Interleukin-6 (IL-6) –572C→G promoter polymorphism is associated with type 2 diabetes risk in Koreans

Objective  Increased levels of inflammatory markers, such as interleukin-6 ( IL -6), are associated with type 2 diabetes (T2DM). We investigated the association of IL-6 gene polymorphisms with T2DM and circulating levels of IL -6 in Koreans.
Subjects  A total of 1477 subjects with normal glucose tolerance and 476 T2DM patients were included.
Measurements  We examined IL-6 – 174G→C, –572C→G, –597G→A and –1363G→T promoter region polymorphisms. The main outcome measures were the odds ratio (OR) on T2DM risk and serum concentrations of IL -6 and high-sensitivity C-reactive protein (hs-CRP).
Results  Homozygosity for the rare G allele IL-6 – 572C→G was associated with a higher risk of T2DM [OR 1·69 (95%CI 1·11–2·58), P  = 0·015]. Serum IL -6 concentrations were associated with the IL-6 – 572C→G genotype in control subjects (G/G: 2·33 ± 0·41: C/G: 1·53 ± 0·09: C/C: 1·72 ± 0·08 ng/l, P  = 0·023). Also in the control group, subjects homozygous for the rare G allele showed significantly higher concentrations of hs-CRP than C/C and C/G carriers (G/G: 13·6 ± 2·9: C/G: 9·2 ± 0·6: C/C: 7·8 ± 0·4 mg/l, P  = 0·003). The C-allele at the IL-6 – 174 SNP was very rare (< 0·01) and –597G→A and –1363G→T were monomorphic in this population.
Conclusions  Our data demonstrate that the IL-6 – 572G/G genotype is associated with higher serum IL -6 and hs-CRP concentrations and with increased risk for T2DM.     

Peroxisome proliferator-activated receptor gamma agonism modifies the effects of growth hormone on lipolysis and insulin sensitivity

Context  Peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists such as thiazolidinediones (TZDs) improve insulin sensitivity in type 2 diabetes mellitus (T2DM) through effects on fat metabolism whereas GH stimulates lipolysis and induces insulin resistance.
Objective  To evaluate the impact of TZDs on fat metabolism and insulin sensitivity in subjects exposed to stable GH levels.
Design  A randomized, placebo-controlled, double-blind parallel-group study including 20 GH-deficient patients on continued GH replacement therapy. The patients were studied before and after 12 weeks.
Intervention  Patients received either pioglitazone 30 mg ( N  = 10) or placebo ( N  = 10) once daily for 12 weeks.
Results  Adiponectin levels almost doubled during pioglitazone treatment ( P =  0·0001). Pioglitazone significantly decreased basal free fatty acid (FFA) levels ( P =  0·02) and lipid oxidation ( P =  0·02). Basal glucose oxidation rate ( P =  0·004) and insulin sensitivity ( P =  0·03) improved in the patients who received pioglitazone treatment. The change in insulin-stimulated adiponectin level after pioglitazone treatment was positively correlated to the change in insulin-stimulated total glucose disposal ( R  = 0·69, P  = 0·04).
Conclusion  The impact of GH on lipolysis and insulin sensitivity can be modified by administration of TZDs.     

Risk of non-Hodgkin lymphoma in association with germline variation in complement genes

Germline mutations in complement genes have been associated with susceptibility to infections and autoimmune diseases, conditions that are associated with non-Hodgkin lymphoma (NHL) risk. To test the hypothesis that common genetic variation in complement genes affect risk of NHL, we genotyped 167 single nucleotide polymorphisms (SNPs) from 31 genes in 441 NHL cases and 475 controls. Principal components (PC) and haplotype analyses were used for gene-level tests of NHL risk, while individual SNPs were modelled as having a log-additive effect. In gene level PC analyses, C2 ( P =  0·023), C5 ( P =  0·0032) and C9 ( P =  0·020) were associated with NHL risk; haplotype analyses showed similar results, as well as a haplotype association for C7 ( P =  0·046). When all four genes were considered simultaneously, only C5 and C9 remained significant ( P <  0·05). In SNP level results from these genes, 10 SNPs had a P <  0·05. However, after correcting for multiple testing, only the C5 SNPs rs7026551 ( q  = 0·015; OR = 1·54, 95% CI 1·21–1·95) and rs2416810 ( q  = 0·015; OR = 1·57; 95% CI 1·22–2·01), and the C9 SNP rs187875 ( q  = 0·015; OR = 0·68; 95% 0·56–0·84) remained noteworthy. Associations were similar for the common NHL subtypes. In summary, we provide evidence for a role of genetic variation in complement genes, particularly C5 and C9 , and NHL risk.     

A randomized study of buffy coat platelets in platelet additive solution stored 1–5 versus 6–7 days prior to prophylactic transfusion of allogeneic haematopoietic progenitor cell transplant recipients

Background and Objective  Storage of platelets > 5 days provides improved availability, logistical management and decreased outdating. Promising results on in vitro parameters and on in vivo post-transfusion recovery and survival of autologous platelets in healthy volunteers have earlier been shown. To provide additional verification, randomized patient transfusion studies are needed.
Materials and Methods  Sixty allogeneic haematopoietic progenitor cell transplant recipients were randomized to receive buffy-coat (BC) platelets stored in platelet additive solution (PAS) for 1–5 days the first time a prophylactic transfusion was needed after transplantation, followed the second time by platelets stored for 6–7 days or vice versa. The corrected count increment (CCI) for 1 and 24 h were calculated.
Results  CCI 1 h and CCI 24 h were higher for platelets stored 1–5 days as compared to 6–7 days, 10·4 ± 5·1 vs. 7·4 ± 3·8 ( P <  0·001) and 5·4 ± 4·1 vs. 2·6 ± 2·6 ( P <  0·001), respectively. Time to next platelet transfusion was significantly longer after a transfusion of platelets stored for 1–5 days as compared to platelets stored for 6–7 days: 2·2 ± 1·1 vs. 1·6 ± 0·8 days, respectively ( P <  0·005). No differences in bleeding events and no transfusion reaction were recorded.
Conclusion  The advantage of an extension of platelet storage time beyond day 5 should be balanced against the increased need for platelet transfusions that may occur and the conceivable risk of transfusion failure.     

Peroxisome proliferator-activated receptor γ (PPAR) agonism reduces the insulin-stimulated increase in circulating interleukin-6 in GH replaced GH-deficient adults

Context  Peroxisome proliferator-activated receptor γ (PPARγ) agonists modify cardiovascular risk factors and inflammatory markers in patients with type 2 diabetes. GH treatment in GH-deficient (GHD) patients may cause insulin resistance and exerts ambiguous effects on inflammatory markers.
Objective  To investigate circulating markers of inflammation and endothelial function in GH replaced GHD patients before and after 12 weeks administration of either pioglitazone 30 mg/day ( N  = 10) or placebo ( N  = 10) in a randomized double-blind parallel design.
Methods  Circulating levels of interleukins (ILs)-1β, IL-2, IL-4, IL-6, IL-8, IL-10, tumour necrosis factor (TNF)-α, high sensitivity C-reactive protein, vascular cell adhesion molecule-I, and osteoprotegerin (OPG) were measured in the basal state and after a 2·5 h hyperinsulinaemic euglycaemic clamp.
Results  Insulin sensitivity improved in the group receiving PPARγ agonist ( P =  0·03). Serum IL-6 levels increased by 114 ± 31% (mean ± SE) in the entire group ( N  = 20) following the hyperinsulinaemic euglycaemic clamp ( P =  0·01) performed at study start. Twelve weeks of PPARγ agonist treatment significantly abrogated this insulin-stimulated increment in IL-6 levels compared to placebo ( P =  0·01). Furthermore PPARγ agonist treatment significantly lowered basal IL-4 levels ( P <  0·05).
Conclusions  (i) IL-6 levels increase during a hyperinsulinaemic clamp in GH replaced patients (ii) This increase in IL-6 is abrogated by PPARγ agonist treatment (iii) we hypothesize that PPARγ agonist-induced improvement of insulin sensitivity may obviate a compensatory rise in IL-6.     

Interleukin 10 polymorphisms as predictors of sustained response in antiviral therapy for chronic hepatitis C infection

Host genetic factors have been reported to influence the natural history of hepatitis C virus (HCV) infection. We examined whether variation in interleukin 10 (IL-10) and tumor necrosis factor alpha (TNF-alpha) genes would predict the likelihood of sustained response to antiviral therapy. Single nucleotide polymorphisms (SNPs) and microsatellites at two loci encoding the cytokines IL-10 and TNF-alpha were determined by polymerase chain reaction (PCR)-based techniques. Their relationship to the outcome of antiviral therapy for chronic HCV infection was studied in 49 white patients who had a virologically sustained response (SR) and in 55 white nonresponders (NR) to a combination of interferon alfa-2b and ribavirin (IFN + R). Several IL-10 variants were more frequent among SRs compared with NRs. Carriage of the -592A or the -819T SNP was associated with SR (odds ratio [OR] = 2.2; P =.016). The -592A/A and the exclusively linked -819T/T genotypes were also associated with SR (OR = 16.6; P =.013 for either). The haplotype consisting of the 108-bp IL-10.R microsatellite and -3575T, -2763C, -1082A, -819T, -592A was also associated with SR (OR = 2.65; P =.01). Stratification for viral genotype, baseline viral RNA concentration, and histologic status identified homozygosity for the haplotype as the principal determinant: all 5 homozygous individuals achieved SR (OR(crude) = 13.7; P =.025; stratified ORs = 1.9-7.0), whereas heterozygotes differed only slightly from wild-type carriers. In contrast, TNF alleles defined by promoter sequences -238G/A and -308G/A were approximately equally distributed among SR and NR. In conclusion, homozygosity for -592A, -819T or the extended haplotype (108bp) - (-2575T) - (-2763C) - (-1082A) - (-819T) - (-592A) is associated with SR to IFN + R.     

Intron polymorphism in the KIAA0350 gene is reproducibly associated with susceptibility to type 1 diabetes (T1D) in the Han Chinese population

Objective  Three independent genome-wide association studies in white populations have reported that single nucleotide polymorphisms (SNPs) in the KIAA0350 gene are associated with susceptibility to type 1 diabetes (T1D). The gene product of KIAA0350 is predicted to be a sugar binding C-type lectin. In the present study, we investigated whether SNPs in this gene were associated with T1D in the Han Chinese population.
Design and methods  In this case-controlled association study, a total of 205 T1D patients and 422 non-diabetic subjects of the Han Chinese population were enrolled. Two SNPs, namely, rs17802927 and rs725613, in the KIAA0350 gene were genotyped using a polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) protocol.
Results  The intron SNP rs725613 was strongly associated with T1D in the Han Chinese population [ P =  0·00007, odds ratio (OR) = 0·527, 95% confidence interval (CI) = 0·383–0·726], and the frequencies of its genotypes in the T1D group significantly differed from those in the control group ( P =  0·0001).
Conclusion  The intron polymorphism rs725613 in the KIAA0350 gene is associated with susceptibility to T1D, and this association is not race specific.     

Protective role of interleukin-10 promoter gene polymorphism in the pathogenesis of invasive pulmonary aspergillosis after allogeneic stem cell transplantation

The current study attempted to evaluate the association between the IL-10 promoter gene single nucleotide polymorphism (SNP) and invasive pulmonary aspergillosis (IPA) after allogeneic stem cell transplantation (SCT) in 105 patients. Three single-nucleotide polymorphisms were investigated in the proximal region of the IL-10 promoter gene (-1082/-819/-592). Two haplotypes (1082*A/819*T/592*A [ATA] and 1082*A/819*C/592*C [ACC]) were found in the current study. The overall incidence of IPA was estimated as 14.1+/-4.5% with a median onset at 186 days post-transplant (62 approximately 405 days). An increased occurrence of IPA was noted dependent on the IL-10 haplotype (0% vs 11.5+/-6.4% vs 19.7+/-7.7% for ACC/ACC vs ATA/ACC vs ATA/ATA haplotype, P=0.0307 when comparing ACC with non-ACC haplotype). In a multivariate survival analysis using Cox's proportional hazard model, the IL-10 promoter gene SNPs were identified as an independent predictive factor for the development of IPA (P=0.012, hazard ratio (HR) 9.3), along with an histocompatibility leukocyte antigen (HLA)-identical donor (P=0.005, HR 16.3), the CD34+ cell dose transplanted (P=0.004, HR 26.5), and time-dependent chronic graft-versus-host disease (GVHD; P=0.049, HR 16.0). The IL-10 ACC haplotype was found to have an apparent protective role in the development of IPA after allogeneic transplantation, regardless of HLA-disparity or chronic GVHD.     

Relationship between IL‐10 gene −1082A/G and −592C/A polymorphisms and the risk of hepatitis C infection: a meta‐analysis

Increasing evidence suggests that interleukin‐10 (IL‐10) gene promoter polymorphisms may be associated with chronic hepatitis C virus (HCV) infection and HCV clearance. To more precisely estimate the association between these variants and the risk of HCV infection, we performed a meta‐analysis of 26 studies describing the IL‐10–1082A/G, –819C/T, –592C/A genotypes, including 4039 chronic HCV infection cases and 2902 controls. When compared with a healthy population, the –1082GG allele had a 43% increased risk of chronic HCV infection in combined populations (GG vs GA + AA: odds ratio (OR) = 1.433, 95% confidence interval (CI) = 1.052–1.952, P = 0.023). In subgroup analysis by ethnicity, a significant increased risk was associated with the ?1082GG genotype in the Caucasian population (GG vs AA: OR = 1.390, 95% CI: 1.108–1.744, P = 0.004; GG vs GA + AA: OR = 1.621, 95% CI: 1.267–2.075, P = 0.000). However, no significant association was found in Asian, African or Chinese populations. Moreover, a higher distribution of ?592A was found in the spontaneously recovered population (AA vs CC: OR = 0.585, 95% CI = 0.387–0.884, P = 0.011; AA + AC vs CC: OR = 0.738, 95% CI = 0.551–0.988, P = 0.041; AA vs AC + CC: OR = 0.788, 95% CI = 0.664–0.935, P = 0.006) than that in the chronic HCV infection population. In conclusion, the IL‐10–1082GG allele may increase the risk of chronic HCV infection in Caucasian population, and people carrying the IL‐10–592A allele are more likely to clear HCV spontaneously.     

Spinal volumetric trabecular bone mass in acromegalic patients: a longitudinal study

Objective  Data on trabecular bone mass in acromegaly are controversial. All the studies are cross-sectional and bone mineral density (BMD) has been evaluated largely by dual X-ray absorptiometry (DXA), which is influenced by bone enlargement. In this study we assessed in acromegalic patients the effects overtime of GH excess on trabecular bone mass measured by single-energy quantitative computed tomography (QCT) which is not influenced by bone size.
Design  Longitudinal retrospective study.
Patients  A total of 46 acromegalic patients followed-up for 48 months (median), subdivided into four groups: group A (eugonadal patients with active disease: n  = 13), group B (hypogonadal patients with active disease; n  = 9), group C (eugonadal patients with controlled disease; n  = 10), group D (hypogonadal patients with controlled disease; n  = 14).
Measurements  Serum GH and IGF-I levels, spinal trabecular BMD, and vertebral fractures were evaluated in all patients. BMD variations were reported as change (Δ) in Z -values (Z-QCT) measured at baseline and end of follow-up per year (Δ Z-QCT).
Results  Δ Z-QCT was greater in group A vs. group B and D ( P = 0·002 and P  = 0·0001, respectively) and in group C vs. group D ( P = 0·009). Multivariate regression analysis showed that hypogonadal status (β = –0·69; P  = 0·001) and baseline duration of hypogonadism (β = 0·44; P  = 0·02) but not baseline duration of acromegaly, length of follow-up and disease activity, were significantly associated with Δ Z-QCT.
Conclusions  This longitudinal study suggests that the effect of chronic GH excess on spinal trabecular bone mass seems to be anabolic in active eugonadal patients but not in hypogonadal ones.     

腹泻型肠易激综合征患者中IL-10基因多态性的研究

目的 探讨腹泻型肠易激综合征（D-IBS）与IL-10基因启动子区域-1082、-819和-592位点单核苷酸多态性之间的关系。方法用扩增受阻突变系统-PCR方法对41例健康对照和43例D-IBS患者IL-10基因启动子区域-1082、-819和-592位点单核苷酸多态性进行研究。结果 -819位点D-IBS患者T／T基因型频率显著高于健康对照组（67．4％比39．0％,P〈0．05）,C／T和C／C基因型频率虽较对照组低（分别为23．3％比43．9％和9．3％比17．1％）,但差异无统计学意义（P〉0．05）;-0592位点D-IBS患者A／A基因型频率显著高于对照组（67．4％比39．0％,P〈0．05）,C／A和C／C基因型频率均较对照组低（分别为23．3％比43．9％和9．3％比17．1％）,但差异无统计学意义（P〉0．05）;-1082位点基因型频率差异无统计学意义（P〉0．05）。IL-10启动子-819位点T等位基因频率在D-IBS患者显著高于健康对照组（79．1％比61．0％,P〈0．05）,C等位基因频率在D-IBS患者显著低于健康对照组（20．9％比39．0％,P〈0．05）;-592位点A等位基因频率在D-IBS患者显著高于对照组（79．1％比61．0％,P〈0．05）,C等位基因频率在D-IBS患者显著低于对照组（20．9％比39．0％,P〈0．05）;-1082位点G或A等位基因频率在D-IBS患者与对照组间差异无统计学意义。结论IL-10基因启动子区域一819T／T和-592A／A基因型可能与D-IBS发生有关。     

Association of interleukin-10 promoter single nucleotide polymorphisms -819 T/C and -592 A/C with aging

Increased inflammatory activity is known to accompany aging. Single nucleotide polymorphisms of inflammatory mediator genes might therefore affect the aging process. Relation of eight SNPs (tumor necrosis factor-alpha [TNF-alpha] -1031 T/C, interleukin-10 [IL-10] -819 T/C, IL-1beta -511 C/T, IL-6 -634 C/G, IL-18 -607 A/C, transforming growth factor-beta [TGF-beta] +869 C/T, matrix metalloproteinase-1 [MMP-1] -1607 1G/2G, and MMP-3 -1171 5A/6A) with age or gender was evaluated in 500 Japanese persons (mean age: 56.7 years old, range: 19-100) by the chi-square test. There was a significant association of IL-10 -819 T/C with age (p =.0026). The association remained significant after multivariate logistic regression analysis (odds ratio for an age interval for 1 year, 1.009; 95% CI, 1.002-1.016). Furthermore, the genotype distribution of IL-10 -819 T/C was completely consistent with that of -592 A/C. These data suggest that IL-10 -819 T/C and -592 A/C may be a promising candidate for an aging-related gene in a Japanese population.     

Effects of interleukin-10 gene polymorphism on the development of gastric cancer and peptic ulcer in Japanese subjects

BACKGROUND: Anti-inflammatory cytokines play an important role in downregulation of inflammation and the prevention of neoplastic disorders. Genetic variations of anti-inflammatory cytokines are assumed to influence such responses. The aim of the present study was to clarify the association between the IL-10 polymorphism, one of the representative anti-inflammatory cytokines, and susceptibility to gastric cancer and peptic ulcer in Japan. METHODS: The IL-10-1082 (A/G)/-819 (T/C)/-592 (A/C) polymorphisms were assessed in Helicobacter pylori-positive patients with gastritis only (n = 162), gastric ulcers (n = 110), duodenal ulcers (n = 94), or gastric cancers (n = 105), and H. pylori-negative controls (n = 168) by allele specific primer-polymerase chain reaction methods. RESULTS: The carriage of IL-10-592 C (age and sex-adjusted odds ratio [OR]: 1.851, 95% confidence interval [CI]: 1.018-3.380) and IL-10-819 C (adjusted OR: 1.868, 95%CI: 1.023-3.411) allele were associated with an increased risk for gastric cancer development, not gastric ulcer and duodenal ulcer. The IL-10-1082 polymorphism had no association with development of gastric cancer and peptic ulcers. The presence of the ATA/GCC haplotype of IL-10-1082/-819/-592 polymorphism significantly increased the risk of gastric cancer development (adjusted OR: 2.805, 95%CI: 1.258-6.254) compared with presence of the ATA/ATA haplotype. CONCLUSIONS: The IL-10-1082/-819/-592 genotype status and haplotype were associated with an increased risk for gastric cancer development, not peptic ulcer, in Japan. The genotyping test of this anti-inflammatory cytokine would be useful for the detection of individuals with higher risk of gastric cancer development.     

PPARγ Pro12Ala Pro/Pro and resistin SNP-420 G/G genotypes are synergistically associated with plasma resistin in the Japanese general population

Objective  The Ala allele of the Pro12Ala polymorphism (rs1801282) of peroxisome proliferator-activated receptor γ (PPARγ) is protective against type 2 diabetes (T2DM). Resistin, secreted from adipocytes, causes insulin resistance in rodents. Resistin gene expression is reduced by the PPARγ ligand. We previously reported that subjects with the G/G genotype of a resistin gene single nucleotide polymorphism (SNP) at –420 (rs1862513) had the highest circulating resistin levels, followed by C/G and C/C. The aim of this study was to determine the relationship among PPARγ Pro12Ala polymorphism, resistin SNP-420, and plasma resistin.
Design, patients and measurements  We cross-sectionally analysed 2077 community-dwelling subjects attending an annual medical check-up. Genotypes were determined by TaqMan analysis. Fasting plasma resistin was measured using ELISA.
Results  Plasma resistin appeared to be higher in subjects with the Pro/Pro genotype of PPARγ than those with Pro/Ala and Ala/Ala genotypes (mean ± SE, 11·6 ± 0·2 vs. 10·4 ± 0·5 μg/l). Multiple regression analysis, adjusted for age, gender, BMI, and resistin SNP-420, revealed that the Pro/Pro genotype was a positive predictor of plasma resistin (PPARγ ,  Pro/Pro vs. Pro/Ala + Ala/Ala, unstandardized regression coefficient (β) = 1·03, P  = 0·0384). The effects of the Pro/Pro genotype of PPARγ (Pro/Pro vs. Pro/Ala + Ala/Ala) and the G/G genotype of resistin SNP-420 (G/G vs. C/C) on plasma resistin were synergistic (β = 4·76, P  = 0·011).
Conclusions  The PPARγ Pro12Ala Pro/Pro and resistin SNP-420 G/G genotypes were synergistically associated with plasma resistin, when adjusted for age, gender, and BMI, in the Japanese general population.     

Association of IL-10 -819C/T, -592A/C polymorphisms with the risk of preeclampsia: An updated meta-analysis

Objective:The purpose of our study was to investigate whether IL-10 -819C/T, -592A/C polymorphisms were associated with preeclampsia (PE) susceptibility.Methods:A comprehensive and systematic literature search was performed through online databases, including Web of Science, PubMed, EMBASE, and Chinese databases. Then eligible literatures were included according to inclusion criteria and exclusion criteria. Statistical data analysis was performed using Stata 10.0 software. Odds ratios (OR) and 95% confidence interval were applied to evaluated the association between IL-10 -819C/T, -592A/C polymorphisms and PE susceptibility.Results:According to inclusion and exclusion criteria, 9 case-control studies, including 1423 cases and 2031 controls, were included in this meta-analysis. Our meta-analysis revealed that no association was found between IL-10 -819C/T, -592A/C polymorphisms and the risk of PE in our study.Conclusion:Our meta-analysis suggested that IL-10 -819C/T and -592A/C polymorphisms had no association with PE susceptibility, but had a significant association with PE susceptibility in Asian and Caucasian.     

Recombinant LH (lutropin alfa) for the treatment of hypogonadotrophic women with profound LH deficiency: a randomized, double-blind, placebo-controlled, proof-of-efficacy study

Objective  To confirm the safety and efficacy of 75 IU lutropin alfa with concomitant follitropin alfa in inducing follicular development in women with profound gonadotrophin deficiency.
Design  Double-blind, randomized, placebo-controlled trial conducted in 25 medical centres in four countries.
Patients  Thirty-nine patients with LH < 1·2 IU/l and FSH < 5·0 IU/l were treated with concomitant 75 IU lutropin alfa and 150 IU follitropin alfa or concomitant placebo and 150 IU follitropin alfa.
Measurements  Primary efficacy end-point (intent-to-treat): follicular development defined by (i) at least one follicle ≥ 17 mm; (ii) serum E₂ level ≥ 400 pmol/l on day of hCG administration (DhCG); and (iii) mid-luteal phase progesterone level ≥ 25 nmol/l.
Results  In the analysis of evaluable patients, 66·7% (16 of 24) of patients given lutropin alfa achieved follicular development compared with 20·0% (2 of 10) of patients receiving placebo ( P =  0·023). In the intent-to-treat analysis, follicular development was achieved in 65·4% (17 of 26) of patients receiving lutropin alfa and 15·4% (2 of 13) of patients receiving placebo ( P =  0·006). The statistical difference between treatment groups was preserved when over-response leading to cycle cancellation was analysed as a failed response ( P =  0·034). Lutropin alfa was well tolerated.
Conclusion  Subcutaneous co-administration of 75 IU lutropin alfa with follitropin alfa is safe and effective in inducing follicular development in women with profound gonadotrophin deficiency.     

Characterization of the anaemia associated with Graves' disease

Background  Graves' disease (GD) is associated with hyperthyroidism. Thyrotoxicosis adversely affects multiple organ systems including haematopoiesis. Anaemia occurring specifically in GD has not been systematically studied previously.
Objective  To define the prevalence and characteristics of the anaemia associated with GD.
Design  Eighty-seven newly diagnosed patients with GD were recruited. Haematological indices, thyroid function and inflammatory parameters were examined at presentation and following successful treatment of hyperthyroidism.
Setting  Tertiary care academic referral centre.
Results  Thirty-three per cent of subjects presented with anaemia. The prevalence of anaemia not attributable to other causes (GD anaemia) was 22%. GD anaemia affected 41·6% (10/24) of men compared to 17·5% of women (11/63). Mean erythropoietin (EPO) levels (15·5 ± 5·3 mIU/ml) were within normal reference limits but significantly higher ( P =  0·004) than those of the non-anaemic controls. Hgb correlated inversely with EPO ( P =  0·05) and CRP ( P =  0·04) levels, a relationship that persisted after multivariate adjustment for TT3 or TT4. With antithyroid therapy for 16 ± 6·3 weeks, Hgb levels normalized in 8 out of 9 subjects with GD anaemia (10·7 ± 0·8 to 13·5 ± 1·3 g/dl, P  = 0·0001). After normalization of Hgb, mean MCV and TIBC were significantly increased, and median ferritin and mean EPO were significantly decreased.
Conclusions  GD anaemia is common, resembles the anaemia of chronic disease, and is associated with markers of inflammation. It corrects promptly with return to the euthyroid state following treatment.     

Endothelial nitric oxide synthase Glu298Asp, 4b/a, and T-786C polymorphisms in type 2 diabetic retinopathy

Objective The possible association between the endothelial nitric oxide (eNOS) gene T‐786C (promoter region), 27‐bp repeat 4b/4a (intron 4), and Glu298Asp (exon 7) polymorphisms with diabetic retinopathy (DR) was investigated. Design A retrospective case‐control study. Patients A total of 872 type 2 diabetes (T2DM) patients were studied, of whom 383 presented with preproliferative/proliferative retinopathy (DR group), and 489 with absent/mild retinopathy (DWR group). Measurements Glu298Asp and T‐786C genotyping was carried out by PCR‐RFLP analysis, while 4b/4a was assessed by PCR. Genotype distribution was compared using the χ²‐test, and the contributions of the polymorphisms to DR were analysed by haplotype analysis and multivariate regression analysis. Results Lower prevalence of mutant 4a (P = 0·011), and heterozygous 4b/4a (P = 0·042) were seen in the DR compared to the DWR groups; the allele and genotype distribution of the Glu298Asp and T‐786C polymorphisms were comparable between DR and DWR groups. Three‐loci haplotype analysis demonstrated significant association between eNOS variants and DR, with protective [haplotype 122 (Glu298/4a/‐786C)], and susceptible haplotypes [haplotypes 112 (Glu298/4b/‐786C) and 222 (Asp298/4a/‐786C)] identified. Multivariate regression analysis confirmed the association between haplotypes 122 (P = 0·015); 112 (P = 0·027), and 222 (P = 0·048) and DR, after controlling for potential covariates (including age, sex, age of disease onset; HbA1c; hypertension, total cholesterol). Conclusions This study identifies genetic variation at the eNOS locus as genetic risk factor for diabetic retinopathy, which may serve as a useful marker of increased susceptibility to the risk of retinopathy.     

Higher serum TSH in thyroid cancer patients occurs independent of age and correlates with extrathyroidal extension

Background  It has previously been shown that higher serum TSH is associated with increased thyroid cancer incidence and advanced-stage disease. In the healthy adult population, mean TSH increases with age. As age over 45 years is a known prognostic indicator for thyroid cancer, it is important to know whether higher TSH in patients with thyroid cancer occurs independent of age.
Objective  To determine the relationship between higher TSH, cancer and age.
Design  A retrospective cohort study.
Patients and methods  A total of 1361 patients underwent thyroid surgery between May 1994 and December 2007 at a single institution. Of these patients, 954 had pathological data, preoperative TSH and complete surgical history available. Data were analysed in relation to age and TSH.
Results  Mean TSH was significantly higher in cancer patients regardless of age < 45 years or ≥ 45 years ( P =  0·046 and P  = 0·027, respectively). When examining age groups < 20, 20–44, 45–59 and ≥ 60 years, there was a trend of rising mean TSH with age. Despite the rise in the benign subgroups, mean TSH was consistently higher in those with cancer vs. those without. On multivariate analysis, higher TSH was independently associated with cancer ( P =  0·039) and pathological features of Hashimoto's thyroiditis ( P =  0·001) but not with age ( P =  0·557). On multivariate analysis of high-risk features associated with poor prognosis, there was a significant association between higher TSH and extrathyroidal extension ( P =  0·002), whereas there was no clear relationship with age, tumour size > 4 cm, and distant metastases.
Conclusion  Independent of age, thyroid cancer incidence correlates with higher TSH. Higher TSH is associated with extrathyroidal extension of disease.