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N-acetyltransferase 2 (NAT2) is the main enzyme metabolizing isoniazid and genotype-based treatment has been studied for years without becoming common practice. To investigate whether genotype-based isoniazid treatment is feasible in Greenland, we sequenced the coding sequence of NAT2 and determined the NAT2 enzyme-activity by caffeine test. No additional genetic variants were identified in the coding sequence of NAT2, so that genotype status in 260 study participants could be assessed by a well-established 7-SNP panel. Studying the enzyme activity by the ratio of the two caffeine metabolites AFMU and 1X in 260 participants showed a high rate of slow phenotypes with intermediate or rapid genotype. These misclassifications were mainly observed in urine samples with pH3, we observed a moderate level of discrepancies (19 of the 116 individuals with intermediate or rapid genotype status having a slow phenotype). Further investigation showed that drinking coffee and not tea or cola was the most important factor for high levels of both metabolites. The concordance between phenotype and genotype status with regard to slow metabolism supported the recommendation of lower isoniazid doses in individuals with slow genotype status in order to avoid liver injury, a frequent side effect. The phenotypical variation observed for individuals with intermediate or rapid genotype status warrants further research before increased dosing of isoniazid can be recommended., EXCLI Journal;Vol. 17 2018

Background— Inuit have lived for thousands of years in an extremely cold environment on a diet dominated by marine-derived fat. To investigate how this selective pressure has affected the genetic regulation of fatty acid metabolism, we assessed 233 serum metabolic phenotypes in a population-based sample of 1570 Greenlanders. Methods and Results— Using array-based and targeted genotyping, we found that rs80356779, a p.Pro479Leu variant in CPT1A , was strongly associated with markers of n -3 fatty acid metabolism, including degree of unsaturation ( P =1.16×10 − 34 ), levels of polyunsaturated fatty acids, n -3 fatty acids, and docosahexaoenic acid relative to total fatty acid levels ( P =2.35×10 − 15 , P =4.02×10 − 19 , and P =7.92×10 − 27 ). The derived allele (L479) occurred at a frequency of 76.2% in our sample while being absent in most other populations, and we found strong signatures of positive selection at the locus. Furthermore, we found that each copy of L479 reduced height by an average of 2.1 cm ( P =1.04×10 − 9 ). In exome sequencing data from a sister population, the Nunavik Inuit, we found no other likely causal candidate variant than rs80356779. Conclusion— Our study shows that a common CPT1A missense mutation is strongly associated with a range of metabolic phenotypes and reduced height in Greenlanders. These findings are important from a public health perspective and highlight the usefulness of complex trait genetic studies in isolated populations.

Introduction Infusion of glyceryl trinitrate (GTN), a donor of nitric oxide, induces immediate headache in humans that in migraineurs is followed by a delayed migraine attack. In order to achieve increased knowledge of mechanisms activated during GTN-infusion this present study aims to investigate transcriptional responses to GTN-infusion in the rat trigeminal ganglia. Methods Rats were infused with GTN or vehicle and trigeminal ganglia were isolated either 30 or 90 minutes post infusion. RNA sequencing was used to investigate transcriptomic changes in response to the treatment. Furthermore, we developed a novel method for Gene Set Analysis Of Variance (GSANOVA) to identify gene sets associated with transcriptional changes across time. Results 15 genes displayed significant changes in transcription levels in response to GTN-infusion. Ten of these genes showed either sustained up- or down-regulation in the 90-minute period after infusion. The GSANOVA analysis demonstrate enrichment of pathways pointing towards an increase in immune response, signal transduction, and neuroplasticity in response to GTN-infusion. Future functional in-depth studies of these mechanisms are expected to increase our understanding of migraine pathogenesis.