Filtering for Genomic Nonsense to Find Biological Significance: SLC13A1 Nonsense Variants Enriched in Founder Population are Associated with Reduced Serum Sulfate and Increased Aspartate Aminotransferase Levels. C. G. Perry, J. A. Perry, J. R. O'Connell, L. M. Yerges-Armstrong, A. R. Shuldiner University of Maryland School of Medicine, Baltimore, MD.

   Inorganic sulfate (SO42-) is an important micronutrient vital for numerous cellular and metabolic processes in human development. Sulfate participates in the biotransformation of multiple compounds via sulfate conjugation (sulfation) mediated by sulfotransferases. Decreased sulfation capacity due to inadequate levels of circulating sulfate alters metabolism and activities of a variety of endogenous compounds and reduces detoxification, increasing toxicity to xenobiotics and some drugs. Additionally, impaired sulfation capacity is associated with autism, neurological diseases, skeletal dysplasias, and premature pubarche; yet little is known about sulfate regulation in humans. Using genomic applications to glean insights into human biology, we systematically identified nonsense, single nucleotide polymorphisms (SNPs) that are rare in the general population but enriched in the Old Order Amish due to a founder effect. Filters and bioinformatics tools were applied to Illumina Human Exome BeadChip data obtained from 1648 Amish subjects. Two non-linked, nonsense SNPs (c.34C>T, p.R12X and c.144G>A, p.W48X) in SLC13A1, which encodes a sulfate transporter responsible for sulfate (re)absorption in the kidneys and intestine, were discovered to be enriched in this Amish cohort compared to outbred populations (1.9-fold (0.49% vs. 0.26%) and 7.2-fold (0.94% vs. 0.13%), respectively, compared to 1000 Genomes European ancestry allele frequencies). Fasting serum sulfate concentration was measured in 175 individuals recruited by genotype. Both R12X and W48X SNPs were significantly associated with a 27-31% decrease in serum sulfate levels (P=2.0x10-5 and P=6.2x10-7, respectively; P=4.3x10-19 for both SNPs combined). We also queried the Amish Disease Research database in a hypothesis-free, phenome-wide association study (PheWAS) manner to identify novel associations with SLC13A1 nonsense SNPs. We observed a PheWAS significant association between SLC13A1 nonsense genotype carriers (R12X or W48X) and a 50% increase in aspartate aminotransferase (AST) levels (P=2.0x10-6). All association studies adjusted for age, age2, sex and relatedness. The increase in AST levels is consistent with low-grade liver damage, possibly due to decreased sulfate levels and an inability to detoxify xenobiotics. Additional studies are warranted to better understand the importance of sulfate in human physiology and its potential role in disease and drug toxicity.

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