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Association analysis of the SLC22A11 (organic anion transporter 4) and SLC22A12 (urate transporter 1) urate transporter locus with gout in New Zealand case-control sample sets reveals multiple ancestral-specific effects.
Arthritis Res Ther. 2013; 15(6):R220.AR

Abstract

INTRODUCTION

There is inconsistent association between urate transporters SLC22A11 (organic anion transporter 4 (OAT4)) and SLC22A12 (urate transporter 1 (URAT1)) and risk of gout. New Zealand (NZ) Māori and Pacific Island people have higher serum urate and more severe gout than European people. The aim of this study was to test genetic variation across the SLC22A11/SLC22A12 locus for association with risk of gout in NZ sample sets.

METHODS

A total of 12 single nucleotide polymorphism (SNP) variants in four haplotype blocks were genotyped using TaqMan® and Sequenom MassArray in 1003 gout cases and 1156 controls. All cases had gout according to the 1977 American Rheumatism Association criteria. Association analysis of single markers and haplotypes was performed using PLINK and Stata.

RESULTS

A haplotype block 1 SNP (rs17299124) (upstream of SLC22A11) was associated with gout in less admixed Polynesian sample sets, but not European Caucasian (odds ratio; OR = 3.38, P = 6.1 × 10-4; OR = 0.91, P = 0.40, respectively) sample sets. A protective block 1 haplotype caused the rs17299124 association (OR = 0.28, P = 6.0 × 10-4). Within haplotype block 2 (SLC22A11) we could not replicate previous reports of association of rs2078267 with gout in European Caucasian (OR = 0.98, P = 0.82) sample sets, however this SNP was associated with gout in Polynesian (OR = 1.51, P = 0.022) sample sets. Within haplotype block 3 (including SLC22A12) analysis of haplotypes revealed a haplotype with trans-ancestral protective effects (OR = 0.80, P = 0.004), and a second haplotype conferring protection in less admixed Polynesian sample sets (OR = 0.63, P = 0.028) but risk in European Caucasian samples (OR = 1.33, P = 0.039).

CONCLUSIONS

Our analysis provides evidence for multiple ancestral-specific effects across the SLC22A11/SLC22A12 locus that presumably influence the activity of OAT4 and URAT1 and risk of gout. Further fine mapping of the association signal is needed using trans-ancestral re-sequence data.

Links

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Authors

Flynn TJ
No affiliation info available
Phipps-Green A
No affiliation info available
Hollis-Moffatt JE
No affiliation info available
Merriman ME
No affiliation info available
Topless R
No affiliation info available
Montgomery G
No affiliation info available
Chapman B
No affiliation info available
Stamp LK
No affiliation info available
Dalbeth N
No affiliation info available
Merriman TR
No affiliation info available

MeSH

AdultCase-Control StudiesFemaleGenetic LociGenetic Predisposition to DiseaseGenome-Wide Association StudyGoutHaplotypesHumansMaleMiddle AgedNew ZealandOligonucleotide Array Sequence AnalysisOrganic Anion TransportersOrganic Anion Transporters, Sodium-IndependentOrganic Cation Transport ProteinsPolymorphism, Single Nucleotide

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24360580

Citation

Flynn, Tanya J., et al. "Association Analysis of the SLC22A11 (organic Anion Transporter 4) and SLC22A12 (urate Transporter 1) Urate Transporter Locus With Gout in New Zealand Case-control Sample Sets Reveals Multiple Ancestral-specific Effects." Arthritis Research & Therapy, vol. 15, no. 6, 2013, pp. R220.
Flynn TJ, Phipps-Green A, Hollis-Moffatt JE, et al. Association analysis of the SLC22A11 (organic anion transporter 4) and SLC22A12 (urate transporter 1) urate transporter locus with gout in New Zealand case-control sample sets reveals multiple ancestral-specific effects. Arthritis Res Ther. 2013;15(6):R220.
Flynn, T. J., Phipps-Green, A., Hollis-Moffatt, J. E., Merriman, M. E., Topless, R., Montgomery, G., Chapman, B., Stamp, L. K., Dalbeth, N., & Merriman, T. R. (2013). Association analysis of the SLC22A11 (organic anion transporter 4) and SLC22A12 (urate transporter 1) urate transporter locus with gout in New Zealand case-control sample sets reveals multiple ancestral-specific effects. Arthritis Research & Therapy, 15(6), R220.
Flynn TJ, et al. Association Analysis of the SLC22A11 (organic Anion Transporter 4) and SLC22A12 (urate Transporter 1) Urate Transporter Locus With Gout in New Zealand Case-control Sample Sets Reveals Multiple Ancestral-specific Effects. Arthritis Res Ther. 2013;15(6):R220. PubMed PMID: 24360580.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Association analysis of the SLC22A11 (organic anion transporter 4) and SLC22A12 (urate transporter 1) urate transporter locus with gout in New Zealand case-control sample sets reveals multiple ancestral-specific effects. AU - Flynn,Tanya J, AU - Phipps-Green,Amanda, AU - Hollis-Moffatt,Jade E, AU - Merriman,Marilyn E, AU - Topless,Ruth, AU - Montgomery,Grant, AU - Chapman,Brett, AU - Stamp,Lisa K, AU - Dalbeth,Nicola, AU - Merriman,Tony R, PY - 2013/07/05/received PY - 2013/12/12/accepted PY - 2013/12/24/entrez PY - 2013/12/24/pubmed PY - 2014/11/5/medline SP - R220 EP - R220 JF - Arthritis research & therapy JO - Arthritis Res Ther VL - 15 IS - 6 N2 - INTRODUCTION: There is inconsistent association between urate transporters SLC22A11 (organic anion transporter 4 (OAT4)) and SLC22A12 (urate transporter 1 (URAT1)) and risk of gout. New Zealand (NZ) Māori and Pacific Island people have higher serum urate and more severe gout than European people. The aim of this study was to test genetic variation across the SLC22A11/SLC22A12 locus for association with risk of gout in NZ sample sets. METHODS: A total of 12 single nucleotide polymorphism (SNP) variants in four haplotype blocks were genotyped using TaqMan® and Sequenom MassArray in 1003 gout cases and 1156 controls. All cases had gout according to the 1977 American Rheumatism Association criteria. Association analysis of single markers and haplotypes was performed using PLINK and Stata. RESULTS: A haplotype block 1 SNP (rs17299124) (upstream of SLC22A11) was associated with gout in less admixed Polynesian sample sets, but not European Caucasian (odds ratio; OR = 3.38, P = 6.1 × 10-4; OR = 0.91, P = 0.40, respectively) sample sets. A protective block 1 haplotype caused the rs17299124 association (OR = 0.28, P = 6.0 × 10-4). Within haplotype block 2 (SLC22A11) we could not replicate previous reports of association of rs2078267 with gout in European Caucasian (OR = 0.98, P = 0.82) sample sets, however this SNP was associated with gout in Polynesian (OR = 1.51, P = 0.022) sample sets. Within haplotype block 3 (including SLC22A12) analysis of haplotypes revealed a haplotype with trans-ancestral protective effects (OR = 0.80, P = 0.004), and a second haplotype conferring protection in less admixed Polynesian sample sets (OR = 0.63, P = 0.028) but risk in European Caucasian samples (OR = 1.33, P = 0.039). CONCLUSIONS: Our analysis provides evidence for multiple ancestral-specific effects across the SLC22A11/SLC22A12 locus that presumably influence the activity of OAT4 and URAT1 and risk of gout. Further fine mapping of the association signal is needed using trans-ancestral re-sequence data. SN - 1478-6362 UR - https://www.unboundmedicine.com/medline/citation/24360580/Association_analysis_of_the_SLC22A11__organic_anion_transporter_4__and_SLC22A12__urate_transporter_1__urate_transporter_locus_with_gout_in_New_Zealand_case_control_sample_sets_reveals_multiple_ancestral_specific_effects_ DB - PRIME DP - Unbound Medicine ER -