Association of a fasting glucose genetic risk score with subclinical atherosclerosis: The Atherosclerosis Risk in Communities (ARIC) study

OBJECTIVE

Elevated fasting glucose level is associated with increased carotid intima-media thickness (IMT), a measure of subclinical atherosclerosis. It is unclear if this association is causal. Using the principle of Mendelian randomization, we sought to explore the causal association between circulating glucose and IMT by examining the association of a genetic risk score with IMT.

RESEARCH DESIGN AND METHODS

The sample was drawn from the Atherosclerosis Risk in Communities (ARIC) study and included 7,260 nondiabetic Caucasian individuals with IMT measurements and relevant genotyping. Components of the fasting glucose genetic risk score (FGGRS) were selected from a fasting glucose genome-wide association study in ARIC. The score was created by combining five single nucleotide polymorphisms (SNPs) (rs780094 [GCKR], rs560887 [G6PC2], rs4607517 [GCK], rs13266634 [SLC30A8], and rs10830963 [MTNR1B]) and weighting each SNP by its strength of association with fasting glucose. IMT was measured through bilateral carotid ultrasound. Mean IMT was regressed on the FGGRS and on the component SNPs, individually.

RESULTS

The FGGRS was significantly associated (P = 0.009) with mean IMT. The difference in IMT predicted by a 1 SD increment in the FGGRS (0.0048 mm) was not clinically relevant but was larger than would have been predicted based on observed associations between the FFGRS, fasting glucose, and IMT. Additional adjustment for baseline measured glucose in regression models attenuated the association by about one third.

CONCLUSIONS

The significant association of the FGGRS with IMT suggests a possible causal association of elevated fasting glucose with atherosclerosis, although it may be that these loci influence IMT through nonglucose pathways.Elevated fasting glucose level is associated with increased carotid intima-media thickness (IMT) (1,2), a measure of subclinical atherosclerosis. However, it is still unclear if this relation is causal, due to unmeasured confounding by other cardiovascular risk factors, or due to the metabolic derangements of diabetes—a disease defined by fasting glucose level.Several recent fasting glucose genome-wide association studies (GWAS) (3–5) and a large GWAS meta-analysis (6) have identified multiple genetic variants with strong associations to fasting plasma glucose level. A recent GWAS in the Atherosclerosis Risk in Communities (ARIC) study found five variants significantly associated with fasting glucose after correction for genome-wide testing (7). Consistent associations for all five of the variants have been reported in other fasting glucose GWAS (6). We demonstrated that these variants are much more strongly associated with fasting glucose in the normal or prediabetic range than in the diabetic range (7).The discovery of genetic variants reproducibly associated with fasting glucose provides the opportunity to investigate a causal association between fasting glucose and cardiovascular disease (CVD) using the theory of Mendelian randomization. Because of random assortment of alleles at the time of gamete formation, genetic variants should not be associated with known and unknown confounders in association analyses. Genetic variants can also be measured very accurately and are thus subject to little measurement error. Finally, genetic variants are also not susceptible to issues of reverse causality (8). Therefore, the proxy use of single nucleotide polymorphisms (SNPs) significantly associated with a trait instead of the trait itself in association analyses can help to explore a causal association between a trait and disease (9). This technique was recently used in a meta-analysis to examine the causal relationship of C-reactive protein to heart disease (10). In this paper, we applied principles of Mendelian randomization to explore whether there is a causal relation between fasting glucose in the nondiabetic range and subclinical atherosclerosis. In order to reduce problems with multiple testing, to create a genetic variable that accounted for a substantive amount of variation in fasting glucose, and to attempt to account for pleiotropic effects of individual SNPs, a composite genetic risk score was used. However, Mendelian randomization results from single SNPs associated with fasting glucose are also presented in the online appendix available at http://diabetes.diabetesjournals.org/cgi/content/full/db10-0839/DC1.     

Incidence and clinical presentation of posttransfusion TT virus infection in prospectively followed transfusion recipients: emphasis on its relevance to hepatitis

BACKGROUND: A novel transfusion-transmissible human DNA virus, TT virus (TTV), has been discovered recently. An attempt was made to determine the incidence and clinical outcome of TTV infection in recipients of blood transfusion. STUDY DESIGN AND METHODS: Serial serum samples collected as part of a prospective study of posttransfusion hepatitis were examined for TTV DNA by a nested PCR assay. RESULTS: Among 150 adults undergoing cardiac surgery, posttransfusion specimens from 59 individuals were positive for TTV DNA. Pretransfusion sera were found to be positive in 13 of these individuals. Therefore, 46 (33.6%) of the 137 previously uninfected patients developed new TTV viremia after transfusion. Among the 46 patients, 3 were coinfected with HCV, 5 were coinfected with HGV, and 38 were infected with TTV alone. No apparent symptoms or signs were noted in the 38 patients infected by TTV alone or the 5 infected with HGV plus TTV. The average peak serum ALT activity was 31 IU per L, with persistently normal levels in 34 of the 38 patients with TTV infection alone. In 8 other patients who subsequently developed well-documented non-A-G hepatitis, 3 were positive for TTV (3/8 vs. 46/137, p = 0.8). In 12 patients followed for more than 1 year, TTV viremia persisted in every case. CONCLUSION: In this population, TTV is transmitted by transfusion to approximately 30 percent of patients who undergo cardiac surgery. Most of the infections appear to become persistent. Despite the high prevalence rate, TTV does not appear to cause hepatitis on its own.     

Alisporivir with peginterferon/ribavirin in patients with chronic hepatitis C genotype 1 infection who failed to respond to or relapsed after prior interferon‐based therapy: FUNDAMENTAL,a Phase II trial

Alisporivir (ALV) is an oral, investigational host‐targeting agent, with pangenotypic activity against hepatitis C virus (HCV). This randomized, double‐blind, placebo‐controlled, Phase II study explored the efficacy and safety of ALV with peginterferon‐α2a/ribavirin (PR) in patients with chronic HCV genotype 1 infection in whom prior PR had failed (43% relapsers, 34% null responders and 23% partial responders). Four‐hundred‐and‐fifty‐nine patients were randomized (1:1:1:1) to ALV 600 mg once daily (QD), ALV 800 mg QD, ALV 400 twice daily (BID) or placebo plus PR for 48 weeks. When the global ALV trial programme was put on clinical hold, all patients in this study had received ≥31 weeks of randomized treatment; patients completed 48 weeks on PR alone. All ALV groups demonstrated superior rates of complete early virologic response (cEVR; primary endpoint) vs PR alone (P ≤ 0.0131), with highest cEVR rate seen with ALV 400 mg BID (74% vs 36% with PR alone; P < 0.0001). Respective SVR12 rates (key secondary endpoint) were 65% vs 26% in prior relapsers, 63% vs 5% in partial responders and 68% vs 3% in null responders. In patients who received >40 weeks of randomized treatment, the SVR12 rate was 89% for ALV 400 mg BID vs 30% for PR alone (P = 0.0053). Rates of viral breakthrough and relapse were lowest with ALV 400 mg BID. One case of pancreatitis (fully recovered) occurred with ALV/PR. Common AEs were headache, fatigue, anaemia, neutropenia and nausea. Hypertension was infrequent, but more common with ALV. ALV merits further investigation in interferon‐free regimens in combination with direct‐acting antiviral agents.     

Brain Metabolism of Less-Educated Patients With Alzheimer Dementia Studied by Positron Emission Tomography

Alzheimer dementia (AD) is the commonest form of dementia. Although illiteracy is associated with high prevalence of dementia of the Alzheimer type (DAT), their relationship is still unclear. Nevertheless, mild DAT in illiterate participants seems to be due to brain atrophy.In this study, we compared the impact of brain metabolism efficiency in healthy participants and less-educated patients with mild DAT using 2-fluoro-2-deoxy-d-glucose (¹⁸F-FDG-PET) positron emission tomography. Out of 43 eligible less-educated participants with dementia, only 23 (14 women and 9 men) met Diagnostic and Statistical Manual (DSM)-III-R or DSM-IV criteria for DAT and AD and were included. Participants with intracranial insults were excluded by brain magnetic resonance imaging and participants with metabolic or systemic conditions were excluded by blood sampling. In addition, 16 cognitively normal elderly (age >70 years), including 7 women and 9 men, were enrolled in the sham group. The PET imaging data were analyzed using statistical parametric mapping (SPM8) to determine reliability and specificity.Glucose metabolic rate was low in the DAT group, especially in the middle temporal gyrus, middle frontal gyrus, superior frontal gyrus, inferior frontal gyrus, posterior cingulate gyrus, angular gyrus, parahippocampal gyrus, middle occipital gyrus, rectal gyrus, and lingual gyrus.Our results showed that DAT patients with less education not only have prominent clinical signs and symptoms related to dementia but also decreased gray matter metabolism.