S. Trompet

Genetic variation in the interleukin-1 beta-converting enzyme associates with cognitive function. The PROSPER study

Inflammation is thought to play an important role in the development of cognitive decline and dementia in old age. The interleukin-1 signalling pathway may play a prominent role in this process. The gene encoding for interleukin-1 beta-converting enzyme (ICE) is likely to influence IL-1 beta levels. Inhibition of ICE decreases the age-related increase in IL-1 beta levels and may therefore improve memory function. We assessed whether genetic variation in the ICE gene associates with cognitive function in an elderly population. All 5804 participants of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) were genotyped for the 10643GC, 9323GA, 8996AG and 5352GA polymorphisms in the ICE gene. Cross-sectional associations between the polymorphisms and cognitive function were assessed with linear regression. Longitudinal associations between polymorphisms, haplotypes and cognitive function were assessed with linear mixed models. All associations were adjusted for sex, age, education, country, treatment with pravastatin and version of test where appropriate. Subjects carrying the variants 10643C and 5352A allele had significantly lower IL-1 beta production levels (P < 0.01). Furthermore, we demonstrated that homozygous carriers of the 10643C and the 5352A allele performed better on all executive function tests at baseline and during follow-up compared to homozygous carriers of the wild-type allele (all P < 0.02). The haplotype with two variants present (10643C and 5352A) was associated with better executive function (all P < 0.02) compared to the reference haplotype without variants. For memory function the same trend was observed, although not significant. Genetic variation in the ICE gene is associated with better performance on cognitive function and lower IL-1 beta production levels. This suggests that low levels of IL-1 beta are protective for memory and learning deficits. Inhibition of ICE may therefore be an important therapeutic target for maintaining cognitive function in old age.

Does Low to Moderate Alcohol Intake Protect Against Cognitive Decline in Older People

OBJECTIVES: To determine whether low to moderate alcohol intake is protective against cognitive decline in older people.

Drug-gene interactions and the search for missing heritability: a cross-sectional pharmacogenomics study of the QT interval

Variability in response to drug use is common and heritable, suggesting that genome-wide pharmacogenomics studies may help explain the ‘missing heritability’ of complex traits. Here, we describe four independent analyses in 33u2009781 participants of European ancestry from 10 cohorts that were designed to identify genetic variants modifying the effects of drugs on QT interval duration (QT). Each analysis cross-sectionally examined four therapeutic classes: thiazide diuretics (prevalence of use=13.0%), tri/tetracyclic antidepressants (2.6%), sulfonylurea hypoglycemic agents (2.9%) and QT-prolonging drugs as classified by the University of Arizona Center for Education and Research on Therapeutics (4.4%). Drug–gene interactions were estimated using covariable-adjusted linear regression and results were combined with fixed-effects meta-analysis. Although drug–single-nucleotide polymorphism (SNP) interactions were biologically plausible and variables were well-measured, findings from the four cross-sectional meta-analyses were null (Pinteraction>5.0 × 10−8). Simulations suggested that additional efforts, including longitudinal modeling to increase statistical power, are likely needed to identify potentially important pharmacogenomic effects.

Non-Homologous End-Joining Pathway Associated with Occurrence of Myocardial Infarction: Gene Set Analysis of Genome-Wide Association Study Data

Purpose DNA repair deficiencies have been postulated to play a role in the development and progression of cardiovascular disease (CVD). The hypothesis is that DNA damage accumulating with age may induce cell death, which promotes formation of unstable plaques. Defects in DNA repair mechanisms may therefore increase the risk of CVD events. We examined whether the joints effect of common genetic variants in 5 DNA repair pathways may influence the risk of CVD events. Methods The PLINK set-based test was used to examine the association to myocardial infarction (MI) of the DNA repair pathway in GWAS data of 866 subjects of the GENetic DEterminants of Restenosis (GENDER) study and 5,244 subjects of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) study. We included the main DNA repair pathways (base excision repair, nucleotide excision repair, mismatch repair, homologous recombination and non-homologous end-joining (NHEJ)) in the analysis. Results The NHEJ pathway was associated with the occurrence of MI in both GENDER (Pu200a=u200a0.0083) and PROSPER (Pu200a=u200a0.014). This association was mainly driven by genetic variation in the MRE11A gene (PGENDERu200a=u200a0.0001 and PPROSPERu200a=u200a0.002). The homologous recombination pathway was associated with MI in GENDER only (Pu200a=u200a0.011), for the other pathways no associations were observed. Conclusion This is the first study analyzing the joint effect of common genetic variation in DNA repair pathways and the risk of CVD events, demonstrating an association between the NHEJ pathway and MI in 2 different cohorts.

Ten-year mortality risk of patients undergoing elective PCI: long-term follow-up of the GENetic Determinants of Restenosis (GENDER) study: No increased mortality risk by restenosis, only by coronary artery disease itself

Although the death rates from cardiovascular diseases (CVD) have declined over the last decades, the burden of disease remains high and CVD remains one of the leading causes of morbidity and mortality in Western developed countries [1, 2] including the Netherlands. [3–6] Tremendous efforts worldwide are put into research and development of novel treatment modalities for CVD to further halt the disease burden, and frequent updates of primary and secondary prevention guidelines should result in the most optimal treatment of each patient with CVD. Besides major improvements in pharmacological treatment with for instance statins, beta-blockers, angiotensin-converting-enzyme inhibitors and antiplatelet agents, interventional treatment modalities such as percutaneous coronary intervention (PCI) have markedly improved the outcome of patients with coronary artery disease. An important complication of percutaneous coronary intervention (PCI) that is still present is coronary restenosis.[7] Coronary restenosis the renarrowing of the treated obstruction results in high morbidity [8] and is even reported to be associated with an increased risk of mortality.[9, 10] Data on long-term follow-up of patients with restenosis are, however, scarce. To explore the relation of restenosis development with long-term mortality, we analysed the 10-year survival of the patients included in the GENetic DEterminants of Restenosis (GENDER) study.[11] The second objective of this report was to investigate whether the treatment strategies after PCI, applied in daily clinical practice over the past 10 years, resulted in a shift in mortality rates and causes of death of these confirmed coronary artery disease (CAD) patients compared with the general population.

Matrix metalloproteinases 2 and 3 gene polymorphisms and the risk of target vessel revascularization after percutaneous coronary intervention: Is there still room for determining genetic variation of MMPs for assessment of an increased risk of restenosis?

Objective: Mixed results have been reported of matrix metalloproteinases (MMP) and their association with restenosis after percutaneous coronary intervention (PCI). The current study examines whether multiple single nucleotide polymorphisms (SNPs), covering the full genomic region of MMP2 and MMP3, were associated with restenosis in the GENDER study population. Methods and results: The GENetic DEterminants of Restenosis (GENDER) study enrolled 3104 consecutive patients after successful PCI. The primary endpoint was clinical restenosis, defined as target vessel revascularization (TVR), occurring in 9.8% of the patients. From the Hapmap database, 19 polymorphisms of MMP2 and 11 of MMP3 were selected. Furthermore, in a subpopulation, a genome-wide association analysis (GWA) was performed. No significant association was found with any of the investigated SNPs, including the previously reported 5A/6A polymorphism (rs3025058), with regard to TVR using single SNP analysis or haplotype analysis. Conclusion: We found no significant association of MMP2 or MMP3 with TVR with this SNP-broad gene approach. Although we did not test all the known polymorphisms of these genes, using tagging analyses we examined those SNPs covering all known haplotypes of MMP2 and MMP3 to conclude that these genes do not correlate with a genetic risk of coronary restenosis after successful PCI.

CETP (Cholesteryl Ester Transfer Protein) Concentration: A Genome-Wide Association Study Followed by Mendelian Randomization on Coronary Artery Disease

Background: We aimed to identify independent genetic determinants of circulating CETP (cholesteryl ester transfer protein) to assess causal effects of variation in CETP concentration on circulating lipid concentrations and cardiovascular disease risk. Methods: A genome-wide association discovery and replication study on serum CETP concentration were embedded in the NEO study (Netherlands Epidemiology of Obesity). Based on the independent identified variants, Mendelian randomization was conducted on serum lipids (NEO study) and coronary artery disease (CAD; CARDIoGRAMplusC4D consortium). RESULTS: In the discovery analysis (n=4248), we identified 3 independent variants (P<5×10−8) that determine CETP concentration. These single-nucleotide polymorphisms were mapped to CETP and replicated in a separate subpopulation (n=1458). Per-allele increase (SE) in serum CETP was 0.32 (0.02) µg/mL for rs247616-C, 0.35 (0.02) µg/mL for rs12720922-A, and 0.12 (0.02) µg/mL for rs1968905-G. Combined, these 3 variants explained 16.4% of the total variation in CETP concentration. One microgram per milliliter increase in genetically determined CETP concentration strongly decreased high-density lipoprotein cholesterol (−0.23 mmol/L; 95% confidence interval, −0.26 to −0.20), moderately increased low-density lipoprotein cholesterol (0.08 mmol/L; 95% confidence interval, 0.00–0.16), and was associated with an odds ratio of 1.08 (95% confidence interval, 0.94–1.23) for CAD risk. Conclusions: This is the first genome-wide association study identifying independent variants that largely determine CETP concentration. Although high-density lipoprotein cholesterol is not a causal risk factor for CAD, it has been unequivocally demonstrated that low-density lipoprotein cholesterol lowering is proportionally associated with a lower CAD risk. Therefore, the results of our study are fully consistent with the notion that CETP concentration is causally associated with CAD through low-density lipoprotein cholesterol.

Genetic variation in the obesity gene FTO is not associated with decreased fat oxidation: the NEO study

Background:The fat mass and obesity-associated (FTO) gene harbors the strongest common genetic variant associated with obesity. Recently, rs1421085-T to -C substitution mapped in FTO was shown to induce a developmental shift of human adipocytes from an energy-combusting beige to an energy-storing white phenotype in vitro. As browning of adipocytes selectively enhances fat oxidation (FatOx), we hypothesized that rs1421085-C in FTO is associated with deceased FatOx compared with carbohydrate oxidation (CarbOx) and an increased respiratory quotient (RQ).Methods:In the Netherlands Epidemiology of Obesity study, a population-based cohort study of middle-aged individuals (45–65 years), anthropometry and genotyping was performed (n=5744), in addition to indirect calorimetry (n=1246). With linear regression analyses, we examined associations of rs1421085 genotype with FatOx, CarbOx and RQ.Results:In the total study population, 36.7% carried the rs1421085-TT genotype, 47.6% rs1421085-CT and 15.7% rs1421085-CC. Mean (s.d.) age was 56 (6) years, mean (s.d.), body mass index (BMI) was 26.3 (4.4)u2009kgu2009m−2 and 56% of the total population were women. Measures of adiposity (difference, 95% confidence interval) were higher in CC carriers compared with that in rs1421085-TT carriers: BMI +0.56 (0.15, 0.98)u2009kgu2009m−2, waist circumference +1.25 (0.02, 2.49)u2009cm and total body fat mass +1.21 (0.28, 2.14)u2009kg. However, no differences in mean FatOx (+2.5 (−2.4, 7.4)u2009mgu2009min−1), CarbOx (−6.1 (−17.4, 5.2)u2009mgu2009min−1) or RQ (−0.01 (−0.02, 0.01)) were observed between the two genotypes.Conclusions:We observed no evidence for associations of rs1421085 in FTO with FatOx and RQ. This indicates that the rs1421085-C allele in FTO induces obesity likely via other pathways than via reduced FatOx.

Visit-to-visit lipid variability: Clinical significance, effects of lipid-lowering treatment, and (pharmaco) genetics

In recent years, visit-to-visit variability of serum lipids has been linked to both clinical outcomes and surrogate markers for vascular disease. In this article, we present an overview of the current evidence connecting this intraindividual variability to these outcome measures, discuss its interplay with lipid-lowering treatment, and describe the literature regarding genetic factors of possible interest. In addition, we undertook an explorative genome-wide association analysis on visit-to-visit variability of low-density lipoprotein cholesterol and high-density lipoprotein cholesterol, examining additive effects in 2530 participants from the placebo arm of the PROspective Study of Pravastatin in the Elderly at Risk trial. While we identified suggestive associations (Pxa0<xa01 × 10-6) at 3 different loci (KIAA0391, amiloride-sensitive cation channel 1 neuronal [ACCN1], and Dickkopf WNT signaling pathway inhibitor 3 [DKK3]), previously published data from the genome-wide association study literature did not suggest plausible mechanistic pathways. Given the large degree of both clinical and methodological heterogeneity in the literature, additional research is needed to harmonize visit-to-visit variability parameters across studies and to definitively assess the possible role of (pharmaco)genetic factors.

Association of fasting triglyceride concentration and postprandial triglyceride response with the carotid intima-media thickness in the middle aged: The Netherlands Epidemiology of Obesity study

BACKGROUNDnPeople are in a postprandial state for the majority of the day, postprandial triglyceride (TG) response may be more important in the etiology of atherosclerosis than fasting TGs.nnnOBJECTIVEnThe objective of the study was to investigate the associations of fasting TG concentration (TGc) and postprandial TG response after a meal challenge with subclinical atherosclerosis, measured by intima-media thickness (IMT) in a middle-aged population.nnnMETHODSnA total of 5574 participants (57% women) with a mean (standard deviation [SD]) age of 56 (6) years were included in this cross-sectional analysis of baseline measurements of The Netherlands Epidemiology of Obesity study. Serum TGc was measured fasting and 30 and 150xa0minutes after a liquid mixed meal, and the incremental area under the curve (TGiAUC) was calculated. With linear regression analyses, we calculated the differences in IMT with 95% confidence intervals, adjusted for confounding factors, and additionally for TGc or TGiAUC.nnnRESULTSnPer SD of TGc (0.82xa0mmol/L), IMT was 8.5xa0μm (2.1, 14.9) greater after adjustment for TGiAUC and confounding factors. Per SD of TGiAUC (24.0xa0mmol/L × min), the difference in IMT was -1.7xa0μm (-8.5, 5.0) after adjustment for fasting TG and confounding factors.nnnCONCLUSIONSnThe association between TG response after a mixed meal and IMT disappeared after adjusting for TGc. The association between fasting TG concentration and IMT persisted after adjustment for postprandial TG response. These findings imply that it is not useful to perform a meal challenge in cardiovascular risk stratification. Our results support use of fasting TGc instead of postprandial TG responses for cardiovascular risk stratification in clinical practice.