Several genes implicated in high-density lipoprotein (HDL) metabolism have been reported to be associated with age-related macular degeneration (AMD). Furthermore, HDL transport the two carotenoids, lutein and zeaxanthin, which are highly suspected to play a key-role in the protection against AMD. The objective is to confirm the associations of HDL-related loci with AMD and to assess their associations with plasma lutein and zeaxanthin concentrations.
Alienor study is a prospective population-based study on nutrition and age-related eye diseases performed in 963 elderly residents of Bordeaux, France. AMD was graded according to the international classification, from non-mydriatic colour retinal photographs. Plasma lutein and zeaxanthin were determined by normal-phase high-performance liquid chromatography. The following polymorphisms were studied: rs493258 and rs10468017 (LIPC), rs3764261 (CETP), rs12678919 (LPL) and rs1883025 (ABCA1).
After multivariate adjustment, the TT genotype of the LIPC rs493258 variant was significantly associated with a reduced risk for early and late AMD (OR=0.64, 95%CI: 0.41-0.99; p=0.049 and OR=0.26, 95%CI: 0.08-0.85; p=0.03, respectively), and with higher plasma zeaxanthin concentrations (p=0.03), while plasma lipids were not significantly different according to this SNP. Besides, the LPL variant was associated with early AMD (OR=0.67, 95%CI: 0.45-1.00; p=0.05) and both with plasma lipids and plasma lutein (p=0.047). Associations of LIPC rs10468017, CETP and ABCA1 polymorphisms with AMD did not reach statistical significance.
These findings suggest that LIPC and LPL genes could both modify the risk for AMD and the metabolism of lutein and zeaxanthin.
Left ventricular (LV) remodeling following myocardial infarction (MI) is characterized by progressive alterations of structure and function, named LV remodeling. Although several risk factors such as infarct size have been identified, LV remodeling remains difficult to predict in clinical practice. Changes within the extracellular matrix, involving matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs), are an integral part of left ventricular (LV) remodeling after myocardial infarction (MI). We investigated the temporal profile of circulating MMPs and TIMPs and their relations with LV remodeling at 1 year and clinical outcome at 3 years in post-MI patients.
This prospective multicentre study included 246 patients with a first anterior MI. Serial echocardiographic studies were performed at hospital discharge, 3 months, and 1 year after MI, and analysed at a core laboratory. LV remodeling was defined as the percent change in LV end-diastolic volume (EDV) from baseline to 1 year. Serum samples were obtained at hospital discharge, 1, 3, and 12 months. Multiplex technology was used for analysis of MMP-1, -2, -3, -8, -9, -13, and TIMP-1, -2, -3, -4 serum levels.
Baseline levels of MMP-8 and MMP-9 were positively associated with changes in LVEDV (P = 0.01 and 0.02, respectively). When adjusted for major baseline characteristics, MMP-8 levels remained an independent predictor LV remodeling (P = 0.025). By univariate analysis, there were positive relations between cardiovascular death or hospitalization for heart failure during the 3-year follow-up and the baseline levels of MMP-2 (P = 0.03), MMP-8 (P = 0.002), and MMP-9 (P = 0.03). By multivariate analysis, MMP-8 was the only MMP remaining significantly associated with clinical outcome (P = 0.02).
Baseline serum MMP-8 is a significant predictor of LV remodeling and cardiovascular outcome after MI and may help to improve risk stratification.
Nicastrin (NCSTN) is a component of the γ-secretase complex and therefore potentially a candidate risk gene for Alzheimer's disease. Here, we have developed a novel functional genomics methodology to express common locus haplotypes to assess functional differences. DNA recombination was used to engineer 5 bacterial artificial chromosomes (BACs) to each express a different haplotype of the NCSTN locus. Each NCSTN-BAC was delivered to knockout nicastrin (Ncstn−/−) cells and clonal NCSTN-BAC+/Ncstn−/− cell lines were created for functional analyses. We showed that all NCSTN-BAC haplotypes expressed nicastrin protein and rescued γ-secretase activity and amyloid beta (Aβ) production in NCSTN-BAC+/Ncstn−/− lines. We then showed that genetic variation at the NCSTN locus affected alternative splicing in human postmortem brain tissue. However, there was no robust functional difference between clonal cell lines rescued by each of the 5 different haplotypes. Finally, there was no statistically significant association of NCSTN with disease risk in the 4 cohorts. We therefore conclude that it is unlikely that common variation at the NCSTN locus is a risk factor for Alzheimer's disease.
Nicastrin; Haplotype variation; Functional genomics; Alzheimer's disease; γ-Secretase complex
Homozygous loss-of-function mutations in TREM2, encoding the triggering receptor expressed on myeloid cells 2 protein, have previously been associated with an autosomal recessive form of early-onset dementia.
We used genome, exome, and Sanger sequencing to analyze the genetic variability in TREM2 in a series of 1092 patients with Alzheimer's disease and 1107 controls (the discovery set). We then performed a meta-analysis on imputed data for the TREM2 variant rs75932628 (predicted to cause a R47H substitution) from three genomewide association studies of Alzheimer's disease and tested for the association of the variant with disease. We genotyped the R47H variant in an additional 1887 cases and 4061 controls. We then assayed the expression of TREM2 across different regions of the human brain and identified genes that are differentially expressed in a mouse model of Alzheimer's disease and in control mice.
We found significantly more variants in exon 2 of TREM2 in patients with Alzheimer's disease than in controls in the discovery set (P = 0.02). There were 22 variant alleles in 1092 patients with Alzheimer's disease and 5 variant alleles in 1107 controls (P<0.001). The most commonly associated variant, rs75932628 (encoding R47H), showed highly significant association with Alzheimer's disease (P<0.001). Meta-analysis of rs75932628 genotypes imputed from genomewide association studies confirmed this association (P = 0.002), as did direct genotyping of an additional series of 1887 patients with Alzheimer's disease and 4061 controls (P<0.001). Trem2 expression differed between control mice and a mouse model of Alzheimer's disease.
Heterozygous rare variants in TREM2 are associated with a significant increase in the risk of Alzheimer's disease. (Funded by Alzheimer's Research UK and others.)
Venous Thrombosis (VT) is a common multifactorial disease with an estimated heritability between 35% and 60%. Known genetic polymorphisms identified so far only explain ~5% of the genetic variance of the disease. This study was aimed to investigate whether pair-wise interactions between common single nucleotide polymorphisms (SNPs) could exist and modulate the risk of VT.
A genome-wide SNP x SNP interaction analysis on VT risk was conducted in a French case–control study and the most significant findings were tested for replication in a second independent French case–control sample. The results obtained in the two studies totaling 1,953 cases and 2,338 healthy subjects were combined into a meta-analysis.
The smallest observed p-value for interaction was p = 6.00 10-11 but it did not pass the Bonferroni significance threshold of 1.69 10-12 correcting for the number of investigated interactions that was 2.96 1010. Among the 37 suggestive pair-wise interactions with p-value less than 10-8, one was further shown to involve two SNPs, rs9804128 (IGFS21 locus) and rs4784379 (IRX3 locus) that demonstrated significant interactive effects (p = 4.83 10-5) on the variability of plasma Factor VIII levels, a quantitative biomarker of VT risk, in a sample of 1,091 VT patients.
This study, the first genome-wide SNP interaction analysis conducted so far on VT risk, suggests that common SNPs are unlikely exerting strong interactive effects on the risk of disease.
Venous thrombosis; Genome-Wide Association Study; Interaction; Factor VIII
Genome-wide association studies (GWAS) that allow for allelic heterogeneity may facilitate the discovery of novel genes not detectable by models that require replication of a single variant site. One strategy to accomplish this is to focus on genes rather than markers as units of association, and so potentially capture a spectrum of causal alleles that differ across populations. Here, we conducted a GWAS of Alzheimer disease (AD) in 2586 Swedes and performed gene-based meta-analysis with three additional studies from France, Canada, and the United States, in total encompassing 4259 cases and 8284 controls. Implementing a newly designed gene-based algorithm, we identified two loci apart from the region around APOE that achieved study-wide significance in combined samples, the strongest finding being for FRMD6 on chromosome 14q (p = 2.6 × 10−14) and a weaker signal for NARS2 that is immediately adjacent to GAB2 on chromosome 11q (p = 7.8 × 10−9). Ontology-based pathway analyses revealed significant enrichment of genes involved in glycosylation. Results suggest that gene-based approaches that accommodate allelic heterogeneity in GWAS can provide a complementary avenue for gene discovery and may help to explain a portion of the missing heritability not detectable with SNPs derived from marker-specific meta-analysis.
Alzheimer; GWAS; association; gene-based; FRMD6; GAB2
Disability is a common condition in the elderly and has been associated with prevalent coronary heart disease (CHD) and with shorter longevity. However, whether disability predicts the occurrence of CHD has been less studied.
To prospectively assess the association between disability and incident fatal and non-fatal CHD among older adults free of cardiovascular disease (CVD). Design and Settings: The Three-City (3C) Study is a French multicentre prospective population-based cohort of 9294 elderly subjects (3469 men and 5645 women) aged 65 and over at baseline between 1999 to 2001 and followed-up during 6 years.
7354 participants with no history of CVD and with available information on disability status. Disability was assessed at baseline with a three levels of a hierarchical scale : no disability, mild disability (mobility only), moderate or severe disability (mobility plus activities of daily living and/or instrumental activities of daily living).
Main Outcome Measure
Incident fatal and non-fatal coronary events (angina pectoris, myocardial infarction, revascularization procedures and CHD death).
At baseline, the mean level of the risk factors increased gradually with the severity of disability. After a median follow-up of 5.2 years, 264 first coronary events including 55 fatal events occurred. Participants with moderate or severe disability had a 1.8-fold (95%CI: 1.1–2.9) increased risk of overall CHD compared to non-disabled subjects in multivariate analysis, while those with mild disability were not at increased CHD risk. The association was found for fatal CHD only, for which the risk increased gradually with the severity of disability (mild disability: HR = 1.8, 95%CI: 0.9–3.8; moderate/severe disability: HR = 4.5, 95%CI: 1.8–11.3; p for trend = 0.002).
These data suggest that the association of disability with incident CHD is mostly due to an association with fatal CHD in community-dwelling elderly subjects.
Activities of Daily Living; Aged; Coronary Disease; epidemiology; etiology; Disabled Persons; classification; statistics & numerical data; Female; France; epidemiology; Geriatric Assessment; Hospitalization; statistics & numerical data; Humans; Incidence; Kaplan-Meier Estimate; Logistic Models; Male; Proportional Hazards Models; Prospective Studies; Questionnaires; Risk Assessment; Risk Factors; Severity of Illness Index; Urban Health; statistics & numerical data; epidemiology; elderly; risk factors; disability; coronary heart disease; atherosclerosis.
By applying an imputation strategy based on the 1000 Genomes project to two genome-wide association studies (GWAS), we detected a susceptibility locus for venous thrombosis on chromosome 11p11.2 that was missed by previous GWAS analyses that had been conducted on the same datasets. A comprehensive linkage disequilibrium and haplotype analysis of the whole locus where twelve SNPs exhibited association p-values lower than 2.23 10−11 and the use of independent case-control samples demonstrated that the culprit variant was a rare variant located ∼1 Mb away from the original hits, not tagged by current genome-wide genotyping arrays and even not well imputed in the original GWAS samples. This variant was in fact the rs1799963, also known as the FII G20210A prothrombin mutation. This work may be of major interest not only for its scientific impact but also for its methodological findings.
To investigate the respective associations and clinical usefulness of the metabolic syndrome (MetS) and its individual components to predict the risk of first coronary heart disease (CHD) events in elderly.
The Three-City is a French prospective multisite community-based cohort.
Three large French cities: Bordeaux, Dijon and Montpellier.
7612 subjects aged 65 and over who were free of CHD at baseline.
Main outcome measures
The MetS was defined by the 2005 National Cholesterol Education Program Adult Treatment Panel III criteria.
During a median follow-up of 5.2 years, 275 first CHD events were adjudicated. The MetS was associated with increased risks of total (adjusted HR: 1.78; 95% CI 1.39 to 2.28), fatal (HR: 2.40; 95% CI 1.41 to 4.09) and non-fatal (HR: 1.64; 95% CI 1.24 to 2.17) CHD events. The association with total CHD was significant in women (HR: 2.56; 95% CI 1.75 to 3.75) but not in men (HR: 1.39; 95% CI 0.99 to 1.94; p for interaction=0.012). When in the same multivariable model, hyperglycemia and abdominal adiposity in women, hyperglycemia, lower HDL cholesterol and abdominal adiposity (inverse association) in men were the components significantly associated with CHD. The components of the MetS but not the MetS itself improved risk prediction beyond traditional risk factors (NRI= 9.35%, p<0;001).
The MetS is a risk marker for CHD in community-dwelling elderly subjects but may not be useful for CHD risk prediction purposes compared to its individual components.
Metabolic syndrome; coronary heart disease; elderly; risk stratification; psychology/psychiatry; epidemiology
We have followed-up on the recent genome-wide association (GWA) of the clusterin gene (CLU) with increased risk for Alzheimer disease (AD), by performing an unbiased resequencing of all CLU coding exons and regulatory regions in an extended Flanders-Belgian cohort of Caucasian AD patients and control individuals (n = 1930). Moreover, we have replicated genetic findings by targeted resequencing in independent Caucasian cohorts of French (n = 2182) and Canadian (n = 573) origin and by performing meta-analysis combining our data with previous genetic CLU screenings.
In the Flanders-Belgian cohort, we identified significant clustering in exons 5-8 of rare genetic variations leading to non-synonymous substitutions and a 9-bp insertion/deletion affecting the CLU β-chain (p = 0.02). Replicating this observation by targeted resequencing of CLU exons 5-8 in 2 independent Caucasian cohorts of French and Canadian origin identified identical as well as novel non-synonymous substitutions and small insertion/deletions. A meta-analysis, combining the datasets of the 3 cohorts with published CLU sequencing data, confirmed that rare coding variations in the CLU β-chain were significantly enriched in AD patients (ORMH = 1.96 [95% CI = 1.18-3.25]; p = 0.009). Single nucleotide polymorphisms (SNPs) association analysis indicated the common AD risk association (GWA SNP rs11136000, p = 0.013) in the 3 combined datasets could not be explained by the presence of the rare coding variations we identified. Further, high-density SNP mapping in the CLU locus mapped the common association signal to a more 5' CLU region.
We identified a new genetic risk association of AD with rare coding CLU variations that is independent of the 5' common association signal identified in the GWA studies. At this stage the role of these coding variations and their likely effect on the β-chain domain and CLU protein functioning remains unclear and requires further studies.
Alzheimer disease; clusterin gene (CLU); genomic resequencing; non-synonymous substitutions; insertions/deletions; β-chain domain; meta-analysis
Herpes simplex virus (HSV) reactivation has been identified as a possible risk factor for Alzheimer's disease (AD) and plasma amyloid-beta (Aβ) levels might be considered as possible biomarkers of the risk of AD. The aim of our study was to investigate the association between anti-HSV antibodies and plasma Aβ levels.
The study sample consisted of 1222 subjects (73.9 y in mean) from the Three-City cohort. IgM and IgG anti-HSV antibodies were quantified using an ELISA kit, and plasma levels of Aβ1–40 and Aβ1–42 were measured using an xMAP-based assay technology. Cross-sectional analyses of the associations between anti-HSV antibodies and plasma Aβ levels were performed by multi-linear regression.
After adjustment for study center, age, sex, education, and apolipoprotein E-e4 polymorphism, plasma Aβ1–42 and Aβ1–40 levels were specifically inversely associated with anti-HSV IgM levels (β = −20.7, P = 0.001 and β = −92.4, P = 0.007, respectively). In a sub-sample with information on CLU- and CR1-linked SNPs genotyping (n = 754), additional adjustment for CR1 or CLU markers did not modify these associations (adjustment for CR1 rs6656401, β = −25.6, P = 0.002 for Aβ1–42 and β = −132.7, P = 0.002 for Aβ1–40; adjustment for CLU rs2279590, β = −25.6, P = 0.002 for Aβ1–42 and β = −134.8, P = 0.002 for Aβ1–40). No association between the plasma Aβ1–42-to-Aβ1–40 ratio and anti-HSV IgM or IgG were evidenced.
High anti-HSV IgM levels, markers of HSV reactivation, are associated with lower plasma Aβ1–40 and Aβ1–42 levels, which suggest a possible involvement of the virus in the alterations of the APP processing and potentially in the pathogenesis of AD in human.
Abdominal aortic aneurysm (AAA) is characterized by increased aortic vessel wall diameter (>1.5 times normal) and loss of parallelism. This disease is responsible for 1–4% mortality occurring on rupture in males older than 65 years. Due to its asymptomatic nature, proteomic techniques were used to search for diagnostic biomarkers that might allow surgical intervention under nonlife threatening conditions.
Pooled human plasma samples of 17 AAA and 17 control patients were depleted of the most abundant proteins and compared using a data-independent shotgun proteomic strategy, Precursor Acquisition Independent From Ion Count (PAcIFIC), combined with spectral counting and isobaric tandem mass tags. Both quantitative methods collectively identified 80 proteins as statistically differentially abundant between AAA and control patients. Among differentially abundant proteins, a subgroup of 19 was selected according to Gene Ontology classification and implication in AAA for verification by Western blot (WB) in the same 34 individual plasma samples that comprised the pools. From the 19 proteins, 12 were detected by WB. Five of them were verified to be differentially up-regulated in individual plasma of AAA patients: adiponectin, extracellular superoxide dismutase, protein AMBP, kallistatin and carboxypeptidase B2.
Plasma depletion of high abundance proteins combined with quantitative PAcIFIC analysis offered an efficient and sensitive tool for the screening of new potential biomarkers of AAA. However, WB analysis to verify the 19 PAcIFIC identified proteins of interest proved inconclusive save for five proteins. We discuss these five in terms of their potential relevance as biological markers for use in AAA screening of population at risk.
Venous Thrombosis (VT) is a common multifactorial disease associated with a major public health burden. Genetics factors are known to contribute to the susceptibility of the disease but how many genes are involved and their contribution to VT risk still remain obscure. We aimed to identify genetic variants associated with VT risk.
We conducted a genome-wide association study (GWAS) based on 551,141 SNPs genotyped in 1,542 cases and 1,110 controls. Twelve SNPs reached the genome-wide significance level of 2.0×10−8 and encompassed four known VT-associated loci, ABO, F5, F11 and FGG. By means of haplotype analyses, we also provided novel arguments in favor of a role of HIVEP1, PROCR and STAB2, three loci recently hypothesized to participate in the susceptibility to VT. However, no novel VT-associated loci came out of our GWAS. Using a recently proposed statistical methodology, we also showed that common variants could explain about 35% of the genetic variance underlying VT susceptibility among which 3% could be attributable to the main identified VT loci. This analysis additionally suggested that the common variants left to be identified are not uniformly distributed across the genome and that chromosome 20, itself, could contribute to ∼7% of the total genetic variance.
This study might also provide a valuable source of information to expand our understanding of biological mechanisms regulating quantitative biomarkers for VT.
Systemic sclerosis (SSc) is an orphan, complex, inflammatory disease affecting the immune system and connective tissue. SSc stands out as a severely incapacitating and life-threatening inflammatory rheumatic disease, with a largely unknown pathogenesis. We have designed a two-stage genome-wide association study of SSc using case-control samples from France, Italy, Germany, and Northern Europe. The initial genome-wide scan was conducted in a French post quality-control sample of 564 cases and 1,776 controls, using almost 500 K SNPs. Two SNPs from the MHC region, together with the 6 loci outside MHC having at least one SNP with a P<10−5 were selected for follow-up analysis. These markers were genotyped in a post-QC replication sample of 1,682 SSc cases and 3,926 controls. The three top SNPs are in strong linkage disequilibrium and located on 6p21, in the HLA-DQB1 gene: rs9275224, P = 9.18×10−8, OR = 0.69, 95% CI [0.60–0.79]; rs6457617, P = 1.14×10−7 and rs9275245, P = 1.39×10−7. Within the MHC region, the next most associated SNP (rs3130573, P = 1.86×10−5, OR = 1.36 [1.18–1.56]) is located in the PSORS1C1 gene. Outside the MHC region, our GWAS analysis revealed 7 top SNPs (P<10−5) that spanned 6 independent genomic regions. Follow-up of the 17 top SNPs in an independent sample of 1,682 SSc and 3,926 controls showed associations at PSORS1C1 (overall P = 5.70×10−10, OR:1.25), TNIP1 (P = 4.68×10−9, OR:1.31), and RHOB loci (P = 3.17×10−6, OR:1.21). Because of its biological relevance, and previous reports of genetic association at this locus with connective tissue disorders, we investigated TNIP1 expression. A markedly reduced expression of the TNIP1 gene and also its protein product were observed both in lesional skin tissue and in cultured dermal fibroblasts from SSc patients. Furthermore, TNIP1 showed in vitro inhibitory effects on inflammatory cytokine-induced collagen production. The genetic signal of association with TNIP1 variants, together with tissular and cellular investigations, suggests that this pathway has a critical role in regulating autoimmunity and SSc pathogenesis.
Systemic sclerosis (SSc) is a connective tissue disease characterized by generalized microangiopathy, severe immunologic alterations, and massive deposits of matrix components in the connective tissue. Epidemiological investigations indicate that SSc follows a pattern of multifactorial inheritance; however, only a few loci have been replicated in multiple studies. We undertook a two-stage genome-wide association study of SSc involving over 8,800 individuals of European ancestry. Combined analyses showed independent association at the known HLA-DQB1 region and revealed associations at PSORS1C1, TNIP1, and RHOB loci, in agreement with a strong immune genetic component. Because of its biological relevance, and previous reports of genetic association at this locus with other connective tissue disorders, we investigated TNIP1 expression. We observed a markedly reduced expression of the gene and its protein product in SSc, as well as its potential implication in control of extra-cellular matrix synthesis, providing a new clue for a link between inflammation/immunity and fibrosis.
Aß peptides are often considered as catabolic by-products of the amyloid ß protein precursor (APP), with unknown physiological functions. However, several biological properties have been tentatively attributed to these peptides, including a role in vasomotion.
We assess whether plasma Aß peptide levels might be associated with systolic and diastolic blood pressure values (SBP and DBP, respectively).
Plasma Aß1-40 and Aß1-42 levels were measured using an xMAP-based assay in 1,972 individuals (none of whom were taking antihypertensive drugs) from 3 independent studies: the French population-based 3C and MONA-LISA (Lille) studies (n = 627 and n = 769, respectively) and the Australian, longitudinal AIBL study (n = 576). In the combined sample, the Aß1-42/ Aß1-40 ratio was significantly and inversely associated with SBP (p = 0.03) and a similar trend was observed for DBP (p = 0.06). Using the median age (69) as a cut-off, the Aß1-42/Aß1-40 ratio was strongly associated with both SBP and DBP in elderly individuals (p = 0.002 and p = 0.03, respectively). Consistently, a high Aß1-42/ Aß1-40 ratio was associated with a lower risk of hypertension in both the combined whole sample (odds ratio [OR], 0.71; 95% confidence interval [CI], 0.56-0.90) and (to an even greater extent) in the elderly subjects (OR, 0.53; 95% CI, 0.37–0.75). Lastly, all these associations appeared to be primarily driven by the level of plasma Aß1-40.
The plasma Aß1-42/Aß1-40 ratio is inversely associated with SBP, DBP and the risk of hypertension in elderly subjects, suggesting that Aß peptides affect blood pressure in vivo. These results may be particularly relevant in Alzheimer's disease, in which a high Aß1-42/Aß1-40 plasma ratio is reportedly associated with a decreased risk of incident disease.
The peroxisome proliferator–activated receptor-γ2 (PPARG2) Pro12Ala polymorphism has been associated with a higher BMI and a lower risk of type 2 diabetes in adulthood. The association between adiposity and PPARG variants can be influenced by environmental factors such as early growth, dietary fat, and (as recently shown) breast-feeding. The objectives of this study were to assess 1) the influence of the PPARG2 Pro12Ala polymorphism on adiposity markers in adolescents and 2) a possible modulating effect of breast-feeding on these associations.
RESEARCH DESIGN AND METHODS
Data on breast-feeding duration, BMI, and genotypes for the Pro12Ala polymorphism were available for 945 adolescents (mean age 14.7 years). The breast-feeding duration was obtained from parental records. We measured weight, height, waist circumference, and six skinfold thicknesses.
No significant associations between the Pro12Ala polymorphism and any of the above-mentioned anthropometric parameters were found. There were significant interactions between the PPARG2 Pro12Ala polymorphism and breast-feeding with regard to adiposity measurements (all adjusted P < 0.05). Indeed, in children who had not been breast-fed, Ala12 allele carriers had higher adiposity parameters (e.g., Δ BMI +1.88 kg/m2, adjusted for age, sex, and center, P = 0.007) than Pro12Pro adolescents. In contrast, in breast-fed subjects, there was no significant difference between Ala12 allele carriers and Pro12Pro children in terms of adiposity measurements, whatever the duration of breast-feeding.
Breast-feeding appears to counter the deleterious effect of the PPARG2 Pro12Ala polymorphism on anthropometric parameters in adolescents.
Since previous observations indicated that the urea cycle may have a role in the Alzheimer’s disease (AD) process, we set out to quantify the expression of each gene involved in the urea cycle in control and AD brains and establish whether these genes could be genetic determinants of AD. We first confirmed that all the urea cycle enzyme genes are expressed in the AD brain. The expression of arginase 2 was greater in the AD brain than in the control brain. The presence of the rare arginase 2 allele rs742869 was associated with an increase in the risk of AD in men and with an earlier age at onset for both genders. None of the other genes in the pathway appeared to be differentially expressed in the AD brain or act as genetic determinants of the disease.
Alzheimer's disease; urea cycle; citrulline NO cycle; ammonium; nitric oxide; polyamines; arginase; association study
Objective To investigate the effect of alcohol intake patterns on ischaemic heart disease in two countries with contrasting lifestyles, Northern Ireland and France.
Design Cohort data from the Prospective Epidemiological Study of Myocardial Infarction (PRIME) were analysed. Weekly alcohol consumption, incidence of binge drinking (alcohol >50 g on at least one day a week), incidence of regular drinking (at least one day a week, and alcohol <50 g if on only one occasion), volume of alcohol intake, frequency of consumption, and types of beverage consumed were assessed once at inclusion. All coronary events that occurred during the 10 year follow-up were prospectively registered. The relation between baseline characteristics and incidence of hard coronary events and angina events was assessed by Cox’s proportional hazards regression analysis.
Setting One centre in Northern Ireland (Belfast) and three centres in France (Lille, Strasbourg, and Toulouse).
Participants 9778 men aged 50-59 free of ischaemic heart disease at baseline, who were recruited between 1991 and 1994.
Main outcome measures Incident myocardial infarction and coronary death (“hard” coronary events), and incident angina pectoris.
Results A total of 2405 men from Belfast and 7373 men from the French centres were included in the analyses, 1456 (60.5%) and 6679 (90.6%) of whom reported drinking alcohol at least once a week, respectively. Among drinkers, 12% (173/1456) of men in Belfast drank alcohol every day compared with 75% (5008/6679) of men in France. Mean alcohol consumption was 22.1 g/day in Belfast and 32.8 g/day in France. Binge drinkers comprised 9.4% (227/2405) and 0.5% (33/7373) of the Belfast and France samples, respectively. A total of 683 (7.0%) of the 9778 participants experienced ischaemic heart disease events during the 10 year follow-up: 322 (3.3%) hard coronary events and 361 (3.7%) angina events. Annual incidence of hard coronary events per 1000 person years was 5.63 (95% confidence interval 4.69 to 6.69) in Belfast and 2.78 (95% CI 2.41 to 3.20) in France. After multivariate adjustment for classic cardiovascular risk factors and centre, the hazard ratio for hard coronary events compared with regular drinkers was 1.97 (95% CI 1.21 to 3.22) for binge drinkers, 2.03 (95% CI 1.41 to 2.94) for never drinkers, and 1.57 (95% CI 1.11 to 2.21) for former drinkers for the entire cohort. The hazard ratio for hard coronary events in Belfast compared with in France was 1.76 (95% CI 1.37 to 2.67) before adjustment, and 1.09 (95% CI 0.79 to 1.50) after adjustment for alcohol patterns and wine drinking. Only wine drinking was associated with a lower risk of hard coronary events, irrespective of the country.
Conclusions Regular and moderate alcohol intake throughout the week, the typical pattern in middle aged men in France, is associated with a low risk of ischaemic heart disease, whereas the binge drinking pattern more prevalent in Belfast confers a higher risk.
The liver X receptors (LXR) α and β regulate lipid and carbohydrate homeostasis and inflammation. Lxrβ-/- mice are glucose intolerant and at the same time lean. We aimed to assess the associations between single nucleotide polymorphisms (SNPs) in LXRβ and risk of type 2 diabetes mellitus (T2DM), obesity and related traits in 3 separate cohort studies.
Twenty LXRβ SNPs were identified by sequencing and genotyped in the HUNT2 adult nested case-control study for T2DM (n = 835 cases/1986 controls). Five tag-SNPs (rs17373080, rs2695121, rs56151148, rs2303044 and rs3219281), covering 99.3% of the entire common genetic variability of the LXRβ gene were identified and genotyped in the French MONICA adult study (n = 2318) and the European adolescent HELENA cross-sectional study (n = 1144). In silico and in vitro functionality studies were performed.
We identified suggestive or significant associations between rs17373080 and the risk of (i) T2DM in HUNT2 (OR = 0.82, p = 0.03), (ii) obesity in MONICA (OR = 1.26, p = 0.05) and (iii) overweight/obesity in HELENA (OR = 1.59, p = 0.002). An intron 4 SNP (rs28514894, a perfect proxy for rs17373080) could potentially create binding sites for hepatic nuclear factor 4 alpha (HNF4α) and nuclear factor 1 (NF1). The C allele of rs28514894 was associated with ~1.25-fold higher human LXRβ basal promoter activity in vitro. However, no differences between alleles in terms of DNA binding and reporter gene transactivation by HNF4α or NF1 were observed.
Our results suggest that rs17373080 in LXRβ is associated with T2DM and obesity, maybe via altered LXRβ expression.
To analyse the relation between various food groups and the frequency of insulin resistance syndrome (IRS).
A sample of 912 men aged 45–64 years was randomly selected. Questionnaires on risk factors and a three consecutive day food diary were completed. Height, weight, waist circumference, and blood pressure were measured. A fasting blood sample was analysed for lipid and glucose measurements. The NCEP‐ATP‐III definition was used to assess IRS. Data were analysed according to quintiles of food groups and medians of dairy products, fish, or cereal grains.
The prevalence of IRS was 23.5%. It reached 29.0%, 28.1% and 28.1% when the intake was below the median for fish, dairy products, and grain, respectively. When consumptions of all three types of food were higher than the median, the prevalence reached 13.1%, and when they were lower, the prevalence was 37.9% (p<0.001). In logistic regression adjusted for confounders (centre, age, physical activities, education level, smoking, dieting, alcohol intake, treatments for hypertension and dyslipidaemia, energy intake, and diet quality index) the odds ratios for IRS (above median value v below) were 0.51 (95% confidence interval, 0.36 to 0.71) for fish, 0.67 (0.47 to 0.94) for dairy products, and 0.69 (0.47 to 1.01) for grain. When intakes of all three kinds of food were high, the OR was 0.22 (0.10 to 0.44).
A high consumption of dairy products, fish, or cereal grains is associated with a lower probability of IRS. The probability decreases when intakes of all three types of food were high.
diet; fish; dairy products; grain; insulin resistance syndrome
Recently, it was suggested that arginase (ARG)1 plays an important role in atherogenesis. However, because of its complex functions depending on vascular cell type, its impact on atherogenesis remains unclear.
To evaluate the association between ARG1 polymorphisms and phenotypes related to atherosclerosis.
Among 10 ARG1 polymorphisms selected from databases, 4 single‐nucleotide polymorphisms (rs2781666; rs2781667; rs2781668; rs17599586) were tested for association with myocardial infarction (MI) in a case–control study (350 cases vs 581 controls), and with common carotid artery (CCA) intima–media thickness (CCA‐IMT) in an independent sample of 963 subjects (Etude du Vieillissement Artériel (EVA) study).
The genotype distribution of the rs2781666 G/T polymorphism differed significantly between MI cases and controls (p = 0.005), and the risk of MI was consistently increased for both GT heterozygotes (OR (95% CI) 1.5 (1.1 to 2.0)) and TT homozygotes (OR (95% CI) 2.2 (1.1 to 4.4)). In the EVA study, the rs2781666 polymorphism was also associated with an increase in CCA‐IMT (p = 0.010), a surrogate marker of MI.
The ARG1 rs2781666 polymorphism was consistently associated with MI and an increased CCA‐IMT. These findings reinforce the hypothesis of a significant role of ARG1 in vascular pathophysiology.
Single nucleotide polymorphisms (SNPs) in the peroxisome proliferator-activated receptor γ (PPARG) gene have been associated with cardiovascular risk factors, particularly obesity and diabetes. We assessed the relationship between 4 PPARG SNPs (C-681G, C-689T, Pro12Ala, and C1431T) and coronary heart disease (CHD) in the PRIME (249 cases/494 controls, only men) and ADVANCE (1,076 cases/805 controls, men or women) studies. In PRIME, homozygote individuals for the minor allele of the PPARG C-689T, Pro12Ala, and C1431T SNPs tended to have a higher risk of CHD than homozygote individuals for the frequent allele (adjusted OR [95% CI] = 3.43 [0.96–12.27], P = .058, 3.41 [0.95–12.22], P = .060 and 5.10 [0.99–26.37], P = .050, resp.). No such association could be detected in ADVANCE. Haplotype distributions were similar in cases and control in both studies. A meta-analysis on the Pro12Ala SNP, based on our data and 11 other published association studies (6,898 CHD cases/11,287 controls), revealed that there was no evidence for a significant association under the dominant model (OR = 0.99
[0.92–1.07], P = .82). However, there was a borderline association under the recessive model (OR = 1.29 [0.99–1.67], P = .06) that became significant when considering men only (OR = 1.73 [1.20–2.48], P = .003). In conclusion, the PPARG Ala12Ala genotype might be associated with a higher CHD risk in men but further confirmation studies are needed.
Alzheimer’s disease (AD) is a genetically heterogeneous disorder characterized by early hippocampal atrophy and cerebral Aβ peptide deposition. Using TissueInfo to screen for genes preferentially expressed in the hippocampus and located in AD linkage regions, we identified a novel gene on 10q24.33 that we call CALHM1. We show that CALHM1 encodes a multipass transmembrane glycoprotein that controls cytosolic Ca2+ concentrations and Aβ levels. CALHM1 homomultimerizes, shares strong sequence similarities with the selectivity filter of the NMDA receptor, and generates a large Ca2+ conductance across the plasma membrane. Importantly, we determined that the CALHM1 P86L polymorphism (rs2986017) is significantly associated with AD in independent case-control studies of 3,404 participants (allele-specific OR=1.44, P=2×10−10). We further found that the P86L polymorphism increases Aβ levels by interfering with CALHM1-mediated Ca2+ permeability. We propose that CALHM1 encodes an essential component of a novel cerebral Ca2+ channel that controls Aβ levels and susceptibility to AD.
The goal of the present study was to assess the effect of genetic variability at the APOA5/A4/C3/A1 cluster locus on the risk of metabolic syndrome.
The APOA5 Ser19Trp, APOA5 -12,238T>C, APOA4 Thr347Ser, APOC3 -482C>T and APOC3 3238C>G (SstI) polymorphisms were analyzed in a representative population sample of 3138 men and women from France, including 932 individuals with metabolic syndrome and 2206 without metabolic syndrome, as defined by the NCEP criteria.
Compared with homozygotes for the common allele, the odds ratio (OR) [95% CI] for metabolic syndrome was 1.30 [1.03–1.66] (p = 0.03) for APOA5 Trp19 carriers, 0.81 [0.69–0.95] (p = 0.01) for APOA5 -12,238C carriers and 0.84 [0.70–0.99] (p = 0.04) for APOA4 Ser347 carriers. Adjustment for plasma triglycerides, (but not for waist girth, HDL, blood pressure or glycemia – the other components of metabolic syndrome) abolished these associations and suggests that triglyceride levels explain the association with metabolic syndrome. There was no association between the APOC3 -482C>T or APOC3 3238C>G polymorphisms and metabolic syndrome. The decreased risk of metabolic syndrome observed in APOA5 -12,238C and APOA4 Ser347 carriers merely reflected the fact that the APOA5 Trp19 allele was in negative linkage disequilibrium with the common alleles of APOA5 -12,238T>C and APOA4 Thr347Ser polymorphisms.
The APOA5 Trp19 allele increased susceptibility to metabolic syndrome via its impact on plasma triglyceride levels.
Perilipins are proteins localized at the surface of the lipid droplet in adipocytes, steroid-producing cells and ruptured atherosclerotic plaques playing a role in the regulation of triglyceride deposition and mobilization. We investigated whether perilipin gene polymorphisms were associated with obesity, type 2 diabetes, and their related variables (anthropometric variables, plasma leptin, lipids, glucose and insulin concentrations) in a cross-sectional random sample of 1120 French men and women aged 35 to 65 years old, including 227 obese (BMI ≥ 30 kg/m2) and 275 type 2 diabetes subjects.
Among 7 perilipin polymorphisms tested, only 2 (rs4578621 and rs894160) of them were frequent enough to be fully investigated and we genotyped the sample using the PCR-RFLP method. No significant associations could be found between any of these polymorphisms and the studied phenotypes.
The rs4578621 and rs894160 polymorphisms of the perilipin gene are not major genetic determinants of obesity and type 2 diabetes-related phenotypes in a random sample of French men and women.