The Patterns of Natural Variation in Human Genes

Crawford, Dana C.; Akey, Dayna T.; Nickerson, Deborah A.

doi:10.1146/annurev.genom.6.080604.162309

Cited by 115 publications

(87 citation statements)

References 121 publications

(118 reference statements)

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“…Dose variance explained by VKORC1 and CYP2C9 was 25% and 9%, respectively, confirming and refining previous estimates. 10,19 Genotype imputation using data from the European HapMap (CEPH European) SNPs and additional variants from approximately 1000 selected candidate genes 26,27 expanded our tests of association in the index population to more than 3 million SNPs across the human genome. However, no significant SNPs outside of those previously described gave robust signals for association.…”

Section: Replication Resultsmentioning

confidence: 99%

“…In addition, we implemented the imputation methods using resequencing data from both the Seattle SNPs (n ϭ 303 genes; pga.gs.washington.edu) and the Environmental Genome Project (n ϭ 613 genes). 26,27 These resequencing efforts focused on candidate genes from inflammatory, clotting, vitamin K, and environmental response pathways (http://gvs.gs.washington.edu/GVS/).…”

Section: Discussionmentioning

confidence: 99%

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A genome-wide scan for common genetic variants with a large influence on warfarin maintenance dose

Cooper

Johnson

Langaee³

et al. 2008

Blood

410

302

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Warfarin dosing is correlated with polymorphisms in vitamin K epoxide reductase complex 1 (VKORC1) and the cytochrome P450 2C9 (CYP2C9) genes. Recently, the FDA revised warfarin labeling to raise physician awareness about these genetic effects. Randomized clinical trials are underway to test genetically based dosing algorithms. It is thus important to determine whether common single nucleotide polymorphisms (SNPs) in other gene(s) have a large effect on warfarin dosing. A retrospective genome-wide association study was designed to identify polymorphisms that could explain a large fraction of the dose variance. White patients from an index warfarin population (n ‫؍‬ 181) and 2 independent replication patient populations (n ‫؍‬ 374) were studied. From the approximately 550 000 polymorphisms tested, the most significant independent effect was associated with VKORC1 polymorphisms (P ‫؍‬ 6.2 ؋ 10 ؊13 ) in the index patients. CYP2C9 (rs1057910 CYP2C9*3) and rs4917639) was associated with dose at moderate significance levels (P ϳ 10 ؊4 ). Replication polymorphisms (355 SNPs) from the index study did not show any significant effects in the replication patient sets. We conclude that common SNPs with large effects on warfarin dose are unlikely to be discovered outside of the CYP2C9 and VKORC1 genes. Randomized clinical trials that account for these 2 genes should therefore produce results that are definitive and broadly applicable. IntroductionThe determination of safe yet effective doses of warfarin for individual patients is one of the most promising clinical applications of pharmacogenetics. [1][2][3] There are large variation in warfarin dose from patient to patient and significant clinical consequences of doses that produce insufficient or excessive pharmacologic effects. Thus, reducing uncertainty in establishing the therapeutic dose in individual patients could improve quality of care as well as expand the range of patients who could be treated. 4 In white patients, genetic factors are more strongly correlated with stabilized warfarin dose than all other known patient-related factors. Warfarin pharmacokinetics are affected by functional polymorphisms (*2, Arg144Cys; *3, Ile359Leu) in cytochrome P450 2C9 (CYP2C9). 5,6 In addition, warfarin's effects are modulated by polymorphisms (eg, Ϫ1639, rs9923231) in the vitamin K epoxide reductase complex 1 (VKORC1) enzyme, a critical component of the vitamin K cycle discovered in part because of its contribution to bleeding disorders and warfarin resistance. 7,8 Both VKORC1 and CYP2C9 polymorphisms independently correlate with warfarin dose 9,10 and other clinical outcomes such as time to stabilized dose, bleeding events, and time within the target therapeutic range. [11][12][13] Combined polymorphisms in VKORC1 and CYP2C9 explain approximately 30% (20%-25% for VKORC1; 5%-10% for CYP2C9) of the variance in the stabilized warfarin dose distribution. 10,14,15 The importance of these strong genetic effects was recognized by recent relabeling of warfarin by the FDA to raise awar...

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Section: Replication Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A genome-wide scan for common genetic variants with a large influence on warfarin maintenance dose

Cooper

Johnson

Langaee³

et al. 2008

Blood

410

302

View full text Add to dashboard Cite

show abstract

“…Five tag single nucleotide polymorphisms (SNPs) were selected based on variation data for 23 European Americans and 24 African Americans resequenced by Seattle SNPs (pga.gs.washington.edu) (21,30) using LDSelect at default settings (r 2 Ͼ 0.64): rs1417938, rs1205, rs2808630, rs3093058, and rs3093066. We also selected rs1800947 given previous reports of its association with decreased CRP levels.…”

Section: Crp Polymorphism Genotypingmentioning

confidence: 99%

CRP Polymorphisms and Progression of Chronic Kidney Disease in African Americans

Hung

Crawford

Griffin

et al. 2010

Clinical Journal of the American Society of Nephrology

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Results: The MAF was higher for the rs2808630_G allele (P ‫؍‬ 0.03) and lower for the rs1205_A allele (P ‫؍‬ 0.03) in the AASK compared with NHANES III. Among AASK participants, the rs3093058_T allele predicted higher CRP concentrations (P < 0.0001) but not CKD progression. The rs2808630_GG genotype was associated with higher risk of the composite endpoint compared with the AA genotype (P ‫؍‬ 0.002). Participants with the rs2808630_GG genotype on angiotensin converting enzyme inhibitors (ACEIs) versus ␤ blockers had increased risk of progression (P ‫؍‬ 0.03).Conclusion: CRP SNPs that were associated with higher levels of CRP did not predict CKD progression. The rs2808630_GG genotype was associated with higher risk of CKD progression, and in patients with this genotype, ACEIs did not slow progression.

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“…Many SNPs in introns are thought to be non-functional (Crawford et al, 2005;Buchanan et al, 2012). Meanwhile, increasing research is revealing that polymorphisms located in introns could influence gene expression by altering splice sites, disrupting a transcription factor-binding site, or a binding site for modified histone proteins (Aklillu et al, 2003;von Ahsen and Oellerich, 2004;Skarratt et al, 2005;Warnecke et al, 2005;Bu et al, 2006;Szafranski et al, 2007;Wang et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

An SduI polymorphism at intron 20 of the Chinese Holstein cow STAT4 gene and its effect on milk performance traits

Song

Zhang²,

Jiang³

et al. 2013

Genet. Mol. Res.

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ABSTRACT. The signal transducer and activator of transcription (STAT) genes are responsive to a wide range of cytokines, growth factors, and hormones, and thus control important biological processes. In humans, STAT4 mutations have been identified as genetic markers for rheumatoid arthritis, systemic lupus erythematosus, and primary Sjögren's syndrome, whereas little research has been conducted on bovine STAT4 mutations and their potential effects. Herein, 585 Chinese Holstein cows were used to investigate STAT4 mutations and their effects on milk performance traits. One haplotype block, containing g.95879G>A, g.96013G>C, was identified in intron 20 of the bovine STAT4 gene by restriction fragment length polymorphism-polymerase chain reaction and DNA sequencing. Two single nucleotide polymorphisms were significantly associated with milk yield at 305 days (P < 0.05), and with protein percentage (P < 0.05). Chinese Holstein cows with the haplotype GGGG had higher milk yields at 305 days and lower protein percentages. These results suggest that the 2 single nucleotide polymorphisms of STAT4 could be used as genetic markers for milk performance traits in Chinese Holstein cows.

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The Patterns of Natural Variation in Human Genes

Cited by 115 publications

References 121 publications

A genome-wide scan for common genetic variants with a large influence on warfarin maintenance dose

A genome-wide scan for common genetic variants with a large influence on warfarin maintenance dose

CRP Polymorphisms and Progression of Chronic Kidney Disease in African Americans

An SduI polymorphism at intron 20 of the Chinese Holstein cow STAT4 gene and its effect on milk performance traits

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