Ruth K G Topless1, Tanya J Major1, Joanne B Cole2,3,4, Tony R Merriman5,6, Jose C Florez2,3,7, Joel N Hirschhorn2,4,8, Murray Cadzow1, Nicola Dalbeth9, Lisa K Stamp10, Philip L Wilcox11, Richard J Reynolds12. 1. Department of Biochemistry, University of Otago, Dunedin, New Zealand. 2. Programs in Metabolism and Medical & Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. 3. Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA. 4. Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, MA, USA. 5. Department of Biochemistry, University of Otago, Dunedin, New Zealand. tony.merriman@otago.ac.nz. 6. Division of Clinical Immunology and Rheumatology, University of Alabama Birmingham, Birmingham, AL, USA. tony.merriman@otago.ac.nz. 7. Department of Medicine, Harvard Medical School, Boston, MA, USA. 8. Department of Genetics, Harvard Medical School, Boston, MA, USA. 9. Department of Medicine, Faculty of Medical Sciences, University of Auckland, Auckland, New Zealand. 10. Department of Medicine, University of Otago Christchurch, Christchurch, New Zealand. 11. Department of Mathematics and Statistics, University of Otago, Dunedin, New Zealand. 12. Division of Clinical Immunology and Rheumatology, University of Alabama Birmingham, Birmingham, AL, USA.
Abstract
BACKGROUND: Prevention of hyperuricaemia (HU) is critical to the prevention of gout. Understanding causal relationships and relative contributions of various risk factors to hyperuricemia is therefore important in the prevention of gout. Here, we use attributable fraction to compare the relative contribution of genetic, dietary, urate-lowering therapy (ULT) and other exposures to HU. We use Mendelian randomisation to test for the causality of diet in urate levels. METHODS: Four European-ancestry sample sets, three from the general population (n = 419,060) and one of people with gout (n = 6781) were derived from the Database of Genotypes and Phenotypes (ARIC, FHS, CARDIA, CHS) and UK Biobank. Dichotomised exposures to diet, genetic risk variants, BMI, alcohol, diuretic treatment, sex and age were used to calculate adjusted population and average attributable fractions (PAF/AAF) for HU (≥0.42 mmol/L [≥7 mg/dL]). Exposure to ULT was also assessed in the gout cohort. Two sample Mendelian randomisation was done in the UK Biobank using dietary pattern-associated genetic variants as exposure and serum urate levels as outcome. RESULTS: Adherence to dietary recommendations, BMI (< 25 kg/m2), and absence of the SLC2A9 rs12498742 urate-raising allele produced PAFs for HU of 20 to 24%, 59 to 69%, and 57 to 64%, respectively, in the three non-gout cohorts. In the gout cohort, diet, BMI, SLC2A9 rs12498742 and ULT PAFs for HU were 12%, 49%, 48%, and 63%, respectively. Mendelian randomisation demonstrated weak causal effects of four dietary habits on serum urate levels (e.g. preferentially drinking skim milk increased urate, β = 0.047 mmol/L, P = 3.78 × 10-8). These effects were mediated by BMI, and they were not significant (P ≥ 0.06) in multivariable models assessing the BMI-independent effect of diet on urate. CONCLUSIONS: Diet has a relatively minor role in determining serum urate levels and HU. In gout, the use of ULT was the largest attributable fraction tested for HU.
BACKGROUND: Prevention of hyperuricaemia (HU) is critical to the prevention of gout. Understanding causal relationships and relative contributions of various risk factors to hyperuricemia is therefore important in the prevention of gout. Here, we use attributable fraction to compare the relative contribution of genetic, dietary, urate-lowering therapy (ULT) and other exposures to HU. We use Mendelian randomisation to test for the causality of diet in urate levels. METHODS: Four European-ancestry sample sets, three from the general population (n = 419,060) and one of people with gout (n = 6781) were derived from the Database of Genotypes and Phenotypes (ARIC, FHS, CARDIA, CHS) and UK Biobank. Dichotomised exposures to diet, genetic risk variants, BMI, alcohol, diuretic treatment, sex and age were used to calculate adjusted population and average attributable fractions (PAF/AAF) for HU (≥0.42 mmol/L [≥7 mg/dL]). Exposure to ULT was also assessed in the gout cohort. Two sample Mendelian randomisation was done in the UK Biobank using dietary pattern-associated genetic variants as exposure and serum urate levels as outcome. RESULTS: Adherence to dietary recommendations, BMI (< 25 kg/m2), and absence of the SLC2A9 rs12498742 urate-raising allele produced PAFs for HU of 20 to 24%, 59 to 69%, and 57 to 64%, respectively, in the three non-gout cohorts. In the gout cohort, diet, BMI, SLC2A9 rs12498742 and ULT PAFs for HU were 12%, 49%, 48%, and 63%, respectively. Mendelian randomisation demonstrated weak causal effects of four dietary habits on serum urate levels (e.g. preferentially drinking skim milk increased urate, β = 0.047 mmol/L, P = 3.78 × 10-8). These effects were mediated by BMI, and they were not significant (P ≥ 0.06) in multivariable models assessing the BMI-independent effect of diet on urate. CONCLUSIONS: Diet has a relatively minor role in determining serum urate levels and HU. In gout, the use of ULT was the largest attributable fraction tested for HU.
Authors: Lina Zgaga; Evropi Theodoratou; Janet Kyle; Susan M Farrington; Felix Agakov; Albert Tenesa; Marion Walker; Geraldine McNeill; Alan F Wright; Igor Rudan; Malcolm G Dunlop; Harry Campbell Journal: PLoS One Date: 2012-06-06 Impact factor: 3.240
Authors: Caitlin Batt; Amanda J Phipps-Green; Michael A Black; Murray Cadzow; Marilyn E Merriman; Ruth Topless; Peter Gow; Andrew Harrison; John Highton; Peter Jones; Lisa Stamp; Nicola Dalbeth; Tony R Merriman Journal: Ann Rheum Dis Date: 2013-09-11 Impact factor: 19.103
Authors: Lisandro D Colantonio; Richard J Reynolds; Tony R Merriman; Angelo Gaffo; Jasvinder A Singh; Timothy B Plante; Ninad S Chaudhary; Nicole D Armstrong; Elsayed Z Soliman; Jeffrey R Curtis; S Louis Bridges; Leslie Lang; George Howard; Monika M Safford; Kenneth G Saag; Paul Muntner; Marguerite Ryan Irvin Journal: J Rheumatol Date: 2021-06-15 Impact factor: 4.666