Background: Plasma concentrations of C-reactive protein (CRP), a marker of chronic inflammation, have been associated with cognitive impairment in old age. However, it is unknown whether CRP is... Show moreBackground: Plasma concentrations of C-reactive protein (CRP), a marker of chronic inflammation, have been associated with cognitive impairment in old age. However, it is unknown whether CRP is causally linked to cognitive decline. Methods and Findings: Within the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) trial, with 5680 participants with a mean age of 75 years, we examined associations of CRP levels and its genetic determinants with cognitive performance and decline over 3.2 years mean follow-up. Higher plasma CRP concentrations were associated with poorer baseline performance on the Stroop test (P = 0.001) and Letter Digit Tests (P, 0.001), but not with the immediate and delayed Picture Learning Test (PLT; both P>0.5). In the prospective analyses, higher CRP concentrations associated with increased rate of decline in the immediate PLT (P = 0.016), but not in other cognitive tests (all p>0.11). Adjustment for prevalent cardiovascular risk factors and disease did not change the baseline associations nor associations with cognitive decline during follow-up. Four haplotypes of CRP were used and, compared to the common haplotype, carrierships associated strongly with levels of CRP (all P < 0.007). In comparison to strong associations of apolipoprotein E with cognitive measures, associations of CRP haplotypes with such measures were inconsistent. Conclusion: Plasma CRP concentrations associate with cognitive performance in part through pathways independent of (risk factors for) cardiovascular disease. However, lifelong exposure to higher CRP levels does not associate with poorer cognitive performance in old age. The current data weaken the argument for a causal role of CRP in cognitive performance, but further study is warranted to draw definitive conclusions. Show less
Polisecki, E.; Peter, I.; Simon, J.S.; Hegele, R.A.; Robertson, M.; Ford, I.; ... ; Prospective Study Pravastatin Elde 2010
Niemann-Pick C1-like 1 protein (NPC1L1) plays a critical role in intestinal cholesterol absorption. Our objective was to examine whether five variants (-133A>G, -18A>C, L272L, V1296V, and U3... Show moreNiemann-Pick C1-like 1 protein (NPC1L1) plays a critical role in intestinal cholesterol absorption. Our objective was to examine whether five variants (-133A>G, -18A>C, L272L, V1296V, and U3_28650A> G) at the NPC1L1 gene have effects on lipid levels, prevalence, and incidence of coronary heart disease (CHD) and lipid-lowering response to pravastatin. We studied 5,804 elderly participants from the PROSPER study, who were randomized to pravastatin 40 mg/day or placebo and were followed on average for 3.2 years. In the adjusted gender-pooled analyses, homozygous carriers of the minor alleles at four NPC1L1 sites (-18A>C, L272L, V1296V, and U3_28650A> G, minor allele frequencies 0.15-0.33) had 2-8% higher LDL-cholesterol (LDL-C) levels at baseline than homozygous carriers of the common alleles (P < 0.05). Homozygotes for the rare alleles also had a significant increase in the risk of CHD events on trial ( range of hazard ratios 1.50-1.67; P < 0.02), regardless of the treatment regimen. The -133 A>G polymorphism and not other variants was associated with 6 month LDL-C lowering (P = 0.02). Our data indicate that variation in the NPC1L1 gene is associated with plasma total and LDL-C levels and CHD risk.-Polisecki, E., I. Peter, J. S. Simon, R. A. Hegele, M. Robertson, I. Ford, J. Shepherd, C. Packard, J. W. Jukema, A. J. M. DeCraen, R. G. J. Westendorp, B. M. Buckley, and E. J. Schaefer. Genetic variation at the NPC1L1 gene locus, plasma lipoproteins, and heart disease risk in the elderly. J. Lipid Res. 2010. 51: 1201-1207. Show less
Welsh, P.; Polisecki, E.; Robertson, M.; Jahn, S.; Buckley, B.M.; Craen, A.J.M. de; ... ; Sattar, N. 2010
Context: Associations between adiposity and circulating inflammation markers are assumed to be causal, although the direction of the relationship has not been proven. Objective: The aim of the... Show moreContext: Associations between adiposity and circulating inflammation markers are assumed to be causal, although the direction of the relationship has not been proven. Objective: The aim of the study was to explore the causal direction of the relationship between adiposity and inflammation using a bidirectional Mendelian randomization approach. Methods: In the PROSPER study of 5804 elderly patients, we related C-reactive protein (CRP) single nucleotide polymorphisms (SNPs) (rs1800947 and rs1205) and adiposity SNPs (FTO and MC4R) to body mass index (BMI) as well as circulating levels of CRP and leptin. We gave each individual two allele scores ranging from zero to 4, counting each pair of alleles related to CRP levels or BMI. Results: With increasing CRP allele score, there was a stepwise decrease in CRP levels (P for trend < 0.0001) and a 1.98 mg/liter difference between extremes of the allele score distribution, but there was no associated change in BMI or leptin levels (P >= 0.89). By contrast, adiposity allele score was associated with 1) an increase in BMI (1.2 kg/m(2) difference between extremes; P for trend 0.002); 2) an increase in circulating leptin (5.77 ng/ml difference between extremes; P for trend 0.0027); and 3) increased CRP levels (1.24 mg/liter difference between extremes; P for trend 0.002). Conclusions: Greater adiposity conferred by FTO and MC4R SNPs led to higher CRP levels, with no evidence for any reverse pathway. Future studies should extend our findings to other circulating inflammatory parameters. This study illustrates the potential power of Mendelian randomization to dissect directions of causality between intercorrelated metabolic factors. (J Clin Endocrinol Metab 95: 93-99, 2010) Show less
Welsh, P.; Polisecki, E.; Robertson, M.; Jahn, S.; Buckley, B.M.; Craen, A.J.M. de; ... ; Sattar, N. 2010
Context: Associations between adiposity and circulating inflammation markers are assumed to be causal, although the direction of the relationship has not been proven. Objective: The aim of the... Show moreContext: Associations between adiposity and circulating inflammation markers are assumed to be causal, although the direction of the relationship has not been proven. Objective: The aim of the study was to explore the causal direction of the relationship between adiposity and inflammation using a bidirectional Mendelian randomization approach. Methods: In the PROSPER study of 5804 elderly patients, we related C-reactive protein (CRP) single nucleotide polymorphisms (SNPs) (rs1800947 and rs1205) and adiposity SNPs (FTO and MC4R) to body mass index (BMI) as well as circulating levels of CRP and leptin. We gave each individual two allele scores ranging from zero to 4, counting each pair of alleles related to CRP levels or BMI. Results: With increasing CRP allele score, there was a stepwise decrease in CRP levels (P for trend < 0.0001) and a 1.98 mg/liter difference between extremes of the allele score distribution, but there was no associated change in BMI or leptin levels (P >= 0.89). By contrast, adiposity allele score was associated with 1) an increase in BMI (1.2 kg/m(2) difference between extremes; P for trend 0.002); 2) an increase in circulating leptin (5.77 ng/ml difference between extremes; P for trend 0.0027); and 3) increased CRP levels (1.24 mg/liter difference between extremes; P for trend 0.002). Conclusions: Greater adiposity conferred by FTO and MC4R SNPs led to higher CRP levels, with no evidence for any reverse pathway. Future studies should extend our findings to other circulating inflammatory parameters. This study illustrates the potential power of Mendelian randomization to dissect directions of causality between intercorrelated metabolic factors. (J Clin Endocrinol Metab 95: 93-99, 2010) Show less
