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1.
Nat Genet ; 50(11): 1505-1513, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30297969

RESUMO

We expanded GWAS discovery for type 2 diabetes (T2D) by combining data from 898,130 European-descent individuals (9% cases), after imputation to high-density reference panels. With these data, we (i) extend the inventory of T2D-risk variants (243 loci, 135 newly implicated in T2D predisposition, comprising 403 distinct association signals); (ii) enrich discovery of lower-frequency risk alleles (80 index variants with minor allele frequency <5%, 14 with estimated allelic odds ratio >2); (iii) substantially improve fine-mapping of causal variants (at 51 signals, one variant accounted for >80% posterior probability of association (PPA)); (iv) extend fine-mapping through integration of tissue-specific epigenomic information (islet regulatory annotations extend the number of variants with PPA >80% to 73); (v) highlight validated therapeutic targets (18 genes with associations attributable to coding variants); and (vi) demonstrate enhanced potential for clinical translation (genome-wide chip heritability explains 18% of T2D risk; individuals in the extremes of a T2D polygenic risk score differ more than ninefold in prevalence).

2.
Nat Genet ; 50(8): 1122-1131, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30054598

RESUMO

The molecular mechanisms underpinning susceptibility loci for type 2 diabetes (T2D) remain poorly understood. Coding variants in peptidylglycine α-amidating monooxygenase (PAM) are associated with both T2D risk and insulinogenic index. Here, we demonstrate that the T2D risk alleles impact negatively on overall PAM activity via defects in expression and catalytic function. PAM deficiency results in reduced insulin content and altered dynamics of insulin secretion in a human ß-cell model and primary islets from cadaveric donors. Thus, our results demonstrate a role for PAM in ß-cell function, and establish molecular mechanisms for T2D risk alleles at this locus.

3.
Environ Pollut ; 229: 984-993, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28781182

RESUMO

A study of 16 United States Environmental Protection Agency (USEPA) priority listed PAHs associated with particulate matter ≤ 10 µm (PM10) was conducted in Singapore during the period 29th May 2015 to 28th May 2016. The sampling period coincided with an extensive, regional smoke haze episode (5th September to 25th October) that occurred as a result of forest and peat fires in neighboring Indonesia. Throughout this study, 54 atmospheric PM10 samples were collected in 24 h periods using a high volume sampler (HVS) and quarts fiber filters (QFF) as the collection medium. Hysplit software for computing 3-D backward air mass trajectories, diagnostic ratio analysis and ring number distribution calculations were used to examine the sources of PAHs in the atmosphere in Singapore. Under normal conditions the total PAH concentrations were in a range from 0.68 ng m-3 to 3.07 ng m-3, while for the high haze period the results showed approximately double the concentrations with a maximum value of 5.97 ng m-3. Diagnostic ratio (DR) and principal component analysis (PCA) were conducted and indicated the contribution of the traffic as a dominant pyrogenic source of PAHs during normal periods, while results from the haze dataset showed relatively strong influence of smoke from peat and forest fires in Indonesia. Environmental and health risk from PAHs were assessed for both regular and hazy days.


Assuntos
Poluentes Atmosféricos/análise , Monitoramento Ambiental , Material Particulado/análise , Hidrocarbonetos Policíclicos Aromáticos/análise , Atmosfera/análise , Indonésia , Análise de Componente Principal , Singapura , Fumaça/análise , Estados Unidos , United States Environmental Protection Agency
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