Effects of the diabetes linked TCF7L2 polymorphism in a representative older population

BACKGROUND: A polymorphism in the transcription factor 7-like 2 (TCF7L2) gene has been found to be associated with type 2 diabetes in case-control studies. We aimed to estimate associations of the marker rs7903146 (C/T) polymorphism with fasting glucose, lipids, diabetes prevalence and complications in an older general population. METHODS: In total, 944 subjects aged ≥ 65 years from the population representative InCHIANTI study were enrolled in this study. Those with fasting blood glucose of ≥ 7 mmol/l or physician diagnosis were considered diabetic. Cut-off points for impaired fasting glucose (IFG) were ≥ 5.6 mmol/l to < 7 mmol/l. RESULTS: In the general population sample, minor (T) allele carriers of rs7903146 had higher fasting blood glucose (FBG) (p = 0.028) but lower fasting insulin (p = 0.030) and HOMA2b scores (p = 0.001), suggesting poorer beta-cell function. T allele carriers also had smaller waist circumference (p = 0.009), lower triglyceride levels (p = 0.006), and higher high-density lipoprotein cholesterol (p = 0.008). The prevalence of diabetes or IFG was 32.4% in TT carriers and 23.3% in CC carriers; adjusted OR = 1.67 (95% confidence interval 1.05 to 2.65, p = 0.031). Within the diabetic and IFG groups, fewer T allele carriers had metabolic syndrome features (p = 0.047) or had experienced a myocardial infarction (p = 0.037). Conversely, T allele carriers with diabetes had poorer renal function (reduced 24-hour creatinine clearance, p = 0.013), and possibly more retinopathy (p = 0.067). Physician-diagnosed dementia was more common in the T carriers (in diabetes p = 0.05, with IFG p = 0.024). CONCLUSION: The TCF7L2 rs7903146 polymorphism is associated with lower insulin levels, smaller waist circumference, and lower risk lipid profiles in the general elderly population. Patients with diabetes who are carriers of the minor allele are less likely to have metabolic-syndrome features, but may experience more microvascular complications, although the number of cases was small. If replicated, these findings may have implications for developing treatment approaches tailored by genotype

Common lipid-altering gene variants are associated with therapeutic intervention thresholds of lipid levels in older people

This is a freely-available open access publication. Please cite the published version which is available via the DOI link in this record.AIMS: There are a large number of common genetic variants that have been robustly associated with low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, or triglyceride concentrations. The majority of these have been identified or confirmed in recent genome-wide association studies, but few studies have assessed the combined effect of known lipid variants. We hypothesized that these variants would influence both the need for interventions and myocardial infarction (MI) outcomes. We aimed to estimate combined effects of proven SNPs on LDL, HDL, and triglyceride concentrations and MI history in a representative older population. METHODS AND RESULTS: In the InCHIANTI Study of Aging (age >or=65 years), we calculated individual dyslipidaemia risk allele counts for increased LDL (range 4-14, n = 594), reduced HDL (5-16, n = 635), and increased triglycerides (7-16, n = 611). Lipid levels were compared with ATPIII National Cholesterol Education Panel (NCEP) intervention guidelines. Individual variants and the APOE haplotype explained <2.1% of the variance in their respective lipid concentrations, with the exception of the CETP SNP rs1800775 and HDL levels (4.76%). Combined risk allele counts outperformed the largest single-SNP effects for LDL (explaining 7.1% of variance) and triglycerides (4.8%), but not HDL (3.4%). Risk alleles were divided as near as possible into quartiles. The 31% of respondents with 10 or more LDL increasing alleles were more likely to have LDL levels above the intervention threshold (OR 3.00, 95% CI 1.67-5.39, P = 2.5 x 10(-4)), compared with the 21% with 7 or less risk alleles. Similarly, the 35% with 13 or more triglyceride risk alleles were more likely to exceed NCEP intervention thresholds (OR 2.98, 95% CI 1.43-6.22, P = 0.004) compared with the 24% with 10 or less alleles. The number of individuals reporting an MI event was small (n = 67), but an event was more common in the 36% of respondents who had the highest combined risk allele score for all three lipids (OR 3.68, 95% CI 1.21-11.2, P = 0.021) compared with the lowest risk 22%. CONCLUSION: In a representative older population, the cumulative effects of proven LDL- and triglyceride-altering genetic variants increased the odds of crossing the lipid-level threshold for therapeutic intervention by approximately three-fold.National Institutes of Health/NIAIntramural Research Program, National Institute on Aging, NIHItalian Ministry of HealthUS National Institute on Agin

Psychopathological Impact in Patients with History of Rheumatic Fever with or without Sydenham's Chorea: A Multicenter Prospective Study

Sydenham's chorea (SC) is a post-streptococcal autoimmune disorder of the central nervous system, and it is a major criterium for the diagnosis of acute rheumatic fever (ARF). SC typically improves in 12-15 weeks, but patients can be affected for years by persistence and recurrencies of both neurological and neuropsychiatric symptoms. We enrolled 48 patients with a previous diagnosis of ARF, with or without SC, in a national multicenter prospective study, to evaluate the presence of neuropsychiatric symptoms several years after SC's onset. Our population was divided in a SC group (n = 21), consisting of patients who had SC, and a nSC group (n = 27), consisting of patients who had ARF without SC. Both groups were evaluated by the administration of 8 different neuropsychiatric tests. The Work and Social Adjustment Scale (WSAS) showed significantly (p = 0.021) higher alterations in the SC group than in the nSC group. Furthermore, 60.4% (n = 29) of the overall population experienced neuropsychiatric symptoms other than choreic movements at diagnosis and this finding was significantly more common (p = 0.00) in SC patients (95.2%) than in nSC patients (33.3%). The other neuropsychiatric tests also produced significant results, indicating that SC can exert a strong psychopathological impact on patients even years after its onset

A genome-wide association study identifies protein quantitative trait loci (pQTLs)

There is considerable evidence that human genetic variation influences gene expression. Genome-wide studies have revealed that mRNA levels are associated with genetic variation in or close to the gene coding for those mRNA transcripts - cis effects, and elsewhere in the genome - trans effects. The role of genetic variation in determining protein levels has not been systematically assessed. Using a genome-wide association approach we show that common genetic variation influences levels of clinically relevant proteins in human serum and plasma. We evaluated the role of 496,032 polymorphisms on levels of 42 proteins measured in 1200 fasting individuals from the population based InCHIANTI study. Proteins included insulin, several interleukins, adipokines, chemokines, and liver function markers that are implicated in many common diseases including metabolic, inflammatory, and infectious conditions. We identified eight Cis effects, including variants in or near the IL6R (p = 1.8×10 -57), CCL4L1 (p = 3.9×10-21), IL18 (p = 6.8×10-13), LPA (p = 4.4×10-10), GGT1 (p = 1.5×10-7), SHBG (p = 3.1×10-7), CRP (p = 6.4×10-6) and IL1RN (p = 7.3×10-6) genes, all associated with their respective protein products with effect sizes ranging from 0.19 to 0.69 standard deviations per allele. Mechanisms implicated include altered rates of cleavage of bound to unbound soluble receptor (IL6R), altered secretion rates of different sized proteins (LPA), variation in gene copy number (CCL4L1) and altered transcription (GGT1). We identified one novel trans effect that was an association between ABO blood group and tumour necrosis factor alpha (TNF-alpha) levels (p = 6.8×10-40), but this finding was not present when TNF-alpha was measured using a different assay , or in a second study, suggesting an assay-specific association. Our results show that protein levels share some of the features of the genetics of gene expression. These include the presence of strong genetic effects in cis locations. The identification of protein quantitative trait loci (pQTLs) may be a powerful complementary method of improving our understanding of disease pathways. © 2008 Melzer et al

Contamination of Runoff Water at Gdańsk Airport (Poland) by Polycyclic Aromatic Hydrocarbons (PAHs) and Polychlorinated Biphenyls (PCBs)

Airport runoff can contain high concentrations of various pollutants, in particular polycyclic aromatic hydrocarbons (PAHs) and polychlorinated biphenyls (PCBs), the environmental levels of which have to be monitored. Airport runoff water samples, collected at the Gdańsk-Rębiechowo Airport from 2008 to 2009, were analysed for PAHs and PCBs by gas chromatography. The aromatic fractions were separated by liquid-liquid extraction and analysed by GC/MS. Total PAH concentrations were 295–6,758 ng/L in 2008 and 180–1,924 ng/L in 2009, while total PCB levels in 2008 ranged from 0.14 to 0.44 μg/L and in 2009 from 0.06 to 0.23 μg/L. The PAH and PCB compositions in airport runoff waters were examined over a range of spatial and temporal scales to determine distributions, trends and possible sources. This pollution is mainly pyrolytic and related to anthropogenic activity. There were significant differences between the samples collected in the two seasons. An understanding of the magnitude of contamination due to airport runoff water is important for the effective management of airport infrastructure

The Death Throes of a Stripped Massive Star: An Eruptive Mass-Loss History Encoded in Pre-Explosion Emission, a Rapidly Rising Luminous Transient, and a Broad-Lined Ic Supernova SN2018gep

We present detailed observations of ZTF18abukavn (SN2018gep), discovered in high-cadence data from the Zwicky Transient Facility as a rapidly rising (1.3 mag/hr) and luminous (M_(g,peak) = −20 mag) transient. It is spectroscopically classified as a broad-lined stripped-envelope supernova (Ic-BL SN). The rapid rise to peak bolometric luminosity and blue colors at peak (t_(rise)∼0.5-3 days, L_(bol)≳3×10^(44) erg sec^(−1), g−r = −0.3) resemble the high-redshift Ic-BL iPTF16asu, as well as several other unclassified fast transients. The early discovery of SN2018gep (within an hour of shock breakout) enabled an intensive spectroscopic campaign, including the highest-temperature (T_(eff) ≳ 40,000K) spectra of a stripped-envelope SN. A retrospective search revealed luminous (M_g ∼ M_r ≈ −14mag) emission in the days to weeks before explosion, the first definitive detection of precursor emission for a Ic-BL. We find a limit on the isotropic gamma-ray energy release E_(γ,iso) < 4.9×10^(48) erg, a limit on X-ray emission L_X < 10^(40) erg sec^(−1), and a limit on radio emission νL_ν ≲ 10^(37) erg sec^(−1). Taken together, we find that the data are best explained by shock breakout in a massive shell of dense circumstellar material (0.02 M⊙) at large radii (3×10^(14)cm) that was ejected in eruptive pre-explosion mass-loss episodes

Inflammatory and Immunological parameters in adults with Down syndrome

<p>Abstract</p> <p>Background</p> <p>The increase in life expectancy within the general population has resulted in an increasing number of elderly adults, including patients with Down syndrome (DS), with a current life expectancy of about 50 years. We evaluate the parameters of humoral and cellular immune response, the quantitative expression of the regulator of calcineurin1 gene (RCAN1) and the production of cytokines. The study group consisted of adults DS (n = 24) and a control group with intellectual disability without Down syndrome (ID) (n = 21) and living in a similar environmental background. It was evaluated serology, immunophenotyping, the quantitative gene expression of RCAN1 and the production of cytokines.</p> <p>Results</p> <p>In the DS group, the results showed an increase in NK cells, CD8, decreased CD19 (p < 0.05) and an increase spontaneous production of IFNgamma, TNFalpha and IL-10 (p < 0.05). There was not any difference in RCAN1 gene expression between the groups.</p> <p>Conclusions</p> <p>These data suggest a similar humoral response in the two groups. The immunophenotyping suggests sign of premature aging of the immune system and the cytokine production show a proinflammatory profile.</p