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Background The α 1 -antitrypsin 11478G→A polymorphism may be associated with attenuated acute α 1 -antitrypsin responses. It was hypothesised that patients with chronic obstructive pulmonary disease (COPD) and this mutation have accelerated lung function decline. Objective To assess whether the 11478G→A polymorphism is associated with attenuated α 1 -antitrypsin responses at COPD exacerbation, and therefore accelerated lung function decline. Methods Lung function decline by genotype was examined in the English Longitudinal Study of Ageing (ELSA; n=1805) and Whitehall II (n=2733) studies. 204 patients with COPD were genotyped in the London cohort and serum α 1 -antitrypsin concentration was measured at baseline and (n=92) exacerbation. Results The 11478G→A genotype frequencies did not vary between COPD cases and controls, or between COPD frequent and infrequent exacerbators. Subjects with the rare A allele experienced more rapid lung function decline in the Whitehall II (A vs non-A: 16 vs 4 ml/year p=0.02) but not ELSA (29 vs 34 ml/year, p=0.46) or London cohorts (26 vs 38 ml/year, p=0.06). Decline was not greater in frequent exacerbator A versus non-A carriers (20 vs 24 ml/year, p=0.58). Upregulation of α 1 -antitrypsin at exacerbation was not demonstrated, even in patients homozygous for the common allele (median exacerbation change −0.07 g/l 11478GG, p=0.87 and −0.09 g/l 11478AA/GA, p=0.92; p=0.90 for difference). In patients with the A allele, there was no correlation between serum α 1 -antitrypsin and serum interleukin 6 (IL-6) concentrations. Conclusion The 11478G→A α 1 -antitrypsin polymorphism is not associated with increased risk of developing COPD, nor accelerated lung function decline. Serum α 1 -antitrypsin may not be upregulated early at COPD exacerbation. In patients with the 11478G→A polymorphism there was no relationship between the serum α 1 -antitrypsin and serum IL-6 concentrations.

Variants in 37 genes have been associated with low density lipoprotein cholesterol (LDL-C) levels, including HFE (High Fe) p.(C282Y), rs1800562. This variant is homozygous in ~90% patients with haemochromatosis. It may reduce signalling to hepcidin, increasing iron absorption. However it has an extended founder haplotype and the mechanism leading to association with LDL-C levels is not known. This study aimed to investigate the effects of predicted iron responsive elements (IREs) and iron on LDL-C associated gene expression. HepG2 cells were treated with 10 µM ferric ammonium citrate (FAC, “free” iron), 30 µM haemin (haem iron), 10 µM desferrioxamine (DFO, parenteral iron chelator) and 100 µM deferiprone (L1, oral iron chelator) for 24 h (> = 4 biological replicates). Total RNA was isolated from cells for real-time quantitative PCR TaqMan assays and relative quantification using the ∆Ct method. The mean of ACTB and HPRT1 was used as the endogenous gene expression control. Eleven LDL-C mRNAs were predicted to contain IREs. SORT1 was predicted to contain a classical IRE in the 3’-untranslated region. SORT1 expression after FAC was 29% lower (p = 0.03) than control cells and was not significantly altered by haemin, DFO or L1. PCSK9 contained a predicted IRE but it was located within coding sequence. PCSK9 mRNA levels showed a trend towards 38% reduction after iron supplementation with FAC (p = 0.05) but were not significantly altered by haemin; they were 117 and 133% higher after iron reduction by chelation with DFO (p = 0.04) and L1 (p = 0.04) respectively compared to control cells. LDLR contained no predicted IRES. LDLR expression was not significantly altered by FAC or haemin but was 72% and 53% higher after treatment with DFO (p = 0.009) and L1 (p = 0.0001). These findings support a mechanism underlying the reported association of the HFE p.(C282Y) variant with lower LDL-C levels involving the regulation of LDL-C – associated gene expression by iron.

Rationale for the study Endothelial protein C receptor (EPCR) is involved in the regulation of thrombin generation and inflammation. PROCR gene variant rs867186 codes for an amino acid substitution (Ser219Gly) within the membrane spanning region of EPCR. The minor allele of the variant has been identified as functional, and associated with increased shedding of EPCR from the endothelial surface.1 Previous analysis has also shown increased coagulation activated markers in those with the Gly allele1.2 Furthermore, while heterozygotes for this variant may be protected from coronary heart disease (CHD), homozygotes had a threefold elevation in CHD risk in a prospective cohort (NPHSII).1 In a case–control study of CHD (HIFMECH), there was a suggestion that the EPCR genotype interacts with factors present in metabolic syndrome, to increase CHD risk.1 Methodology NPHSII was analysed to further assess the CHD risk associated with EPCR Ser219Gly in those who have been identified as diabetic, or as having ‘metabolic syndrome’, during 15 years9 follow-up. Results Individuals who were Gly/Gly and had ‘metabolic syndrome’ had a fourfold increase in CHD risk compared with Ser/Ser (HR=4.72, CI 1.69 to 13.4) p=0.006; or an eightfold increase in risk above those who were Ser/Ser without metabolic syndrome (HR=8.02, CI 2.89 to 22.2) p=0.006. No Gly/Gly individuals without metabolic syndrome had a CHD event. Conclusions Homozygotes for the Gly allele are present at a frequency of ∼1%. If the findings in the study can be replicated, the variant would constitute a considerable CHD risk in 1% of diabetics. Replication studies are under way in three further, large prospective cohorts.

Objectives To assess the performance of a panel of common single nucleotide polymorphisms (genotypes) associated with type 2 diabetes in distinguishing incident cases of future type 2 diabetes (discrimination), and to examine the effect of adding genetic information to previously validated non-genetic (phenotype based) models developed to estimate the absolute risk of type 2 diabetes. Design Workplace based prospective cohort study with three 5 yearly medical screenings. Participants 5535 initially healthy people (mean age 49 years; 33% women), of whom 302 developed new onset type 2 diabetes over 10 years. Outcome measures Non-genetic variables included in two established risk models—the Cambridge type 2 diabetes risk score (age, sex, drug treatment, family history of type 2 diabetes, body mass index, smoking status) and the Framingham offspring study type 2 diabetes risk score (age, sex, parental history of type 2 diabetes, body mass index, high density lipoprotein cholesterol, triglycerides, fasting glucose)—and 20 single nucleotide polymorphisms associated with susceptibility to type 2 diabetes. Cases of incident type 2 diabetes were defined on the basis of a standard oral glucose tolerance test, self report of a doctor’s diagnosis, or the use of anti-diabetic drugs. Results A genetic score based on the number of risk alleles carried (range 0-40; area under receiver operating characteristics curve 0.54, 95% confidence interval 0.50 to 0.58) and a genetic risk function in which carriage of risk alleles was weighted according to the summary odds ratios of their effect from meta-analyses of genetic studies (area under receiver operating characteristics curve 0.55, 0.51 to 0.59) did not effectively discriminate cases of diabetes. The Cambridge risk score (area under curve 0.72, 0.69 to 0.76) and the Framingham offspring risk score (area under curve 0.78, 0.75 to 0.82) led to better discrimination of cases than did genotype based tests. Adding genetic information to phenotype based risk models did not improve discrimination and provided only a small improvement in model calibration and a modest net reclassification improvement of about 5% when added to the Cambridge risk score but not when added to the Framingham offspring risk score. Conclusion The phenotype based risk models provided greater discrimination for type 2 diabetes than did models based on 20 common independently inherited diabetes risk alleles. The addition of genotypes to phenotype based risk models produced only minimal improvement in accuracy of risk estimation assessed by recalibration and, at best, a minor net reclassification improvement. The major translational application of the currently known common, small effect genetic variants influencing susceptibility to type 2 diabetes is likely to come from the insight they provide on causes of disease and potential therapeutic targets.