%0 Journal Article %J Pharmacogenet Genomics %D 2011 %T Cerivastatin, genetic variants, and the risk of rhabdomyolysis. %A Marciante, Kristin D %A Durda, Jon P %A Heckbert, Susan R %A Lumley, Thomas %A Rice, Ken %A McKnight, Barbara %A Totah, Rheem A %A Tamraz, Bani %A Kroetz, Deanna L %A Fukushima, Hisayo %A Kaspera, Rüdiger %A Bis, Joshua C %A Glazer, Nicole L %A Li, Guo %A Austin, Thomas R %A Taylor, Kent D %A Rotter, Jerome I %A Jaquish, Cashell E %A Kwok, Pui-Yan %A Tracy, Russell P %A Psaty, Bruce M %K Adult %K Aged %K Aged, 80 and over %K Aryl Hydrocarbon Hydroxylases %K Case-Control Studies %K Cytochrome P-450 CYP2C8 %K Female %K Genetic Variation %K Genome-Wide Association Study %K Glucuronosyltransferase %K Humans %K Hydroxymethylglutaryl-CoA Reductase Inhibitors %K Male %K Middle Aged %K Organic Anion Transporters %K Polymorphism, Single Nucleotide %K Pyridines %K Rhabdomyolysis %K Risk %K Ryanodine Receptor Calcium Release Channel %K Solute Carrier Organic Anion Transporter Family Member 1b1 %X

OBJECTIVE: The withdrawal of cerivastatin involved an uncommon but serious adverse reaction, rhabdomyolysis. The bimodal response, rhabdomyolysis in a small proportion of users, points to genetic factors as a potential cause. We conducted a case-control study to evaluate genetic markers for cerivastatin-associated rhabdomyolysis.

METHODS: This study had two components: a candidate gene study to evaluate variants in CYP2C8, UGT1A1, UGT1A3, and SLCO1B1; and a genome-wide association study to identify risk factors in other regions of the genome. A total of 185 rhabdomyolysis cases were frequency matched to statin-using controls from the Cardiovascular Health Study (n=374) and the Heart and Vascular Health Study (n=358). Validation relied on functional studies.

RESULTS: Permutation test results suggested an association between cerivastatin-associated rhabdomyolysis and variants in SLCO1B1 (P=0.002), but not variants in CYP2C8 (P=0.073) or UGTs (P=0.523). An additional copy of the minor allele of SLCO1B1 rs4149056 (p.Val174Ala) was associated with the risk of rhabdomyolysis (odds ratio: 1.89; 95% confidence interval: 1.40-2.56). In transfected cells, this variant reduced cerivastatin transport by 40% compared with the reference transporter (P<0.001). The genome-wide association study identified an intronic variant (rs2819742) in the ryanodine receptor 2 gene (RYR2) as significant (P=1.74E-07). An additional copy of the minor allele of the RYR2 variant was associated with a reduced risk of rhabdomyolysis (odds ratio: 0.48; 95% confidence interval: 0.36-0.63).

CONCLUSION: We identified modest genetic risk factors for an extreme response to cerivastatin. Disabling genetic variants in the candidate genes were not responsible for the bimodal response to cerivastatin.

%B Pharmacogenet Genomics %V 21 %P 280-8 %8 2011 May %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/21386754?dopt=Abstract %R 10.1097/FPC.0b013e328343dd7d %0 Journal Article %J Hum Mol Genet %D 2011 %T Genome-wide association study for serum urate concentrations and gout among African Americans identifies genomic risk loci and a novel URAT1 loss-of-function allele. %A Tin, Adrienne %A Woodward, Owen M %A Kao, Wen Hong Linda %A Liu, Ching-Ti %A Lu, Xiaoning %A Nalls, Michael A %A Shriner, Daniel %A Semmo, Mariam %A Akylbekova, Ermeg L %A Wyatt, Sharon B %A Hwang, Shih-Jen %A Yang, Qiong %A Zonderman, Alan B %A Adeyemo, Adebowale A %A Palmer, Cameron %A Meng, Yan %A Reilly, Muredach %A Shlipak, Michael G %A Siscovick, David %A Evans, Michele K %A Rotimi, Charles N %A Flessner, Michael F %A Köttgen, Michael %A Cupples, L Adrienne %A Fox, Caroline S %A Köttgen, Anna %K Adult %K African Americans %K Aged %K Animals %K CHO Cells %K Cricetinae %K European Continental Ancestry Group %K Female %K Genetic Loci %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Gout %K Humans %K Loss of Heterozygosity %K Male %K Middle Aged %K Organic Anion Transporters %K Organic Cation Transport Proteins %K Polymorphism, Single Nucleotide %K Uric Acid %K Young Adult %X

Serum urate concentrations are highly heritable and elevated serum urate is a key risk factor for gout. Genome-wide association studies (GWAS) of serum urate in African American (AA) populations are lacking. We conducted a meta-analysis of GWAS of serum urate levels and gout among 5820 AA and a large candidate gene study among 6890 AA and 21 708 participants of European ancestry (EA) within the Candidate Gene Association Resource Consortium. Findings were tested for replication among 1996 independent AA individuals, and evaluated for their association among 28 283 EA participants of the CHARGE Consortium. Functional studies were conducted using (14)C-urate transport assays in mammalian Chinese hamster ovary cells. In the discovery GWAS of serum urate, three loci achieved genome-wide significance (P< 5.0 × 10(-8)): a novel locus near SGK1/SLC2A12 on chromosome 6 (rs9321453, P= 1.0 × 10(-9)), and two loci previously identified in EA participants, SLC2A9 (P= 3.8 × 10(-32)) and SLC22A12 (P= 2.1 × 10(-10)). A novel rare non-synonymous variant of large effect size in SLC22A12, rs12800450 (minor allele frequency 0.01, G65W), was identified and replicated (beta -1.19 mg/dl, P= 2.7 × 10(-16)). (14)C-urate transport assays showed reduced urate transport for the G65W URAT1 mutant. Finally, in analyses of 11 loci previously associated with serum urate in EA individuals, 10 of 11 lead single-nucleotide polymorphisms showed direction-consistent association with urate among AA. In summary, we identified and replicated one novel locus in association with serum urate levels and experimentally characterize the novel G65W variant in URAT1 as a functional allele. Our data support the importance of multi-ethnic GWAS in the identification of novel risk loci as well as functional variants.

%B Hum Mol Genet %V 20 %P 4056-68 %8 2011 Oct 15 %G eng %N 20 %1 http://www.ncbi.nlm.nih.gov/pubmed/21768215?dopt=Abstract %R 10.1093/hmg/ddr307 %0 Journal Article %J Nat Commun %D 2018 %T Large-scale whole-exome sequencing association studies identify rare functional variants influencing serum urate levels. %A Tin, Adrienne %A Li, Yong %A Brody, Jennifer A %A Nutile, Teresa %A Chu, Audrey Y %A Huffman, Jennifer E %A Yang, Qiong %A Chen, Ming-Huei %A Robinson-Cohen, Cassianne %A Mace, Aurelien %A Liu, Jun %A Demirkan, Ayse %A Sorice, Rossella %A Sedaghat, Sanaz %A Swen, Melody %A Yu, Bing %A Ghasemi, Sahar %A Teumer, Alexanda %A Vollenweider, Peter %A Ciullo, Marina %A Li, Meng %A Uitterlinden, André G %A Kraaij, Robert %A Amin, Najaf %A van Rooij, Jeroen %A Kutalik, Zoltán %A Dehghan, Abbas %A McKnight, Barbara %A van Duijn, Cornelia M %A Morrison, Alanna %A Psaty, Bruce M %A Boerwinkle, Eric %A Fox, Caroline S %A Woodward, Owen M %A Köttgen, Anna %K Exome %K Genetic Predisposition to Disease %K Glucose Transport Proteins, Facilitative %K Humans %K Kidney Function Tests %K Meta-Analysis as Topic %K Organic Anion Transporters %K Organic Cation Transport Proteins %K Protein Structure, Secondary %K Uric Acid %X

Elevated serum urate levels can cause gout, an excruciating disease with suboptimal treatment. Previous GWAS identified common variants with modest effects on serum urate. Here we report large-scale whole-exome sequencing association studies of serum urate and kidney function among ≤19,517 European ancestry and African-American individuals. We identify aggregate associations of low-frequency damaging variants in the urate transporters SLC22A12 (URAT1; p = 1.3 × 10) and SLC2A9 (p = 4.5 × 10). Gout risk in rare SLC22A12 variant carriers is halved (OR = 0.5, p = 4.9 × 10). Selected rare variants in SLC22A12 are validated in transport studies, confirming three as loss-of-function (R325W, R405C, and T467M) and illustrating the therapeutic potential of the new URAT1-blocker lesinurad. In SLC2A9, mapping of rare variants of large effects onto the predicted protein structure reveals new residues that may affect urate binding. These findings provide new insights into the genetic architecture of serum urate, and highlight molecular targets in SLC22A12 and SLC2A9 for lowering serum urate and preventing gout.

%B Nat Commun %V 9 %P 4228 %8 2018 10 12 %G eng %N 1 %R 10.1038/s41467-018-06620-4