ICCFGG 2022
#13 QTL analysis of a uremic toxin indicates the xanthine dehydrogenase gene may be a risk factor for chronic kidney disease in cats. Jeffrey Brockman 1 ,Regina Hollar 1 , Eden Ephraim Gebreselassie 1 , Leslie A. Lyons 2 jeff_brockman@hillspet.com 1 Hill’s Pet Nutrition, 2 University of Missouri, USA Chronic kidney disease (CKD) is a common affliction of aging cats with a prevalence rate of 2-4% in all cats and 30-40% in cats greater than 10 years of age. We have recently observed that N-methyl- 2-pyridone-5-carboxamide (2PY), the end product of nicotinic acid metabolism, and a known uremic toxin in humans, is elevated greater than 3-fold (p < 3.88E-26) on average in the serum of cats with CKD compared with controls. N-methyl-2-pyridone-5-carboxamide exacerbates kidney damage through its inhibition of poly ADP-ribose polymerase 1 (PARP-1), which detects DNA damage and initiates DNA repair mechanisms in tissues. Using QTL analysis on serum 2PY levels in a cohort of 780 cats, we have identified two independent SNPs that result in amino acid changes in the xanthine dehydrogenase (XDH) gene. The presence of both variants results in elevated serum 2PY levels. 1-methyl-Nicotinamide is metabolized to 2PY by the enzyme aldehyde oxidase, which is encoded by the gene aldehyde oxidase 1 (AOX1), and is expressed mainly in the liver. The protein encoded by XDH, expressed mainly in the gut, forms a dimer that has both a dehydrogenase and an aldehyde oxidase active site. Both amino acids that we identified as variants in the cat XDH gene lie in or next to the aldehyde oxidase active site of the xanthine dehydrogenase protein. Both of the SNPs have been validated as exceeding genome wide significance in a QTL analysis of serum 2PY levels in an independent cohort of 430 cats. Our goal is to reduce uremic toxins and slow the progression of chronic kidney disease in cats through improved nutrition. In a study evaluating the effect of a prebiotic blend on uremic toxins in cats with chronic renal disease, we see a 40% reduction in their serum 2PY levels when fed the therapeutic food.
#14 Dog10K: A public canid genomics resource to advance demographic and functional studies
Jennifer Meadows 1,2 jennifer.meadows@imbim.uu.se 1 Uppsala University, Sweden; 2 Dog10K consortium
Phase I of the Dog10K project marks the release and analysis of >30M single nucleotide- and structural variants from 1929 individuals; 1591 mixed and breed dogs, 281 village dogs and 57 wolves. The variant set spans the autosomes, X chromosome and mitochondria. Estimates using autosomal SNVs revealed that for 239/259 breeds (N‚â•3), >75% of within breed variation has been discovered. Observed variation reflects the sharp reduction in genetic diversity associated with domestication and breed formation. Mixed and breed dogs were the major class in this dataset, but accounted for only 15.3% of private alleles, followed by wolves (14.7%) and village dogs (11.8%). Runs of homozygosity analyses reflected fine pattens patterns of population history, while Ohana- based selection scans detected signatures specific to ancestry components. Assigning function to variants showed that 43% of Dog10K variation was novel to this catalogue, but of these, 98% were rare (allele frequency <1%). As expected, genetic variation was not evenly spread along the
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