IL-6 promoter polymorphism -174 is associated with new-onset diabetes after transplantation

New-onset diabetes after transplantation (NODAT) is a serious complication of transplantation. This study tested whether IL-6 production capacity may influence the development of NODAT in two different groups of patients. The occurrence of NODAT was analyzed with respect to IL-6 gene promoter polymorphism at position -174 (G-->C) and other relevant risk factors retrospectively in 217 renal transplant recipients and prospectively in 132. A linear increase in both circulating IL-6 (P = 0.09) and C-reactive protein (an indicator of basal IL-6 secretion; P = 0.03) concentrations from the CC genotype to the GG genotype was observed. In the multivariate model, the CC genotype was associated with a decreased risk for NODAT compared with the GG genotype in the two cohorts. Homeostasis Model Assessment for Insulin Resistance also revealed lesser insulin sensitivity in the GG carriers than in the CC carriers (2.15 +/- 2 versus 1.32 +/- 1.03; P = 0.03). Subgroup analysis showed that the influence of IL-6 gene promoter polymorphism on the development of NODAT was restricted mostly to overweight patients. These results highly suggest that IL-6 production capacity influences the development of NODAT and that diabetes-inducing drug administration should be limited in overweight patients who carry the GG genotype.     

Interaction of interleukin-6 and estrogen receptor gene polymorphisms on bone mass accrual in Chinese adolescent girls

We assessed the main and interaction effects of interleukin-6 and estrogen receptor gene polymorphisms on bone mass accrual in Chinese adolescent girls. A total of 228 premenarche Chinese girls (9-11.5 years old) were recruited for a 2-year follow-up study. Bone mineral density (BMD) at the total body, lumbar spine (L1-L4), and total left hip were measured by dual-energy X-ray absorptiometry at baseline and follow-up. The -174G/C and -634C/G polymorphism of IL-6 gene, and PvuII and XbaI polymorphisms of the estrogen receptor (ER)-alpha gene, were determined. The -634C/G polymorphism of the IL-6 gene and PvuII polymorphism of ER-alpha gene were significantly associated with bone mass accrual after adjusting the potential confounding factors. Girls with pp genotype of ER-alpha gene had greater percentage accrual in BMD of total body (P = 0.010) and femoral intertrochanter (P = 0.038) than their PP and Pp counterparts. Girls with CC genotype of IL-6 -634G/C gene had higher percentage accrual in BMD of total body (P = 0.032) and femoral trochanter (P = 0.048) than their CG + GG counterparts. Significant interaction effects of IL-6 -634C/G polymorphism and ER-alpha PvuII polymorphism were observed on percentage change in BMD of total left hip (P = 0.009) and femoral intertrochanter (P = 0.007). The genotype CC (IL-6 -634C/G) x pp (ER-alpha PvuII) was associated with greater BMD accrual than other genotype combination in Chinese adolescent girls. We found that the IL-6 -634C/G and ER-alpha PvuII polymorphism were significantly associated with BMD accrual and that they have an interactional effect on BMD accrual in Chinese adolescent girls.     

The C-174G promoter polymorphism of the IL-6 gene affects energy expenditure and insulin sensitivity

Interleukin-6 (IL-6) is a pleiotropic cytokine expressed in many tissues. IL-6 null mice show low energy expenditure, but the effect of the variants of the IL-6 gene on energy expenditure has not been previously studied in humans. Therefore, we investigated the effect of the C-174G promoter polymorphism of the IL-6 gene on energy expenditure, measured by indirect calorimetry in healthy Finnish subjects (n = 124). We also measured insulin sensitivity by the hyperinsulinemic-euglycemic clamp. Subjects with the C-174C genotype of the IL-6 gene had significantly lower energy expenditure than subjects with the G-174C or G-174G genotypes both in fasting (CC 13.68 +/- 1.98, CG 14.73 +/- 1.57, GG 14.81 +/- 2.01 kcal x kg(-1) x min(-1); P = 0.012) and during the euglycemic-hyperinsulinemic clamp (CC 15.24 +/- 2.05, CG 16.62 +/- 2.06, GG 16.66 +/- 2.50 kcal x kg(-1) x min(-1); P = 0.007). Moreover, subjects homozygous for the C allele had lower rates of whole-body glucose uptake than carriers of the G allele (CC 50.95 +/- 13.91, CG 59.40 +/- 14.17, GG 59.21 +/- 15.93 micro mol x kg(-1) x min(-1); P = 0.016). The rates of both oxidative (P = 0.013) and nonoxidative (P = 0.016) glucose disposal were significantly affected by the IL-6 promoter polymorphism. In conclusion, the C-174C promoter polymorphism of the IL-6 gene influences energy expenditure and insulin sensitivity in healthy normoglycemic subjects. Whether this polymorphism is a risk factor for obesity or type 2 diabetes can be estimated only in prospective population-based studies.     

Functional variants in the lymphotoxin-alpha gene predict cardiovascular disease in dialysis patients

TNF-beta that is encoded by lymphotoxin-alpha gene (LTA) regulates adhesion molecules and IL-6. Previously, a genome-wide case-control study showed that LTA gene variants predisposed to cardiovascular disease (CVD). In a prospective study of 775 dialysis patients, LTA and IL-6 gene variants were tested as independent predictors of CVD risk. Four polymorphisms in the LTA gene and one in the IL-6 gene were genotyped. CVD events were ascertained from medical records. During a mean follow-up of 2.6 yr, 294 first-incident CVD events occurred. The LTA 26Asn variant predicted higher adjusted CVD risk (hazard ratio HR 1.33 for each additional copy of Asn allele; 95% confidence interval 1.14 to 1.55; P = 0.0003). Two other nonsynonymous polymorphisms in the LTA, 13Agr and 51Pro, were associated with lower inflammatory activity and CVD risk. LTA haplotypes (based on all four single-nucleotide polymorphisms) were associated with inflammatory markers and predicted CVD risk (P = 0.005) after adjustment. These LTA genotype associations were independent of the IL-6 -174G/C genotype association that was reported recently. LTA and IL-6 gene variants independently predicted risk for CVD among dialysis patients, suggesting that susceptibility in multiple inflammatory pathways contribute to the development of CVD.     

Influence of interleukin-6 promoter polymorphism -174 g/c on kidney graft outcome

Background

The cytokine interleukin-6 (IL-6) is important in both immune responses and cardiovascular diseases. The IL-6 promoter polymorphism −174 G/C is associated with increased plasma concentrations of IL-6. The relationship between IL-6 polymorphisms and graft survival, cardiovascular events, and new-onset diabetes mellitus after kidney transplantation is controversial.

Objective

To analyze whether IL-6 (−174 G/C) polymorphism influences kidney graft survival or development of chronic allograft nephropathy, cardiovascular events, or new- onset diabetes.

Methods

The IL-6 promoter polymorphism (−174 G/C) was analyzed using the polymerase chain reaction with sequence-specific primers in 335 kidney transplant recipients. Data for graft survival, chronic graft nephropathy, cardiovascular events, and new-onset diabetes were obtained retrospectively from clinical records. Categorical variables were compared between individuals with CC, GG, and GC genotypes using χ² tests. Survival analysis was performed using the Kaplan-Meier method, comparing groups using the log-rank test.

Results

No significant differences were observed in 5-year graft survival between individuals with CC and GC/GG genotypes (85.3% vs 77.1%; P = .22). Nor were significant differences noted in the rates of chronic allograft nephropathy (37.5% vs 33.8%; P = .48), cardiovascular events (10.0% vs 23.0%; P = .10), or new-onset diabetes (7.5% vs 11.8%; P = .28).

Conclusion

There is no association between IL-6 (−174 G/C) polymorphism and graft survival or development of chronic allograft nephropathy, cardiovascular events, or new- onset diabetes.     

Impact of cytokine gene polymorphism on cardiovascular risk in renal transplant recipients

Cardiovascular events are the leading causes of morbidity and mortality in renal transplant recipients (RTR). Given the role of inflammation in atherosclerosis, the contribution of functional polymorphisms of cytokines to cardiovascular diseases (CVD) was assessed in RTR in this study. Polymorphisms of tumour necrosis factor alpha (TNF-alpha) gene [-308 (G-->A), -238 (G-->A)], interleukin-10 (IL-10) gene [-1082(A-->G), -819 (T-->C), -592 (A-->C)], transforming growth factor beta 1 (TGF-beta1) gene [codon 10 (T-->C), codon 25 (G-->C)], carotis intima media thickness (CIMT), left ventricular mass index (LVMI), 24-h ambulatory blood pressure and serum lipoprotein homocysteine level, erythrocyte sedimentation rate, serum C-reactive protein (CRP) and serum fibrinogen level of RTR were determined. Seventy-two RTR (26 cadaveric allograft, 46 living-related allograft, 43 male, 29 female) were included in this study. LVMI were similar in TNF-alpha, IL-10 and TGF-beta1 genotypes. Right and left CIMT were higher in TT genotype (n = 16) than CT (n = 46) and CC (n = 10) genotypes of TGF-beta1 codon 10 (T-->C) gene polymorphism (RCIMT, 7.7 +/- 2.2 mm vs. 7.0 +/- 1.4 mm vs. 5.9 +/- 1.4 mm, P = 0.025; LCIMT, 8.5 +/- 2.5 mm vs. 7.0 +/- 1.3 mm vs. 6.1 +/- 1.2 mm, P = 0.002). Lipoprotein (a) level of TT genotype (35.5 +/- 22.5 mg/dl) was higher than CC (4.1 +/- 2.8 mg/dl) and CT (20.4 +/- 11.2 mg/dl) genotypes of TGF-beta1 codon 10 (T-->C) gene polymorphism (P = 0.037). High producers of cytokine IL-10 -1082 [GG (n = 22) vs. AA + AG (n = 50)] and low producers of TGF-beta codon 25 [GC + CC (n = 17) vs. GG (n = 55)] had lower IMT of carotid artery but the difference did not reach statistical significance (P > 0.05). The CIMT of renal transplant patients was similar in IL-10 (-819, -592) and TNF-alpha (-308, -238) genotypes. No difference was observed in 24-h ambulatory blood pressure levels, serum lipoproteins, plasma homocysteine level, erythrocyte sedimentation rate, serum CRP, serum fibrinogen level in IL-10, TNF-alpha and TGF-beta1 genotypes. Besides the well-known factors, TGF-beta1 gene polymorphisms might play a role in CVD in RTR even at early stages of asymptomatic atherosclerosis.     

Interactions of interleukin-6 promoter polymorphisms with dietary and lifestyle factors and their association with bone mass in men and women from the Framingham Osteoporosis Study.

Lifestyle and dietary factors may influence the association of IL-6 polymorphisms with bone mass. In 1574 unrelated men and women from the Framingham Offspring Cohort, we observed significant hip BMD differences between IL-6 -174 genotypes only in older women, those without estrogens, and those with a poor calcium intake. Hence, association of IL-6 polymorphisms with BMD may be limited to discrete population subgroups. INTRODUCTION: Interleukin (IL)-6 plays a central role in the pathogenesis of osteoporosis. Two functional variants in the IL-6 promoter have previously been associated with IL-6 expression, bone resorption levels, and BMD in late postmenopausal women, but results were conflicting in different populations. We hypothesized that the association between IL-6 promoter alleles and BMD may be affected by interactions with lifestyle and dietary factors known to influence bone turnover. MATERIALS AND METHODS: Among the Offspring Cohort of the Framingham Heart Study, 1574 unrelated men and women were genotyped for IL-6 -572 and -174 alleles. Interaction analyses with years since menopause, estrogen status, physical activity, smoking, dietary calcium, vitamin D, and alcohol intake were based on BMD measurements at the hip. RESULTS AND CONCLUSIONS: In models that considered only the main effects of IL-6 polymorphisms, no significant association with BMD was observed in either gender. In contrast, p values (0.003-0.096 by ANOVA) suggestive of an interaction between IL-6 -174 genotypes and years since menopause, estrogen status, dietary calcium, and vitamin D intake were observed in women (n = 819). In turn, BMD was significantly lower with genotype -174 GG compared with CC, and intermediate with GC, in women who were more than 15 years past menopause and in those without estrogens or with calcium intake <940 mg/day. In estrogen-deficient women with poor calcium intake, BMD differences between genotypes CC and GG were 10.2% at femoral neck (p = 0.012), 12.0% at trochanter (p = 0.012), and 16.8% at Ward's area (p = 0.0014). In contrast, no such interactions were observed in men (n = 755). In conclusion, IL-6 genetic variation was prominently associated with hip BMD in late postmenopausal women, those without estrogen replacement therapy, and those with inadequate calcium intake. In contrast, IL-6 polymorphisms are unlikely to be significant determinants of bone mass in other women or men.     

Interleukin-6 gene polymorphism is related to bone mineral density during and after puberty in healthy white males: a cross-sectional and longitudinal study.

Bone mineral density (BMD) is under strong genetic control and is the major determinant of fracture risk. The cytokine interleukin-6 (IL-6) is an important regulator of bone metabolism and is involved in mediating the effects of androgens and estrogens on bone. Recently, a G/C polymorphism in position -174 of the IL-6 gene promoter was found. We investigated this genetic polymorphism in relation to BMD during late puberty and to peak bone mass, in healthy white males. We identified the IL-6 genotypes (GG, GC, and CC) in 90 boys, age 16.9 +/- 0.3 years (mean +/- SD), using polymerase chain reaction (PCR). BMD (g/cm2) at the femoral neck, lumbar spine, and total body was measured using dual energy X-ray absorptiometry. The volumetric BMD (vBMD; mg/cm3) of the lumbar spine was estimated. Differences in BMD in relation to the genotypes were calculated using analysis of variance (ANOVA). Subjects with the CC genotype had 7.9% higher BMD of the femoral neck (p = 0.03), 7.0% higher BMD of the lumbar spine (p < 0.05), and 7.6% higher vBMD of the lumbar spine (p = 0.04), compared with their GG counterparts. Using multiple regression, the IL-6 genotypes were independently related to total body BMD (CC > GG; p = 0.03), humerus BMD (CC > GG; p < 0.05), neck BMD (CC > GG; p = 0.01), spine BMD (CC > GG; p = 0.01), and spine vBMD (CC > GG; p = 0.008). At age 19.3 +/- 0.7 years (mean +/- SD; 88 men) the IL-6 genotypes were still independent predictors for total body BMD (CC > GG; p = 0.03), humerus BMD (CC > GG; p = 0.03), spine BMD (CC > GG; p = 0.02), and spine vBMD (CC > GG; p = 0.003), while the IL-6 genotypes were not related to the increase in bone density seen after 2 years. We have shown that polymorphism of the IL-6 gene is an independent predictor of BMD during late puberty and of peak bone mass in healthy white men.     

Nonimmunologic complications and gene polymorphisms of immunoregulatory cytokines in long-term renal transplants

BACKGROUND: While the influence of cytokine gene polymorphisms on immunologic complications after organ transplantation is widely evaluated, little is known about predictive value of cytokine genotype for the development of nonimmunologic post-transplant complications: hypertension, dyslipoproteinemia, diabetes mellitus, hyperuricemia. METHODS: The -1082IL-10, -308TNF-alpha, transforming growth factor-beta1 (TGF-beta1) (codon 10, 25), -174IL-6, +874IFN-gamma gene single nucleotide polymorphisms (SNP) were studied in 278 long-term renal transplants by polymerase chain reaction-sequence specific primer (PCR-SSP) with respect to nonimmunologic post-transplant complications. RESULTS: Significant association of the TGF-beta (codon 25) GG genotype with hyperuricemia (P= 0.0013) and dyslipoproteinemia (P= 0.0171) was found. The TGF-beta1 (codon 25) CG genotype was detected more frequently in patients with normal uric acid levels. The +874IFN-gamma AA genotype was associated with type 2/steroid-induced diabetes (P= 0.0127). Frequency of the -1082IL-10 AG genotype was significantly higher in hyperuricemic patients versus controls (P= 0.0022). No associations of polymorphisms in the tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), TGF-beta codon 10 genes with hyperuricemia, dyslipoproteinemia, or diabetes were detected. We failed to observe significant differences in cytokine genotype distribution between hypertensive and normotensive patients. CONCLUSION: We established an association of particular cytokine genotypes with nonimmunologic post-transplant complications. This supports an idea that assessment of cytokine SNPs may allow more accurate prediction of nonimmunologic complications and appropriate adjustment of pre-emptive treatments in long-term transplant patients.     

The interleukin-6 -174promoter polymorphism is associated with long-term kidney allograft survival

BACKGROUND: Th1-dependent effector mechanisms may be responsible for allograft rejection. Recently, interleukin-6 (IL-6) has been shown to antagonize CD4+ T cells to effector Th2 cells and, in the process, differentiate them into Th1 cells. METHODS: To assess the role of IL-6 in long-term allograft survival, 158 patients after first cadaveric kidney transplantation were analyzed for the biallelic -174G-->C promoter polymorphism of the IL-6 gene. RESULTS: Carriers of the -174C-allele (genotype GC/CC) had an inferior three-year graft survival (71/104 = 68.3%; P = 0.0059) with a 3.7-fold increased relative risk of graft loss compared to carriers of the -174GG-genotype (48/54 = 88.9%). The -174GC/CC-genotype retained its negative impact on graft survival when other established prognostic factors and further cytokine polymorphisms (-308TNF-alpha, TGF-beta1 codon 10 & 25, -592/-819/-1082IL-10 and +874IFN-gamma) were considered simultaneously. CONCLUSIONS: Since the clinical impact on transplant outcome seems as important as matching for histocompatibility antigens, genotyping of the IL-6 -174polymorphism may offer a new method for identifying patients at increased risk of allograft loss.     

No association between deletion-type angiotensin-converting enzyme gene polymorphism and left-ventricular hypertrophy in hemodialysis patients

Left-ventricular hypertrophy (LVH), a bad prognostic sign, is a common finding in hemodialysis patients. The aim of the study was to analyze factors, including angiotensin-converting enzyme (ACE) genotype that may have an effect on the development of LVH in hemodialysis patients. Seventy-nine hemodialysis patients (42 males, 37 females, mean age 37.7 +/- 13.1 years) and 82 age- and sex-matched normotensive healthy controls (40 males, 42 females, mean age 35.6 +/- 5.7 years) were included. Left-ventricular mass index (LVMI) was higher in the hemodialysis group compared to controls (170.1 +/- 69.3 versus 84.9 +/- 15.7 g/m(2), p < 0.001). Fourty-three hypertensive patients in the hemodialysis group had an increased LVMI compared to 36 normotensive hemodialysis patients (194.2 +/- 75.5 versus 141.2 +/- 48.0 g/m(2), p < 0.001). On univariate analysis, LVMI was found to be correlated with blood pressure (r = 0.38, p < 0.001), time spent on dialysis (r = 0.22, p = 0.02) and hemoglobin levels (r = -0.21, p = 0.03). No correlation was found between LVMI and age (r = 0.09, p = 0.22), predialytic creatinine (r = 0.09, p = 0.21) and albumin (r = -0.10, p = 0.18). On multivariate analysis for the predictors of LVMI, blood pressure, time spent on dialysis and hemoglobin levels were also found to be significant. LVMI in DD, ID and II genotypes were 155.0 +/- 71.2, 181.6 +/- 60.6, and 163.6 +/- 83.4 g/m(2), respectively (p > 0.05). No association between LVMI and DD genotype was found. ACE genotype distribution was similar in hemodialysis patients and healthy controls. It was concluded that LVH in hemodialysis patients was mainly related to hypertension, anemia and time spent on dialysis and the DD genotype had no effect on LVMI in hemodialysis patients.     

Cardiac hypertrophy and remodeling in relation to ACE and angiotensinogen genes genotypes in Chinese dialysis patients

BACKGROUND: Genetic polymorphisms of the angiotensinogen (AGT) and angiotensin-converting enzyme (ACE) genes are associated with increased risk of hypertension and left ventricular hypertrophy (LVH) in hypertensive subjects. However, the extent to which these polymorphisms are related to LVH and remodeling in dialysis patients remains unknown. METHODS: Two hundred and forty-six end-stage renal disease (ESRD) patients on peritoneal dialysis and 183 control subjects, all of Chinese origin, were genotyped for the ACE insertion/deletion (I/D) and the AGT M235T gene polymorphisms. Left ventricular mass index (LVMi) and relative wall thickness were measured using echocardiography. RESULTS: Prevalence of ACE DD and AGT TT genotype was 14% and 83%, respectively, in ESRD patients and did not differ significantly from controls. A total percentage of 95% of our patients had LVH (171 with concentric and 63 with eccentric hypertrophy). Adjusting for age, gender, body mass index, duration of dialysis, diabetes, renal diagnosis, hematocrit, systolic and diastolic blood pressure, dialysis urea clearance, residual glomerular filtration rate, and use of converting enzyme inhibitors or angiotensin receptor blockers, AGT TT genotype remained independently associated with greater LVMi (coefficient = 28.73; 95% CI, 5.72 to 51.75; P = 0.015) and relative wall thickness (coefficient = 0.072; 95% CI, 0.022 to 0.122; P = 0.005) than MT/MM genotypes. LVMi and relative wall thickness did not differ significantly among patients with DD, DI, and II genotypes. No statistical significant interaction was noted between ACE and AGT gene polymorphism in relation to LVMi and relative wall thickness. CONCLUSION: Polymorphism of the AGT M235T gene but not ACE I/D gene is associated with greater LVMi and relative wall thickness, indicating more concentric LVH, in Chinese peritoneal dialysis patients. Possible synergistic effects between AGT and ACE gene polymorphism require further evaluation in a larger population.     

Association of interleukin-18 promoter polymorphism and atherosclerotic diseases in Chinese patients with diabetic nephropathy

Aim: Interleukin‐18 (IL‐18) is a pro‐inflammatory cytokine and possibly plays an important role in the pathogenesis of cardiovascular disease. The relationship between two IL‐18 gene polymorphisms, namely C‐607A and G‐137C, and cardiovascular disease in patients with diabetic nephropathy was examined. Methods: Two hundred and twenty patients (91 male) with diabetic nephropathy were studied. The IL‐18 promoter genotypes were determined. All patients were then prospectively followed for the cardiovascular events. Cardiovascular mortality and all‐cause mortality were also compared. Results: Mean age was 64.3 ± 10.6 years; average follow up was 73.9 ± 33.6 months. The frequencies of CC, CA and AA genotypes of the C‐607A polymorphism were 25.5%, 48.2% and 26.8%, respectively; GG, GC and CC genotypes of the G‐137C polymorphism were 71.8%, 25.0% and 3.2%, respectively. Neither of the polymorphisms were associated with the development of primary cardiovascular end‐point. Cardiovascular survival was 84.8% and 70.6% at 60 months for GG and GC/CC genotypes of the G‐137C polymorphism, respectively (P = 0.027); the corresponding actuarial survival was 69.0% and 54.8%, respectively (P = 0.053). However, the G‐137C genotype was not an independent predictor of cardiovascular or actuarial survival after adjusting for confounders by multivariate analysis with the Cox model. The C‐607A polymorphism had no significant effect on cardiovascular or actuarial survival. Conclusion: The G‐137C polymorphism of the IL‐18 promoter is associated with the cardiovascular mortality, and a trend of association with all‐cause mortality, in patients with diabetic nephropathy. The association, however, becomes insignificant after adjusting for confounding factors. Further studies are needed to test other genetic determinants of the association between systemic inflammation and cardiovascular disease in renal failure patients.     

Interleukin-6 polymorphism: a genetic risk factor for cardiac transplant related coronary vasculopathy?

AIMS: Interleukin- (IL-) 6 is a pleiotropic cytokine with effects on the acute phase response, inflammation, and vascular function. A G to C polymorphism has been described at position -174 in the promoter region of the IL-6 gene. We investigated the influence of this polymorphism on the development of cardiac transplant related coronary vasculopathy (CV). METHODS: Sequence specific polymerase chain reaction identified the -174*G/C allele for 116 cardiac transplant recipients. Coronary disease was identified by routine surveillance post-transplant coronary angiography. RESULTS: Prevalence of the -174*G/C polymorphism was different between the transplant and control cohorts; *CC 27.6%, *CG 45.7%, and *GG 26.7% vs. 13.2%, 44.1% and 42.7% respectively (p = 0.004). Median time to the first diagnosis of CV was different between the 3 alleles; *CC 2.8 years (2.0-4.0); *CG 3.9 years (2.1-4.5); *GG 5.3 years (3.2-6.1) (p = 0.05). By Kaplan-Meier survival analysis C homozygotes developed CV significantly earlier than the other cohorts (p = 0.035). At 5 years 100% of C homozygotes had evidence for CV. G homozygotes had a more gradual onset of CV with an approximate 60% prevalence at 5 years. *CC genotype was the most predictive risk factor for CV development (Hazard ratio 4.2 (95% CI 1.3-12.9); p = 0.014). Increasing donor age was also significant (Hazard ratio 1.04 (95% CI, 1.0-1.08); p = 0.023). CONCLUSIONS: Polymorphism at position -174 within the promoter region of the IL-6 gene may be an important risk factor for cardiac transplant related coronary vasculopathy. This may improve patient selection and allow tailored immunosuppressive treatment.     

Influence of cytokine gene polymorphisms on erythropoetin dose requirements in chronic haemodialysis patients.

BACKGROUND: Chronic inflammation influences renal anaemia and reduce erythropoetin effectiveness. Chronic kidney disease and haemodialysis (HD) induce elevated cytokine and C-reactive protein (CRP) levels at an inter-individually variable extent. These differences are in part due to polymorphisms within cytokine genes, e.g. for pro-inflammatory interleukin-6 (IL-6) and anti-inflammatory interleukin-10 (IL-10). We hypothesized that these polymorphisms influence erythropoetin effectiveness. METHODS: Genotyping for polymorphisms of IL-6 (-174G/C) and IL-10 (-1082G/A) genes was done in 460 prevalent HD patients. Erythropoetin requirements were determined after three months of stable dosing of erythropoesis stimulating proteins (ESP). The effect of the cytokine genotypes was evaluated by multiple regression analysis. RESULTS: The presence of the IL-6 -174G allele (found to be related with higher secretion of IL-6) was associated with a 26% higher ESP dose compared with individuals without the G allele (P = 0.008). The IL-10 -1082 G/A polymorphism was not associated with ESP needs. Multivariate analysis detected a predictive value for ESP dose of the IL-6 polymorphism (P = 0.022), the haemoglobin level and the dose of i.v. iron, but not of age, gender, dialysis vintage, ferritin or the CRP value. CONCLUSIONS: Presence of the IL-6 allele -174G is related to higher ESP doses in chronic HD patients. The polymorphism of the anti-inflammatory IL-10 does not influence ESP dose, probably due to the fact that this cytokine has directly inhibitory effects on haematopoiesis in addition to its beneficial effects on inflammation.     

Interactions of interleukin-6 gene polymorphisms with calcium intake and physical activity on bone mass in pre-menarche Chinese girls

Summary  This study assessed independent associations and interactions of IL-6 promoter alleles (−174G/C and −634C/G), calcium intake and physical activity with bone mass among pre-menarche Chinese girls. The −634 CC carriers, greater calcium intake and physical activity were associated with better bone mass. The gene-bone association was more pronounced among girls with high physical activity or with low calcium intake. Introduction  The association between interleukin (IL)-6 promoter polymorphisms and bone mass remains in debate. This cross-sectional study examined the association between the IL-6 promoter alleles (−174G/C and −634C/G) and bone mass, and assessed if the association could be modified by calcium intake or physical activity in pre-menarche Chinese girls. Methods  Two-hundred and twenty-eight healthy pre-menarche girls aged 9–11 years were recruited from primary schools in Guangzhou, China by sending letters to parents. None of them had diseases or medications known to affect bone metabolism. The IL-6 promoter genotypes were determined by PCR-RFLP, and BMD and BMC at the total body, lumbar spine, total hip and femoral neck were measured by DXA. Calcium intake and physical activity were assessed by face-to-face questionnaire interview. Results  One hundred and seventy-six subjects completed the entire study. We did not detect gene polymorphism at the IL-6 −174G/C locus, all were GG homozygotes. The IL-6 −634C/G polymorphism was significantly associated with both BMD and BMC even after adjusting for age and weight. Girls with CC genotype had higher levels of BMC and BMD than G allele carriers (+8.3% for the total body BMC, and +2.9%, +5.8%, and +5.7% for BMDs at the total body, total hip, and femoral neck, respectively; P < 0.05). The favorable effect of physical activity on BMDs at the total hip and femoral neck was much more pronounced in CC carriers than in G allele carriers, and the CC genotype associated higher BMDs at the total hip and femoral neck were observed only in girls with high level physical activity (P for interactions = 0.036 and 0.021, adjusted for age and weight). Calcium had a more benefit to the total body BMC in G allele carriers than in CC carriers, and the G allele-associated lower total body BMC was found only in subjects with low calcium intake. Conclusion  The IL-6 −634C/G polymorphism was significantly associated with BMD and the association might be modified by calcium intake or physical activity in pre-menarche Chinese girls.