Systematic literature review of immunoglobulin trends for anti-CD20 monoclonal antibodies in multiple sclerosis.

OBJECTIVE: To exp lore changes in immunoglobulin (Ig) levels for people with relapsing-multiple sclerosis (RMS) treated with ocrelizumab or ofatumumab and the relationship between Ig levels and infections. METHODS: A systematic literature review (SLR) was conducted to identify clinical trials and real-world evidence (RWE) studies on Ig levels over time and studies on associations with infections for ocrelizumab and ofatumumab for people with RMS through 10 September 2021. Searches were conducted in Embase, MEDLINE, Cochrane Library, trial registries, and recent conference abstracts. RESULTS: Of 1,580 articles identified, 30 reporting on 11 trials and 5 RWE studies were included. Ocrelizumab trials (n = 4) had 24-336 weeks of follow-up and reported decreasing Ig G (IgG) levels, while RWE (n = 5) had 52-78 weeks of follow-up and reported IgG to be stable or decrease only slightly. IgG levels were stable in ofatumumab trials (n = 5; 104-168 weeks of follow-up), but no RWE or longer-term studies were identified. No apparent association between decreased Ig levels and infections was observed during ofatumumab treatment (ASCLEPIOS I/II), while for ocrelizumab, the only data on apparent associations between decreased IgG levels and serious infection rates were for a pooled population of people with RMS or primary progressive MS. CONCLUSION: Decreasing IgG levels have been correlated with increased infection risk over time. IgG levels appeared to decrease over time in ocrelizumab trials but remained relatively stable over time in ofatumumab trials. Additional research is needed to understand differences between ocrelizumab and ofatumumab and identify people at risk of decreasing IgG levels and infection.

PAYER PERSPECTIVES ON FUTURE ACCEPTABILITY OF COMPARATIVE EFFECTIVENESS AND RELATIVE EFFECTIVENESS RESEARCH.

OBJECTIVES: Our objective was to gather perspectives from payers on how comparative effectiveness research (CER) in the United States and relative effectiveness (RE) research in Europe will impact evidentiary standards for access decisions of new drugs by 2020. METHODS: We conducted semi-structured interviews with fourteen senior officials representing public and private payers, health technology assessment groups, and pricing and reimbursement bodies in the United States and Europe. An online survey assessed current use of CER/RE evidence and potential trends that might influence its use for decision making by 2020. A semi-structured interview elicited payers' definitions of CER/RE and was structured around four hypothetical cases resembling drugs expected to be more common or poised to create policy challenges by 2020. Topics included acceptance of study designs and analytic methods associated with CER/RE. A systematic content review was done to extract relevant information. RESULTS: According to key informants, randomization will remain an essential component for assessing comparative or relative effectiveness. They anticipate greater use of policy levers such as conditional reimbursement or prior authorization to manage diffusion of new drugs. Case studies provided important insights into situations when certain types of CER evidence may be acceptable (e.g., observational data when differences between drugs are largely convenience). CONCLUSIONS: Industry perceptions that CER/RE will change payers' evidentiary requirements in the future are consistent with our findings. Growing investment in payers' own data and increased reliance on policy tools to control diffusion of new drugs may also influence the type of evidence industry will be required to produce by 2020.

The efficacy, safety, and immunogenicity of plague vaccines: A systematic literature review.

Plague remains endemic in many parts of the world, and despite efforts, no preventative vaccine is available. We performed a systemic review of available randomised controlled trials (RCTs) of live, attenuated, or killed plague vaccines vs. placebo, no intervention, or other plague vaccine to evaluate their efficacy, safety, and immunogenicity. Data sources included MEDLINE, Embase, and the Cochrane Library; clinical trial registers; and reference lists of included studies. Primary outcomes were efficacy, safety, and immunogenicity. Risk of bias was assessed using the Cochrane Collaborations tool. Only 2 RCTs, both on subunit vaccines, were included out of the 75 screened articles. The 2 trials included 240 participants with a follow-up of 3 months and 60 participants with a follow-up of 13 months, respectively. Safety evidence was limited, but both vaccines were well tolerated, with only mild to moderate adverse events. Both vaccines were immunogenic in a dose-dependent manner. However, given the limited data identified in this systematic review, we are unable to quantify the efficacy of vaccines to prevent plague, as well as their long-term safety and immunogenicity. More trials of plague vaccines are needed to generate additional evidence of their long-term effects.

Subcutaneous immunoglobulin use in immunoglobulin-naive patients with primary immunodeficiency: a systematic review.

Aim: Identify and describe published literature on the use of subcutaneous immunoglobulin (SCIG) as initial immunoglobulin (IG)-replacement therapy for patients with primary immunodeficiency diseases (PID). Methods: We systematically identified and summarized literature in MEDLINE, Embase, BioSciences Information Service and Cochrane Library assessing efficacy/effectiveness, safety/tolerability, health-related quality-of-life (HRQoL) and dosing regimens of SCIG for IG-naive patients with PID. Results: Sixteen studies were included. In IG-naive patients, SCIG managed/reduced infections and demonstrated similar pharmacokinetic parameters to IG-experienced patients; adverse events were mostly minor injection-site pain or discomfort. Three studies reported improvements in HRQoL. Quality of studies was difficult to assess due to limited reporting. Conclusion: Although studies were lacking, available data suggest IG-naive and IG-experienced patients initiating SCIG likely have similar outcomes.

Impact of Patient Characteristics on Treatment Outcomes in Symptomatic Venous Thromboembolism: Results of HOKUSAI-VTE Randomized Trial Analysis.

Introduction In patients with venous thromboembolism (VTE), direct oral anticoagulants (DOACs) such as edoxaban, apixaban, dabigatran, and rivaroxaban are more convenient, safer, and just as effective as vitamin K antagonists (VKAs). Limited information is known about the effects of patient characteristics on VTE efficacy and safety of DOACs compared with VKAs, without appropriate effect modifier adjustment comparisons of DOACs may be biased. This study considers the effect of variables that can modify the efficacy and safety of edoxaban and warfarin, using patient-level data. Materials and Methods The primary efficacy and safety outcomes in the HOKUSAI-VTE study were VTE recurrence and clinically relevant bleeding, respectively. Potential effect modifiers were age, creatinine clearance, and weight. The relationship between the percentage of time in international normalized ratio (INR) control and outcomes were considered for the warfarin arm. Univariate and multivariate regression were performed for each patient characteristic. Results The relationship between treatment and VTE recurrence differed by age (interaction p = 0.007) and by creatinine clearance ( p = 0.05). VTE recurrence differed by age for patients in the warfarin arm but not for those in the edoxaban arm and differed by INR control in the warfarin arm ( p < 0.005). A stronger relationship between creatinine clearance and clinically relevant bleeding was found in the warfarin arm than in the edoxaban arm ( p = 0.04). Clinically relevant bleeding differed by the percentage of time in INR control in the warfarin arm ( p < 0.005). Age appeared to be a more important effect modifier than creatinine clearance in patients with VTE. Discussion The finding that efficacy in older patients was greater for those taking edoxaban than for those taking warfarin in the HOKUSAI-VTE study needs further investigation. Modification of the treatment effect by age for those taking warfarin might bias estimates of comparative effectiveness among DOACs if VKAs are the reference treatment.

Comparative Efficacy of Treatments for Previously Treated Multiple Myeloma: A Systematic Literature Review and Network Meta-analysis.

PURPOSE: New therapies, including daratumumab plus lenalidomide plus dexamethasone (DRd) and daratumumab plus bortezomib plus dexamethasone (DVd), have recently been approved in the United States for patients with multiple myeloma (MM) who have received at least 1 prior line of therapy. However, few treatments have been compared in head-to-head clinical trials to determine the most efficacious therapy. In an update of the POLLUX (Phase 3 Study Comparing DRd Versus Rd in Subjects with Relapsed or Refractory Multiple Myeloma [RRMM]) trial, median progression-free survival (PFS) for DRd was not reached; the hazard ratio compared with Rd was 0.41. In an update of the CASTOR (Phase 3 Study Comparing DVd Versus Vd in Subjects with RRMM) trial, median PFS for DVd was 16.7 months, compared with 7.1 months for Vd with a PFS hazard ratio of 0.31. A systematic literature review and network meta-analysis (NMA) was performed to estimate the relative efficacy of treatments for previously treated patients with MM. METHODS: A systematic search of MEDLINE, EMBASE, BioSciences Information Service, and the Cochrane Library databases was conducted from initiation to September 2016. Abstracts published by international congresses (2014-2016) and bibliographies of pertinent systematic reviews and meta-analyses were also searched. Eligible studies consisted of randomized controlled trials (RCTs) or long-term follow-up studies with >1 treatment arm assessing the efficacy or safety of MM therapies. An NMA was conducted by using Bayesian fixed effect mixed-treatment comparisons. Outcomes considered were hazard ratios for PFS and odds ratios for overall response rate (ORR). FINDINGS: In total, 108 articles reporting 27 RCTs were included in the NMA. Data formed 2 evidence networks: RCTs with DRd and RCTs with DVd. Primary analysis of PFS found that DRd and DVd had a higher probability of being the best treatments (probability, 0.997 and 0.999, respectively) and had the lowest risk of progression or death than other treatments approved by the US Food and Drug Administration for the treatment of MM. Results from sensitivity analyses using time to progression as a proxy for missing PFS data were consistent. DRd and DVd also showed improved ORR compared with other treatments. Subgroup analyses of PFS in patients treated with only 1 prior therapy were like the results of the primary analyses. IMPLICATIONS: This NMA provides comparative efficacy for MM treatments not studied in head-to-head RCTs. The NMA suggests that, compared with other approved MM treatments in the United States, DRd and DVd have a higher probability of providing the longest PFS in patients who have received at least 1 prior therapy and in patients who have received only 1 prior therapy.

Cost-Effectiveness of Olaratumab in Combination with Doxorubicin for Patients with Soft Tissue Sarcoma in the United States.

BACKGROUND: Standard first-line treatments for advanced soft tissue sarcoma (STS) have changed little for 40 years, and outcomes have been poor. Recently, the United States (US) Food and Drug Administration conditionally approved olaratumab in combination with doxorubicin (Olara + Dox) based on a randomized phase II trial that reported a significant 11.8-month improvement in median survival versus single-agent doxorubicin (Dox). The present study investigated the cost-effectiveness of Olara + Dox compared with Dox and five other standard-of-care regimens from the US payer perspective. METHODS: An economic model was constructed to estimate costs and outcomes over patients' lifetimes from start of therapy. Progression-free and overall survival were based on survival analysis of patient-level data and a meta-analysis. Adverse-event rates were based on trials. Costs were from published sources. RESULTS: Olara + Dox resulted in an estimated additional 1.27 life-years (LYs) compared with Dox, with an increase in total expected lifetime costs of $133,653. The incremental cost-effectiveness ratio (ICER) was estimated at $105,408 per LY gained; in a fully incremental analysis, all other regimens were dominated (higher costs and lower LYs or a higher ICER). CONCLUSION: Olara + Dox is cost-effective for STS treatment compared with Dox and other standard-of-care regimens at willingness-to-pay thresholds of $150,000 per LY and above.

Mutational analysis in UK patients with a clinical diagnosis of familial hypercholesterolaemia: relationship with plasma lipid traits, heart disease risk and utility in relative tracing.

As part of a randomised trial [Genetic Risk Assessment for Familial Hypercholesterolaemia (FH) Trial] of the psychological consequences of DNA-based and non-DNA-based diagnosis of FH, 338 probands with a clinical diagnosis of FH (46% with tendon xanthomas) were recruited. In the DNA-based testing arm (245 probands), using single-strand conformation polymorphism of all exons of the low-density lipoprotein receptor (LDLR) gene, 48 different pathogenic mutations were found in 62 probands (25%), while 7 (2.9%) of the patients had the R3500Q mutation in the apolipoprotein B (APOB) gene. Compared to those with no detected mutation, mean untreated cholesterol levels in those with the APOB mutation were similar, while in those with an LDLR mutation levels were significantly higher (None=9.15+/-1.62 vs LDLR=9.13+/-1.16 vs APOB=10.26+/-2.07 mmol/l p<0.001, respectively). Thirty seven percent of the detected mutations were in exon 3/4 of LDLR, and this group had significantly higher untreated cholesterol than those with other LDLR mutations (11.71+/-2.39 mmol/l vs 9.88+/-2.44 mmol/l, p=0.03), and more evidence of coronary disease compared to those with other LDLR or APOB mutations (36 vs 13% p=0.04). Of the probands with a detected mutation, 54 first-degree relatives were identified, of whom 27 (50%) had a mutation. Of these, 18 had untreated cholesterol above the 95th percentile for their age and gender, but there was overlap with levels in the non-carrier relatives such that 12% of subjects would have been incorrectly diagnosed on lipid levels alone. In the non-DNA-based testing arm (82 probands) only 19 of the 74 relatives identified had untreated cholesterol above the 95th percentile for their age and gender, which was significantly lower (p<0.0005) than the 50% expected for monogenic inheritance. These data confirm the genetic heterogeneity of LDLR mutations in the UK and the deleterious effect of mutations in exon 3 or 4 of LDLR on receptor function, lipids and severity of coronary heart disease. In patients with a clinical diagnosis of FH but no detectable mutation, there is weaker evidence for a monogenic cause compared with relatives of probands with LDLR mutations. This supports the usefulness of DNA testing to confirm diagnosis of FH for the treatment of hyperlipidaemia and for further cascade screening.

Peroxisome proliferator-activated receptor alpha gene variation influences age of onset and progression of type 2 diabetes.

Dysregulation of fatty acid metabolism is important in the pathogenesis of type 2 diabetes. Peroxisome proliferator-activated receptor (PPAR)alpha is a master regulator of fatty acid catabolism, and PPARalpha activators delay the onset of type 2 diabetes. We examined association between three PPARalpha gene polymorphisms (an A-->C variant in intron 1, the L162V variant, and the intron 7 G-->C variant) and age at diagnosis of type 2 diabetes in 912 Caucasian type 2 diabetic subjects. Individually, PPARalpha gene variants did not influence age at diagnosis, but in combination, the rare alleles of both the intron 1 A-->C (P < 0.001) and intron 7 G-->C (P = 0.025) variants synergistically lowered age at diagnosis (interaction P < 0.001). Overall, the PPARalpha haplotype signficantly influenced age at diagnosis (P = 0.027), with the C-L-C and C-V-C haplotypes (intron 1-L162V-intron 7) accelerating onset of diabetes by 5.9 (P = 0.02) and 10 (P = 0.03) years, respectively, as compared with the common A-L-G haplotype, and was associated with an odds ratio for early-onset diabetes (age at diagnosis

+9/+9 Homozygosity of the bradykinin receptor gene polymorphism is associated with reduced fat-free mass in chronic obstructive pulmonary disease.

BACKGROUND: The etiology of muscle wasting in chronic obstructive pulmonary disease (COPD) is incompletely understood. We previously showed that the D rather than the I polymorphic variant of the angiotensin-converting enzyme (ACE) gene is associated with preserved quadriceps strength in COPD. If the ACE D allele influences skeletal muscle through increased ACE-related kinin degradation [and reduced activity at the bradykinin type 2 receptor (BK(2)R)], we might expect a similar association with the +9 BK(2)R genotype in this population as well. OBJECTIVE: The objective was to test the hypothesis that the BK(2)R gene polymorphism is a determinant of fat-free mass and quadriceps strength in patients with COPD. DESIGN: In a cross-sectional design we determined BK(2)R genotype, fat-free mass, and quadriceps strength in 110 COPD patients with a mean (+/-SD) predicted forced expiratory volume in 1 s of 34.3 +/- 16.4% and in 104 healthy age-matched control subjects. RESULTS: The mean (+/-SD) fat-free mass index (in kg/m(2)) was significantly lower in 37 patients homozygous for the +9 allele than in carriers of the -9 allele (15.7 +/- 1.8 compared with 16.7 +/- 2.3; P = 0.038); the same pattern was true for quadriceps maximal voluntary force (30.8 +/- 10.4 and 36.4 +/- 12.8 kg; P = 0.02), respectively. No significant effect of BK(2)R genotype on inspiratory muscle strength or on any variable in control subjects was observed. There was no interaction between the effect of the BK(2)R and ACE genotypes on quadriceps strength. CONCLUSIONS: The genotype associated with reduced BK(2)R expression is associated with reduced fat-free mass and quadriceps strength in COPD. However, alterations in the activity at the BK(2)R do not seem to account for the previously identified association of quadriceps strength with ACE genotype.

A common variant in the glutathione S transferase gene is associated with elevated markers of inflammation and lipid peroxidation in subjects with diabetes mellitus.

INTRODUCTION: Glutathione S transferases (GST) are enzymes responsible for the metabolism of numerous xenobiotics and play a major cellular antioxidant role. Our aim was firstly, to examine the association between the GST M1/GST mu-1 (GSTM1) and GST T1/GST theta-1 (GSTT1) gene variants with markers of oxidative stress and inflammation in diabetic patients, and secondly to examine the association and potential interaction between these variants and cigarette smoking. METHODS: Seven hundred and seventy-three Caucasian subjects with diabetes and 2592 Caucasian non-diabetic subjects were successfully genotyped. Plasma total antioxidant status, C-reactive protein (CRP), oxidized-LDL (Ox-LDL) and LDL-mean/peak particle diameter were recorded in the diabetes sample. RESULTS: No association was seen between genotype and cardiovascular disease (CVD) risk. In the diabetic subjects, GSTT1-1 compared to GSTT1-0 subjects had significantly higher CRP (p=0.001), Ox-LDL (p=0.004) and smaller LDL particles (p=0.01). In subjects without CVD, there was a significant interaction between the GSTT1-1 variant and smoking in determining Ox-LDL (p=0.04). Furthermore, CVD risk was higher in smokers compared to non-smokers with GSTT1-1. No significant associations were observed by GSTM1. Within the non-diabetic sample, no association was observed between genotype and prospective coronary heart disease (CHD) risk. Of note, the frequency of the GSTT1-1 variant was significantly lower in the diabetes subjects compared to the non-diabetic sample (p=0.01). CONCLUSIONS: This study demonstrates an association between the GSTT1-1 variant and markers of inflammation and lipid peroxidation. Furthermore this variant interacts with smoking to increase lipid peroxidation.

Insight into the nature of the CRP-coronary event association using Mendelian randomization.

BACKGROUND: It is unclear wheather the association between C-reactive protein (CRP) and incident coronary events is free from bias and confounding. Individuals homozygous for a +1444C>T polymorphism in the CRP gene have higher circulating concentrations of CRP. Since the distribution of this polymorphism occurs at random during gamete formation, its association with coronary events should not be biased or confounded. METHODS: We calculated the weighted mean difference in CRP between individuals with variants of the +1444C>T polymorphism in the CRP gene among 4,659 European men from six studies (genotype-intermediate phenotype studies). We used this difference together with data from previous observational studies to compute an expected odds ratio (OR) for non-fatal myocardial infarction (MI) among individuals homozygous for the T allele. We then performed four new genetic association studies (6,201 European men) to obtain a summary OR for the association between the +1444C>T polymorphism and non-fatal MI (genotype-disease studies). RESULTS: CRP was 0.68 mg/l [95% confidence interval (95% CI) 0.31-1.10; P = 0.0001] higher among subjects homozygous for the +1444-T allele, with no confounding by a range of covariates. The expected ORs among TT subjects for non-fatal MI corresponding to this difference in CRP was 1.20 (95% CI 1.07-1.38) using the Reykjavik Heart study data and 1.25 (1.09-1.43) for all observational studies to 2004. The estimate for the observed adjusted-OR for non-fatal MI among TT subjects was 1.01 (95% CI 0.74-1.38), lower than both expected ORs. CONCLUSIONS: A common CRP gene polymorphism is associated with important differences in CRP concentrations, free from confounding. The null association of this variant with coronary events suggests possible residual confounding (or reverse causation) in the CRP-coronary event association in observational studies, though the confidence limits are still compatible with a modest causal effect. Additional studies of genotype (or haplotype) and coronary events would help clarify whether or not the link between CRP and coronary events in observational studies is causal.

Apolipoprotein AIV gene variant S347 is associated with increased risk of coronary heart disease and lower plasma apolipoprotein AIV levels.

The impact of common variants in the apolipoprotein gene cluster (APOC3-A4-A5) on prospective coronary heart disease (CHD) risk was examined in healthy UK men. Of the 2808 men followed over 9 years, 187 had a clinically defined CHD event. Examination of 9 single nucleotide polymorphisms (SNPs) in this group revealed that homozygotes for APOA4 S347 had significantly increased risk of CHD [hazard ratio (HR) of 2.07 (95%CI 1.04 to 4.12)], whereas men homozygous for APOC3 1100T were protected [HR 0.28 (95%CI 0.09 to 0.87)]. In stepwise multiple regression analysis, after entering all the variants and adjusting for established risk factors APOA4 T347S alone remained in the model. Using all nine SNPs, the highest risk-estimate haplotypes carried APOA4 S347 and rare alleles of the two flanking intergenic markers. The protective effect of APOC3 1100T could be explained by negative linkage disequilibrium with these alleles. To determine the association of APOA4 T347S with apoAIV levels, the relationship was examined in 1600 healthy young European men and women. S347 homozygotes had significantly lower apoAIV plasma levels (13.64+/-0.59 mg/dL) compared with carriers of the T347 allele (14.90+/-0.12 mg/dL) (P=0.035). These results demonstrate that genetic variation in and around APOA4, independent of the effects of triglyceride, is associated with risk of CHD and apoAIV levels, supporting an antiatherogenic role for apoAIV.

EQ-5D Utilities in Chronic Spontaneous/Idiopathic Urticaria.

OBJECTIVES: To obtain utility estimates suitable for use in economic models for chronic spontaneous (idiopathic) urticaria (CSU). METHODS: Patient-level data from three randomized clinical trials-ASTERIA I, ASTERIA II and GLACIAL-were analysed. Health states were derived from the Urticaria Activity Score over 7 days (UAS7); higher scores denote greater activity. The health state score ranges were urticaria free: 0; well-controlled urticaria: 1-6; mild urticaria: 7-15; moderate urticaria: 16-27; and severe urticaria: 28-42. The mean EQ-5D utilities were calculated for each health state. A mixed model was used to predict the EQ-5D according to UAS7 health states in a pooled data set containing all treatment arms and time points from the three trials. Pooled trial data were validated through visual comparisons and interaction terms. Fixed and random effects for trials and patients were included, along with the following covariates: UAS7 health state at baseline (moderate or severe); presence of angioedema at baseline and during follow-up; duration of CSU; number of previous CSU medications; visit; current treatment; and patient age and sex. RESULTS: There was a consistent improvement in EQ-5D utilities as urticaria activity decreased. The mean utilities ranged from 0.710 (severe urticaria) to 0.780 (moderate urticaria), 0.829 (mild urticaria), 0.862 (well-controlled urticaria) and 0.894 (urticaria free). Sensitivity and subgroup analyses confirmed the robustness of the results. CONCLUSION: The results suggest that EQ-5D utility scores increase with decreasing urticaria activity. EQ-5D utility scores enable the health-related quality of life of CSU patients to be compared with that of patients with other diseases.

Human paraoxonase gene cluster polymorphisms as predictors of coronary heart disease risk in the prospective Northwick Park Heart Study II.

The anti-atherogenic effect of HDL has been suggested to be partly due to the action of HDL-associated paraoxonase (PON). Three distinct enzymes have been identified, encoded by PON1, PON2 and PON3, clustered on chromosome 7q21-q22. Two cSNPs in PON1 (L55M and Q192R) and one in PON2 (S311C) have been implicated as independent risk factors for coronary heart disease (CHD) in some, but not all, studies. A PON3 SNP (A99A) was identified and the effect of these four PON SNPs on HDL levels and CHD risk was examined in the prospective Northwick Park Heart Study II (NPHSII). Genotype frequencies did not differ between cases and controls but the CHD risk associated with smoking was significantly modified by PON1 L55M genotype. Compared to LL non-smokers, LL smokers had a hazard ratio (HR) of 1.30 (95% CI 0.81-2.06) while M-allele carriers had a HR of 1.76 (1.17-2.67). When genotypes were analysed in combination, men with the genotype PON1 55 LM/MM+PON2 311 CC, had HR of 3.54 (1.81-6.93) compared to PON1 LL+PON2 SS/SC men (interaction P=0.004). These effects were independent of classical risk factors. These data demonstrate the importance of stratifying by environmental factors and the use of multiple SNPs for genetic analysis.

Peroxisome proliferator-activated receptor alpha gene variants influence progression of coronary atherosclerosis and risk of coronary artery disease.

BACKGROUND: Peroxisome proliferator-activated receptor alpha (PPARalpha) regulates the expression of genes involved in lipid metabolism and inflammation, making it a candidate gene for atherosclerosis and ischemic heart disease (IHD). METHODS AND RESULTS: We investigated the association between the leucine 162 to valine (L162V) polymorphism and a G to C transversion in intron 7 of the PPARalpha gene and progression of atherosclerosis in the Lopid Coronary Angiography Trial (LOCAT), a trial examining the effect of gemfibrozil treatment on progression of atherosclerosis after bypass surgery and on risk of IHD in the second Northwick Park Heart Study (NPHS2), a prospective study of healthy middle-aged men in the United Kingdom. There was no association with plasma lipid concentrations in either study. Both polymorphisms influenced progression of atherosclerosis and risk of IHD. V162 allele carriers had less progression of diffuse atherosclerosis than did L162 allele homozygotes with a similar trend for focal atherosclerosis. Intron 7 C allele carriers had greater progression of atherosclerosis than did G allele homozygotes. The V162 allele attenuated the proatherosclerotic effect of the intron 7 C allele. Homozygotes for the intron 7 C allele had increased risk of IHD, an effect modulated by the L162V polymorphism CONCLUSIONS: The PPARalpha gene affects progression of atherosclerosis and risk of IHD. Absence of association with plasma lipid concentrations suggests that PPARalpha affects atherosclerotic progression directly in the vessel wall.

Influence of factor VII gene polymorphisms and environmental factors on plasma coagulation factor VII concentrations in middle-aged women with and without manifest coronary heart disease.

Plasma concentrations of coagulation factorVII (FVII) are determined by environmental and genetic factors. The influence of functional polymorphisms in the FVII gene (-670A>C, -402G>A, -401G>T and R353Q) and of established cardiovascular risk factors on plasma concentrations of FVII were investigated in a representative sample of middle-aged women with (n=238) and without (n=220) coronary heart disease (CHD). Specific and sensitive assays were used to measure FVII antigen (VIIag) and activated factorVII (VIIa). The effect of genotypes was markedly stronger on VIIa than on VIIag, with the percentage variation in FVII levels accounted for by genotypes being greater in controls than in patients. Of the four polymorphisms examined, only the R353Q contributed to the variation inVIIa (24.1% in patients and 30.3% in controls). The -401G>T and -670A>C promoter polymorphisms together accounted for 12.2% of the variation in VIIag amongst patients whereas the -401G>T polymorphism alone contributed 19.7% of the variation in VIIag in controls. Serum triglycerides exerted a major influence onVIIag in both patients (13.0%) and controls (7.2%). Three main haplotypes emerged from the four polymorphisms which accounted for 98% of all haplotypes. Large-scale prospective studies of CHD including FVII haplotypes and sensitive and specific FVII measurements are needed in women.

Nonfasting apolipoprotein B and triglyceride levels as a useful predictor of coronary heart disease risk in middle-aged UK men.

OBJECTIVE: The Apolipoprotein-related Mortality Risk (AMORIS) study concluded that the apolipoprotein (apo)B/apoA-I ratio was the best predictor of coronary heart disease (CHD) risk. We have compared the pairwise combinations of total cholesterol, triglycerides (TGs), apoB, high density lipoprotein (HDL) cholesterol, low density lipoprotein cholesterol, and apoA-I on CHD risk prediction in middle-aged men. METHODS AND RESULTS: Healthy middle-aged men (n=2508), free of CHD at baseline, were examined prospectively. Over 6 years of follow-up, there were 163 CHD events (including acute myocardial infarction, coronary artery surgery, and ECG evidence of silent myocardial infarction). The relative risk (RR) of CHD associated with cholesterol, TGs, apoB, apoA-I, apoB/apoA-I, low density lipoprotein cholesterol, and HDL cholesterol were examined by survival analysis. The apoB/apoA-I ratio was associated with the strongest effect on the RR (3.58, 95% CI 2.08 to 6.19). In multivariate analysis, apoA-I had no significant effect on risk. Examining RR by quartiles, apoB and HDL in combination (RR 8.38, 95% CI 3.21 to 21.92) were better predictors of CHD risk than apoB and TGs (RR 4.05, 95% CI 1.57 to 6.23). However, apoB and TGs in combination added risk information over and above lifestyle factors, whereas apoB and HDL cholesterol did not. CONCLUSIONS: The combined evaluation of apoB with TGs provides useful diagnostic criteria for CHD risk.

Inflammatory response to coronary artery bypass surgery: does the heme-oxygenase-1 gene microsatellite polymorphism play a role?

BACKGROUND: Heme-oxygenase 1 (HO-1) is a rate-limiting enzyme in the degradation of heme to bilirubin, ferritin and carbon monoxide (CO) and may have significant anti-inflammatory function. The HO-1 gene promoter region shows microsatellite polymorphism with different (GT)n repeats, reported to differently induce gene expression, with the short allele associated with higher gene expression. We measured the acute inflammatory response using coronary artery bypass surgery (CABG) as a well-characterized and uniform stimulus and examined the correlation between levels of IL-6, C-reactive protein (CRP) and fibrinogen and their relationship to HO-1 genotype. METHODS: Two hundred and seventy-five consecutive patients undergoing CABG were genotyped for the HO-1 promoter polymorphism using PCR and automated DNA capillary sequencer. IL-6, CRP and fibrinogen were measured at baseline and 6, 24, 48, 72, 96 and 120 hours after CABG. RESULTS: Complete IL-6, CRP and fibrinogen measures were available in 220 patients. Before surgery IL-6 levels showed a strong correlation with CRP and fibrinogen (r = 0.48, P < 0.0001; r = 0.41, P < 0.0001 respectively), with a significant correlation between CRP and fibrinogen (r = 0.61, P < 0.0001). All three acute phase reactants showed a significant increase after CABG. After surgery, peak IL-6 was strongly correlated with peak CRP (r = 0.34, P = 0.0009) but not with peak fibrinogen (r = 0.15, P = 0.13), while peak CRP and peak fibrinogen were significantly correlated (r = 0.415, P < 0.0001). HO-1 allelic repeats ranged from 22-42, with (GT)25 and (GT)32 being the two most common alleles, and subsequently divided into three groups according to previous published work: <30 (GT)n were designated as S (short), 30-37 (GT)n as M (middle) and long repeats with >37 (GT)n as L (long); allele frequency 0.35, 0.58 and 0.07 respectively. Baseline CRP differed by genotype: those carrying at least one long allele having higher CRP than those with no long allele (3.76 +/- 0.79 vs. 2.07 +/- 0.17, P = 0.013). Conversely, those carrying at least one short allele had higher fibrinogen levels than those with no short allele (3.83 +/- 0.79 vs. 3.51 +/- 0.88, P = 0.006). CONCLUSIONS: There is a strong correlation between the measured acute phase reactants both at baseline and after the inflammatory response to CABG in patients with coronary disease. There was an association between the HO-1 microsatellite polymorphism and CRP and fibrinogen levels at baseline but there was no similar association following CABG. This may indicate that HO-1 is associated with chronic atherosclerotic inflammatory processes rather than acute.

The microsatellite polymorphism of heme oxygenase-1 is associated with baseline plasma IL-6 level but not with restenosis after coronary in-stenting.

BACKGROUND: Vascular smooth muscle cells (VSMCs) can express heme-oxygenase (HO), a rate-limiting enzyme in the degradation of heme to bilirubin, ferritin and carbon monoxide (CO). VSMC-derived CO can suppress VSMC proliferation and may serve as an antiproliferation factor. The promoter region of HO-1 shows a polymorphism with different (GT) n repeats that has been reported to differently induce gene expression. The objective of this study was to examine the effect of this variation on the occurrence of restenosis after in-stent treatment in patients with coronary artery disease. METHODS: Candidates who underwent coronary stent implantation were genotyped for the HO-1 promoter polymorphism using polymerase chain reaction (PCR) and automated DNA capillary sequencer. Serum levels of IL-6 and C-reactive protein (CRP) were obtained at baseline, 24 hours and 48 hours after stenting. The primary end point for the study was angiographic evidence of in-stent restenosis at 6 months. All parameters for evaluation of restenosis were analysed by quantitative computer-assisted angiographic analysis (QCA). RESULTS: One hundred and eighty-seven patients who underwent coronary stent implantation were studied of whom 27.8% showed > or = 50% restenosis after 6 months. The distribution of (GT) n repeats of all patients in the promoter region of HO-1 genotype ranged from 22 to 42, with (GT) 25 and (GT) 32 being the two most common alleles. The allelic repeats were divided into the short class (S) with 29 (GT) n, the middle class (M) with 30-37 (GT) n and the long class (L) with 38 (GT) n. There was no significant difference in the restenosis between the genotype groups or between post operation levels of inflammation markers, but carriers of the S allele (n = 120) had 33.3% lower baseline IL-6 compared with non-S carriers (n = 67, P = 0.0008). CONCLUSIONS: Although no association was observed between the HO-1 promoter polymorphism and coronary in-stent restenosis following the stent procedure, the association with plasma IL-6 levels suggests that HO-1 S allele might protect from the atherosclerotic inflammatory process.