ARD Online First, published on February 9, 2015 as 10.1136/annrheumdis-2014-206534 Clinical and epidemiological research
CONCISE REPORT
Lack of gene–diuretic interactions on the risk of incident gout: the Nurses’ Health Study and Health Professionals Follow-up Study Ying Bao,1 Gary Curhan,1,2 Tony Merriman,3 Robert Plenge,2 Peter Kraft,4 Hyon K Choi1,5 Handling editor Tore K Kvien ▸ Additional material is published online only. To view please visit the journal online (http://dx.doi.org/10.1136/ annrheumdis-2014-206534). For numbered affiliations see end of article. Correspondence to Dr Hyon K Choi, Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Bulfinch 165, Boston, MA 02114, USA; [email protected] Received 25 August 2014 Revised 14 January 2015 Accepted 15 January 2015
ABSTRACT Background Diuretic-induced gout might occur only among those with a genetic predisposition to hyperuricaemia, as suggested by a recent study with 108 self-reported gout cases. Methods We examined the role of urate genes on the risk of diuretic-induced incident gout in 6850 women from the Nurses’ Health Study (NHS) and in 4223 men from the Health Professionals Follow-up Study (HPFS). Two published genetic risk scores (GRSs) were calculated using urate-associated single-nucleotide polymorphisms for 8 (GRS8) and 29 genes (GRS29). Results Our analyses included 727 and 354 confirmed incident gout cases in HPFS and NHS, respectively. The multivariate relative risk (RR) for diuretic use was 2.20 and 1.69 among those with GRS8 < and ≥ the median ( p for interaction=0.27). The corresponding RRs using GRS29 were 2.19 and 1.88 ( p for interaction=0.40). The lack of interaction persisted in NHS (all p values >0.20) and in our analyses limited to those with hypertension in both cohorts. SLC22A11 (OAT4) showed a significant interaction only among women but in the opposite direction to the recent study. Conclusions In these large prospective studies, individuals with a genetic predisposition for hyperuricaemia are not at a higher risk of developing diuretic-induced gout than those without.
INTRODUCTION
To cite: Bao Y, Curhan G, Merriman T, et al. Ann Rheum Dis Published Online First: [ please include Day Month Year] doi:10.1136/ annrheumdis-2014-206534
Gout is a common and excruciatingly painful inflammatory arthritis caused by hyperuricaemia. In addition to various environmental risk factors for gout, substantial genetic predisposition has also been recognised.1 The majority of the eight genes discovered by the initial genome-wide association studies (GWAS) are involved in the renal uratetransport system.1–3 In 2013, the Global Urate Genetics Consortium identified and replicated 20 additional genome-wide significant loci in association with serum urate concentrations.4 Diuretics, particularly thiazide and loop diuretics, increase the risk of incident gout,5 6 likely through urate transporters (eg, OAT4)3 and volume depletion promoting urate reabsorption.7 If diuretic use differentially affects the risk of gout according to a certain genetic predisposition for hyperuricaemia, such genes could be used to predict gout risk in relation to diuretic use. Indeed, a recent analysis based on the Atherosclerosis Risk in Communities (ARIC) study (with 108 self-reported incident cases
of gout) reported that diuretic-induced gout occurs only among those with a genetic predisposition to hyperuricaemia.3 To our knowledge, no study has replicated or refuted these findings. To examine these issues with a large number of confirmed cases of incident gout (N=1081), we analysed GWAS data obtained from participants in the Nurses’ Health Study (NHS) and the Health Professionals Follow-up Study (HPFS).
PARTICIPANTS AND METHODS Study population As described previously in detail,8 9 NHS and HPFS are prospective cohorts of women and men, respectively, who have been administered the validated food frequency questionnaire (FFQ) every four years, as well as biennial questionnaires for new disease diagnoses and drug use (including diuretics). The current analysis included 6850 and 4223 initially healthy women and men, respectively, of European ancestry for whom genotype data based on GWAS were available10 and who were gout-free at baseline.
Assessment of incident gout cases, diuretic use and covariates We ascertained incident gout cases using the American College of Rheumatology (ACR) gout survey criteria, as described previously.8 9 In NHS, diuretic use (ie, thiazides and loop diuretics) was determined in 1980, 1982, 1988, 1994 and every two years thereafter. In HPFS, diuretic use was determined in 1986 and every two years thereafter. Baseline and biennial follow-up questionnaires inquired about physician-diagnosed hypertension. A participant was considered to have hypertension from the time first reported on the questionnaire. Dietary covariates were obtained via validated FFQs. Information on non-dietary factors (eg, medication or supplement use, medical conditions, menopausal status and postmenopausal hormone use) was assessed every two to four years.6 8 9 11–15
Genotyping and genetic risk score We selected single-nucleotide polymorphisms (SNPs) known to be associated with serum urate levels. Two sets of genetic risk scores (GRSs) were calculated as published previously; one based on 8 SNPs2 (GRS8, used by the ARIC study above3) and the other based on 29 SNPs (GRS29, a new score incorporating additional novel genes4)
Bao Y, et al. Ann Rheum Dis 2015;0:1–5. doi:10.1136/annrheumdis-2014-206534
1
Copyright Article author (or their employer) 2015. Produced by BMJ Publishing Group Ltd (& EULAR) under licence.
2
(4.3) (21.5) (10.5) (0.6) (0.7) (0.2) (1.0) (1.3)
47.9 (6.7) 123.7 (14.6) 78.9 (7.7) 16.4 24.1 (4.1) 13.5 (15.9) 6.7 (10.3) 0.2 (0.5) 1.1 (0.8) 0.2 (0.2) 0.9 (1.0) 1.4 (1.3) 9.7 (6.6) (14.1) (7.4)
48.1 123.5 78.4 14.5 24.3 15.2 6.8 0.3 1.1 0.2 1.0 1.4 9.6 (3.0) (25.7) (16.1) (0.5) (0.9) (0.3) (1.0) (1.3) (3.0) (26.1) (16.5) (0.5) (0.9) (0.3) (1.0) (1.4)
Values are age-adjusted (except for age). BMI, body mass index; HPFS, Health Professionals Follow-up Study; MET, metabolic equivalent of task; NHS, Nurses’ Health Study; SNP, single-nucleotide polymorphism.
(4.3) (21.7) (10.8) (0.6) (0.8) (0.2) (1.0) (1.3)
47.9 (6.7) 123.8 (14.5) 78.9 (7.7) 16.7 24.2 (4.0) 13.5 (15.9) 6.6 (10.0) 0.2 (0.5) 1.1 (0.8) 0.2 (0.2) 0.9 (1.0) 1.4 (1.4) 9.6 (6.6) (14.1) (7.3)
CONCISE REPORT
Lack of gene–diuretic interactions on the risk of incident gout: the Nurses’ Health Study and Health Professionals Follow-up Study Ying Bao,1 Gary Curhan,1,2 Tony Merriman,3 Robert Plenge,2 Peter Kraft,4 Hyon K Choi1,5 Handling editor Tore K Kvien ▸ Additional material is published online only. To view please visit the journal online (http://dx.doi.org/10.1136/ annrheumdis-2014-206534). For numbered affiliations see end of article. Correspondence to Dr Hyon K Choi, Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Bulfinch 165, Boston, MA 02114, USA; [email protected] Received 25 August 2014 Revised 14 January 2015 Accepted 15 January 2015
ABSTRACT Background Diuretic-induced gout might occur only among those with a genetic predisposition to hyperuricaemia, as suggested by a recent study with 108 self-reported gout cases. Methods We examined the role of urate genes on the risk of diuretic-induced incident gout in 6850 women from the Nurses’ Health Study (NHS) and in 4223 men from the Health Professionals Follow-up Study (HPFS). Two published genetic risk scores (GRSs) were calculated using urate-associated single-nucleotide polymorphisms for 8 (GRS8) and 29 genes (GRS29). Results Our analyses included 727 and 354 confirmed incident gout cases in HPFS and NHS, respectively. The multivariate relative risk (RR) for diuretic use was 2.20 and 1.69 among those with GRS8 < and ≥ the median ( p for interaction=0.27). The corresponding RRs using GRS29 were 2.19 and 1.88 ( p for interaction=0.40). The lack of interaction persisted in NHS (all p values >0.20) and in our analyses limited to those with hypertension in both cohorts. SLC22A11 (OAT4) showed a significant interaction only among women but in the opposite direction to the recent study. Conclusions In these large prospective studies, individuals with a genetic predisposition for hyperuricaemia are not at a higher risk of developing diuretic-induced gout than those without.
INTRODUCTION
To cite: Bao Y, Curhan G, Merriman T, et al. Ann Rheum Dis Published Online First: [ please include Day Month Year] doi:10.1136/ annrheumdis-2014-206534
Gout is a common and excruciatingly painful inflammatory arthritis caused by hyperuricaemia. In addition to various environmental risk factors for gout, substantial genetic predisposition has also been recognised.1 The majority of the eight genes discovered by the initial genome-wide association studies (GWAS) are involved in the renal uratetransport system.1–3 In 2013, the Global Urate Genetics Consortium identified and replicated 20 additional genome-wide significant loci in association with serum urate concentrations.4 Diuretics, particularly thiazide and loop diuretics, increase the risk of incident gout,5 6 likely through urate transporters (eg, OAT4)3 and volume depletion promoting urate reabsorption.7 If diuretic use differentially affects the risk of gout according to a certain genetic predisposition for hyperuricaemia, such genes could be used to predict gout risk in relation to diuretic use. Indeed, a recent analysis based on the Atherosclerosis Risk in Communities (ARIC) study (with 108 self-reported incident cases
of gout) reported that diuretic-induced gout occurs only among those with a genetic predisposition to hyperuricaemia.3 To our knowledge, no study has replicated or refuted these findings. To examine these issues with a large number of confirmed cases of incident gout (N=1081), we analysed GWAS data obtained from participants in the Nurses’ Health Study (NHS) and the Health Professionals Follow-up Study (HPFS).
PARTICIPANTS AND METHODS Study population As described previously in detail,8 9 NHS and HPFS are prospective cohorts of women and men, respectively, who have been administered the validated food frequency questionnaire (FFQ) every four years, as well as biennial questionnaires for new disease diagnoses and drug use (including diuretics). The current analysis included 6850 and 4223 initially healthy women and men, respectively, of European ancestry for whom genotype data based on GWAS were available10 and who were gout-free at baseline.
Assessment of incident gout cases, diuretic use and covariates We ascertained incident gout cases using the American College of Rheumatology (ACR) gout survey criteria, as described previously.8 9 In NHS, diuretic use (ie, thiazides and loop diuretics) was determined in 1980, 1982, 1988, 1994 and every two years thereafter. In HPFS, diuretic use was determined in 1986 and every two years thereafter. Baseline and biennial follow-up questionnaires inquired about physician-diagnosed hypertension. A participant was considered to have hypertension from the time first reported on the questionnaire. Dietary covariates were obtained via validated FFQs. Information on non-dietary factors (eg, medication or supplement use, medical conditions, menopausal status and postmenopausal hormone use) was assessed every two to four years.6 8 9 11–15
Genotyping and genetic risk score We selected single-nucleotide polymorphisms (SNPs) known to be associated with serum urate levels. Two sets of genetic risk scores (GRSs) were calculated as published previously; one based on 8 SNPs2 (GRS8, used by the ARIC study above3) and the other based on 29 SNPs (GRS29, a new score incorporating additional novel genes4)
Bao Y, et al. Ann Rheum Dis 2015;0:1–5. doi:10.1136/annrheumdis-2014-206534
1
Copyright Article author (or their employer) 2015. Produced by BMJ Publishing Group Ltd (& EULAR) under licence.
2
(4.3) (21.5) (10.5) (0.6) (0.7) (0.2) (1.0) (1.3)
47.9 (6.7) 123.7 (14.6) 78.9 (7.7) 16.4 24.1 (4.1) 13.5 (15.9) 6.7 (10.3) 0.2 (0.5) 1.1 (0.8) 0.2 (0.2) 0.9 (1.0) 1.4 (1.3) 9.7 (6.6) (14.1) (7.4)
48.1 123.5 78.4 14.5 24.3 15.2 6.8 0.3 1.1 0.2 1.0 1.4 9.6 (3.0) (25.7) (16.1) (0.5) (0.9) (0.3) (1.0) (1.3) (3.0) (26.1) (16.5) (0.5) (0.9) (0.3) (1.0) (1.4)
Values are age-adjusted (except for age). BMI, body mass index; HPFS, Health Professionals Follow-up Study; MET, metabolic equivalent of task; NHS, Nurses’ Health Study; SNP, single-nucleotide polymorphism.
(4.3) (21.7) (10.8) (0.6) (0.8) (0.2) (1.0) (1.3)
47.9 (6.7) 123.8 (14.5) 78.9 (7.7) 16.7 24.2 (4.0) 13.5 (15.9) 6.6 (10.0) 0.2 (0.5) 1.1 (0.8) 0.2 (0.2) 0.9 (1.0) 1.4 (1.4) 9.6 (6.6) (14.1) (7.3)
