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Global genetic analyses reveal strong inter-ethnic variability in the loss of activity of the organic cation transporter OCT1

Overview of attention for article published in Genome Medicine, June 2015
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  • In the top 25% of all research outputs scored by Altmetric
  • High Attention Score compared to outputs of the same age (88th percentile)
  • Above-average Attention Score compared to outputs of the same age and source (53rd percentile)

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1 news outlet
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5 tweeters

Citations

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64 Dimensions

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51 Mendeley
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Title
Global genetic analyses reveal strong inter-ethnic variability in the loss of activity of the organic cation transporter OCT1
Published in
Genome Medicine, June 2015
DOI 10.1186/s13073-015-0172-0
Pubmed ID
Authors

Tina Seitz, Robert Stalmann, Nawar Dalila, Jiayin Chen, Sherin Pojar, Joao N. Dos Santos Pereira, Ralph Krätzner, Jürgen Brockmöller, Mladen V. Tzvetkov

Abstract

The organic cation transporter OCT1 (SLC22A1) mediates the uptake of vitamin B1, cationic drugs, and xenobiotics into hepatocytes. Nine percent of Caucasians lack or have very low OCT1 activity due to loss-of-function polymorphisms in OCT1 gene. Here we analyzed the global genetic variability in OCT1 to estimate the therapeutic relevance of OCT1 polymorphisms in populations beyond Caucasians and to identify evolutionary patterns of the common loss of OCT1 activity in humans. We applied massively parallel sequencing to screen for coding polymorphisms in 1,079 unrelated individuals from 53 populations worldwide. The obtained data was combined with the existing 1000 Genomes data comprising an additional 1,092 individuals from 14 populations. The identified OCT1 variants were characterized in vitro regarding their cellular localization and their ability to transport 10 known OCT1 substrates. Both the population genetics data and transport data were used in tandem to generate a world map of loss of OCT1 activity. We identified 16 amino acid substitutions potentially causing loss of OCT1 function and analyzed them together with five amino acid substitutions that were not expected to affect OCT1 function. The variants constituted 16 major alleles and 14 sub-alleles. Six major alleles showed improper subcellular localization leading to substrate-wide loss in activity. Five major alleles showed correct subcellular localization, but substrate-specific loss of activity. Striking differences were observed in the frequency of loss of OCT1 activity worldwide. While most East Asian and Oceanian individuals had completely functional OCT1, 80 % of native South American Indians lacked functional OCT1 alleles. In East Asia and Oceania the average nucleotide diversity of the loss-of-function variants was much lower than that of the variants that do not affect OCT1 function (ratio of 0.03) and was significantly lower than the theoretically expected heterozygosity (Tajima's D = -1.64, P < 0.01). Comprehensive genetic analyses showed strong global variations in the frequency of loss of OCT1 activity with selection pressure for maintaining OCT1 activity in East Asia and Oceania. These results not only enable pharmacogenetically-based optimization of drug treatment worldwide, but may help elucidate the functional role of human OCT1.

Twitter Demographics

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Mendeley readers

The data shown below were compiled from readership statistics for 51 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 51 100%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 8 16%
Researcher 7 14%
Student > Master 6 12%
Student > Doctoral Student 4 8%
Student > Bachelor 4 8%
Other 14 27%
Unknown 8 16%
Readers by discipline Count As %
Biochemistry, Genetics and Molecular Biology 13 25%
Pharmacology, Toxicology and Pharmaceutical Science 10 20%
Medicine and Dentistry 6 12%
Agricultural and Biological Sciences 6 12%
Computer Science 1 2%
Other 6 12%
Unknown 9 18%

Attention Score in Context

This research output has an Altmetric Attention Score of 13. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 06 July 2015.
All research outputs
#419,237
of 5,320,841 outputs
Outputs from Genome Medicine
#161
of 571 outputs
Outputs of similar age
#21,549
of 185,425 outputs
Outputs of similar age from Genome Medicine
#19
of 41 outputs
Altmetric has tracked 5,320,841 research outputs across all sources so far. Compared to these this one has done particularly well and is in the 92nd percentile: it's in the top 10% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 571 research outputs from this source. They typically receive a lot more attention than average, with a mean Attention Score of 16.2. This one has gotten more attention than average, scoring higher than 71% of its peers.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 185,425 tracked outputs that were published within six weeks on either side of this one in any source. This one has done well, scoring higher than 88% of its contemporaries.
We're also able to compare this research output to 41 others from the same source and published within six weeks on either side of this one. This one has gotten more attention than average, scoring higher than 53% of its contemporaries.