding 95% confidence intervals (CIs). The analysis was carried out using SPSS v.12.0 (SPSS, Chicago, IL). A result with p<0.05 was considered statistically significant. An exact test according to Weir was used to test whether the frequency distribution of genotypes in all type 2 diabetes mellitus patients was in Hardy–Weinberg equilibrium (HWE) (p≥0.05) (Weir, 1996; Zintzaras and Stefanidis, 2005; Zintzaras et al., 2006).

The associations were also examined using the generalized odds ratio (OR_G) as defined by Zintzaras (2010). The OR_G is a genetic model-free approach and provides an estimate of the overall risk effect by utilizing the complete genotype distribution. The application of the OR_G metric in genetic association studies (1) overcomes the difficulty of defining a priori an unknown model of inheritance for a polymorphism and (2) utilizes the complete genotype distribution, providing an estimate of the overall risk effect. The OR_G express the probability of a subject being a case (DM+DN) relative to probability of being a control (DM−DN), given that the case has a higher mutational load than the control (Zintzaras, 2010). The OR_G was calculated using ORGGASMA (http://biomath.med.uth.gr/) (Zintzaras, 2010).

Furthermore, the mode of inheritance in genetic association was estimated using the degree of dominance index (h) as defined by Zintzaras and Santos (2011, 2012). The h-index is defined as the ratio of the natural logarithms of the ORs of the two orthogonal contrasts (models): the co-dominant and the additive models. In the presence of significant association, when the additive model is significant and the co-dominant model is not significant, “non-dominance” (or complete “additiviness”) is assumed and h=0. When the co-dominant model is significant (irrespectively of the significant level of the additive contrast), “dominance” is assumed and h>0 or h<0, depending on the risk-position of the heterozygotes.

Results

Overall 359 unrelated patients with type 2 diabetes (196 males, mean age 67±10 years) participated in the study. Table 1 shows the demographic and clinical characteristics of all participants and the two study groups: patients with type 2 diabetes and DN (cases; n=173, 104 males, mean age 69±10 years) and patients with type 2 diabetes free of DN (controls; n=186, 92 males, mean age 65±9 years). There were significant differences for age (p=0.001) and sex distribution (p=0.045). The cases with DN and controls free of DN were matched for the duration of type 2 diabetes mellitus (13.5±9.8 vs. 14.0±6.9 years, p=0.244). In comparison with controls, cases had a lower BMI (28.6±5.5 vs. 30.9±5.5 kg/m², p=0.001) and the prevalence of hypertension was higher (80.7% in cases vs. 68.3% in controls, p=0.008). In contrast, levels of glycosylated hemoglobin (HbA_1c; 7.46%±1.69% in cases vs. 7.39%±1.33% in controls, p=0.706) were comparable in the two groups (Table 1).

Table 1.

Demographic and Clinical Characteristics of All Patients with Type 2 Diabetes Mellitus, Who Participated in the Case–Control Study on the Risk of Diabetic Nephropathy

Variables
Study groups	All participants	DM with DN	DM free of DN	p-Value ^a
n	359	173	186	n.a.
Sex (m/f )	196/163	104/69	92/94	0.045
Age (years)	67±10	69±10	65±9	0.001
BMI (kg/m²)	29.8±5.6	28.6±5.5	30.9±5.5	0.001
Hypertension (%)	74.2	80.7	68.3	0.008
Coronary heart disease (%)	43.7	53.2	34.9	0.001
DM duration (years)	13.7±8.3	13.5±9.8	14.0±6.9	0.244
HbA_1c (%)	7.42±1.51	7.46±1.69	7.39±1.33	0.706
Albuminuria (mg/day)	346±658	625±768	14.9±9.1	0.001
Creatinine (mg/dL)	2.12±2.34	3.41±2.91	0.98±0.21	0.001

Mann–Whitney U test or chi-squared test as appropriate.

n.a., Not applicable; DM, type 2 diabetes mellitus; DN, diabetic nephropathy.

The IL1B genotype distribution of cases and controls is shown in Table 2. The genotype distribution of all patients with type 2 diabetes (n=359) was in HWE (p=0.177). There was a significant difference in the genotype distribution between the group of cases with DN compared with diseased controls free of DN (p=0.014) (Table 2). The OR_G (Zintzaras, 2010) was (1.74, 95% CI=1.20–2.52) (Table 2), indicating that for any two subjects, one with DM+DN and one with DM−DN, the odds of being with DM+DN was twofold higher than the odds of being DM−DN, given that the subject with DM+DN has higher mutational load than the one with DM−DN. Alternatively, there are two times as many cases–controls (type 2 diabetics with DN–without DN) pairs in the study for which the case (DM+DN) has the largest mutational load as there are pairs for which the control (DM−DN) has the largest mutational load. Subjects who are homozygous for T allele were considered to have the highest mutational load, those homozygous for C allele to have the lowest, and heterozygous to have an intermediate load.

Table 2.

Distribution of IL1B C−511T (rs16944) Genotypes in Patients with Type 2 Diabetes Mellitus and Diabetic Nephropathy (DM with DN; Cases) and Patients with Type 2 Diabetes Free of Nephropathy (DM Free of DN; Controls) Are Shown

	Distribution of the IL1B C−511T genotypes
Population (n)	CC n (%)	CT n (%)	TT n (%)	p-Value	OR_G (95% CI)
Controls free of DN (186)	104 (55.9)	66 (35.5)	16 (8.6)
Cases with DN (173)	71 (41.0)	77 (44.5)	25 (14.5)	0.014^a	1.74 (1.20–2.52)^a
Overall DM (359)	175 (48.7)	143 (39.8)	41 (11.4)

The p-value (by chi-squared test) and the OR_G are calculated.

Comparison with controls.

OR_G, generalized odds ratio; CI, confidence interval.

Table 3 shows the association results for the additive (contrast of homozygotes), the recessive, and the dominant models for allele T and the co-dominant model. The risk of developing DN is significantly enhanced in IL1B T allele carriers (dominant model) and in homozygotes (additive model): (OR=1.82, 95% CI=1.20–2.77) (p=0.005) and (OR=2.29, 95% CI=1.14–4.59) (p=0.018) respectively. Thus, there is an approximately twofold probability for DN in T allele carriers in contrast to non-carriers. However, the recessive model for T allele (p=0.097) and the co-dominant model (p=0.085) produced non-significant results. The adjusted ORs derived similar results, in all settings (Table 3).

Table 3.

Association Results for the Additive (Contrast of Homozygotes), Recessive, and Dominant Models for the T Allele and the Co-Dominant Model of the IL1B C−511T Polymorphism

	Cases with type 2 diabetes and nephropathy
Genetic contrasts for allele T	OR (95% CI)	p-Value	OR adjusted (95% CI)
Additive model	2.29 (1.14–4.59)	0.023	2.53 (1.20–5.36)
Recessive model	1.79 (0.92–3.49)	0.097	1.96 (0.93–3.88)
Dominant model	1.82 (1.20–2.77)	0.006	1.96 (1.26–3.08)
Co-dominant model	1.46 (0.95–2.23)	0.085	1.53 (0.97–2.40)

The unadjusted (OR) and adjusted odds ratios (OR_adjusted) with the corresponding 95% CI are shown. p-Values derived from the Fisher's exact test are also shown. Adjusted OR by sex, age, BMI (kg/m²), existence of hypertension, and additionally by glycosylated hemoglobin (HbA_1c; %) was determined using multiple logistic regression.

BMI, body mass index.

Considering that the additive model is significant and the co-dominant is non-significant, the mode of inheritance is “non-dominance,” or complete “additiveness,” with the degree of dominance being h=0. The interpretation would then be that the heterozygote CT “lies” in the middle of the two homozygotes (in terms of risk disease; DM+DN), with the mutant homozygote TT having the maximum susceptibility of being DM+DN and the wild-type homozygote CC having the least.

Discussion

In our study, we explored various genetic contrast models to determine whether the IL1B C−511T polymorphism has an effect on the onset of DN in patients with type 2 diabetes mellitus. Our results show that T allele carriage (dominant model for T) frequency was significantly higher in patients with type 2 diabetes with DN in comparison with patients without nephropathy. The risk for DN was further elevated in homozygotes for the T allele (additive model), however, the corresponding ORs were not consistent with a dose effect of T. The OR_G, a genetic model-free approach (Zintzaras, 2010), showed that in type 2 diabetics there is a two-fold higher risk for DN, given that the type 2 diabetics with DN have higher mutational load than those without DN. The risk for DN was further elevated in homozygotes for the T allele (additive model), however, the corresponding ORs were not consistent with a dose effect of T. This fact is further supported by the degree of dominance index, which was h=0, indicating complete “additiveness” (Zintzaras and Santos, 2011, 2012).

This study is the first to investigate the risk of developing DN in relation to the IL1B C−511T polymorphism in a Caucasian population with type 2 diabetes. One previously published case–control study, which included a Korean population with type 2 diabetes, also showed a significant association between carriage of the T allele and DN (Lee et al., 2004). However, two additional studies in Caucasians with type 1 diabetes rendered conflicting results (Tarnow et al., 1997; Loughrey et al., 1998).

In agreement with our findings, there is accumulating evidence on the central role of inflammatory processes and especially of the inflammatory cytokines, including IL-1β, in the pathogenesis of glomerular injury in diabetes mellitus (Maeda, 2008; Navarro-Gonzalez and Mora-Fernandez, 2008). Tesch (2008) has demonstrated with animal models that infiltrating macrophages are linked to perturbations of renal function and that knock-out of MCP-1 results in protection from renal damage. Thus, the inflammatory cytokine IL-1β may constitute a link between metabolic (i.e., hyperglycemic) perturbations and pathologic inflammatory alterations typical for DN with resulting matrix accumulation. Advanced glycation end products acting on mesangial and endothelial cell cultures lead to IL-1 overexpression, an effect that has also been etected on renal tissue of experimental models with DN. In turn, IL-1 stimulates mesangial cell proliferation and extracellular matrix production.

The C−511T polymorphism has been associated with alterations of gene transcription (Rogus et al., 2008) and IL-1β protein production (Pociot et al., 1992; Hall et al., 2004; Rogus et al., 2008). Therefore, it may be readily assumed that the T allele genotype is a susceptibility marker for DN. Alternatively, the T allele genotype of the IL1B gene is in linkage disequilibrium with another locus that plays a significant pathogenetic role for DN. In this case, the difference in haplotype structure, based on the linkage disequilibrium around C−511T, may explain the contradictory results in the studies of different populations (Tarnow et al., 1997; Loughrey et al., 1998; Lee et al., 2004). However, no other variants within the IL1B gene have shown significant association with DN in any population so far.

The conclusion reached in the present study was based on a relatively small number of subjects and thus, the results should be interpreted with caution. However, it is well known that candidate–gene studies lack power to detect weak genetic risk effects of common variants. For example, to achieve power of >80% of detecting a modest genetic risk (OR=1.2) of a variant with prevalence 10%, a sample size of more than 10,000 subjects is needed (Zintzaras and Lau, 2008b), a size that a single institution is hard to achieve. The power of the study is 75% (given the decrease of effect size is roughly 20%, the minor allele frequency is 45%, and the prevalence of DN 4%), assuming a significance level of 5%. It is notable, that in previous similar studies the number of cases was also relatively small, ranged from 95 to 234 (Loughrey et al., 1998; Lee et al., 2004). Nevertheless, the finding of the present study could be pooled in a future meta-analysis of multiple studies, providing more power to detect significant associations (Zintzaras and Lau, 2008a).

Conclusion

In summary, in this study of a Caucasian population there is considerable evidence that the C−511T polymorphism of IL1B, which is characterized by an increased IL-1β synthesis, is associated with the development of nephropathy in type 2 diabetes mellitus. The above findings reinforce the need of additional case–control studies to clarify the role of IL1B in susceptibility to DN.

Footnotes

Acknowledgments

The study has been funded by the Deutsche Forschungsgemeinschaft Transregio 57 (project 3). We are grateful to the generous support with patient recruitment by the following physicians: Dr. Heddaeus, Dr. Drube, Dr. Wölbert, Dr. Weidemann, Dr. Mann, and Dr. Heidenreich and wish to express our gratitude to the commitment of all patients willing to participate in this study.

Disclosure Statement

No competing financial interests exist.

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Association Between the Interleukin-1β Gene ( IL1B ) C−511T Polymorphism and the Risk of Diabetic Nephropathy in Type 2 Diabetes: A Candidate–Gene Association Study

Abstract

Introduction

Materials and Methods

Participants

Genotyping

Statistical methods

Results

Discussion

Conclusion

Footnotes

Acknowledgments

Disclosure Statement

References