TY - JOUR

T1 - Association of plasma uric acid with ischaemic heart disease and blood pressure

T2 - mendelian randomisation analysis of two large cohorts

AU - Palmer, Tom M.

AU - Nordestgaard, Børge G.

AU - Benn, Marianne

AU - Tybjærg-Hansen, Anne

AU - Davey Smith, George

AU - Lawlor, Debbie A.

AU - Timpson, Nicholas J.

PY - 2013/7/18

Y1 - 2013/7/18

N2 - OBJECTIVES: To assess the associations between both uric acid levels and hyperuricaemia, with ischaemic heart disease and blood pressure, and to explore the potentially confounding role of body mass index.DESIGN: Mendelian randomisation analysis, using variation at specific genes (SLC2A9 (rs7442295) as an instrument for uric acid; and FTO (rs9939609), MC4R (rs17782313), and TMEM18 (rs6548238) for body mass index).SETTING: Two large, prospective cohort studies in Denmark.PARTICIPANTS: We measured levels of uric acid and related covariables in 58,072 participants from the Copenhagen General Population Study and 10,602 from the Copenhagen City Heart Study, comprising 4890 and 2282 cases of ischaemic heart disease, respectively.MAIN OUTCOME: Blood pressure and prospectively assessed ischaemic heart disease.RESULTS: Estimates confirmed known observational associations between plasma uric acid and hyperuricaemia with risk of ischaemic heart disease and diastolic and systolic blood pressure. However, when using genotypic instruments for uric acid and hyperuricaemia, we saw no evidence for causal associations between uric acid, ischaemic heart disease, and blood pressure. We used genetic instruments to investigate body mass index as a potentially confounding factor in observational associations, and saw a causal effect on uric acid levels. Every four unit increase of body mass index saw a rise in uric acid of 0.03 mmol/L (95% confidence interval 0.02 to 0.04), and an increase in risk of hyperuricaemia of 7.5% (3.9% to 11.1%).CONCLUSION: By contrast with observational findings, there is no strong evidence for causal associations between uric acid and ischaemic heart disease or blood pressure. However, evidence supports a causal effect between body mass index and uric acid level and hyperuricaemia. This finding strongly suggests body mass index as a confounder in observational associations, and suggests a role for elevated body mass index or obesity in the development of uric acid related conditions.

AB - OBJECTIVES: To assess the associations between both uric acid levels and hyperuricaemia, with ischaemic heart disease and blood pressure, and to explore the potentially confounding role of body mass index.DESIGN: Mendelian randomisation analysis, using variation at specific genes (SLC2A9 (rs7442295) as an instrument for uric acid; and FTO (rs9939609), MC4R (rs17782313), and TMEM18 (rs6548238) for body mass index).SETTING: Two large, prospective cohort studies in Denmark.PARTICIPANTS: We measured levels of uric acid and related covariables in 58,072 participants from the Copenhagen General Population Study and 10,602 from the Copenhagen City Heart Study, comprising 4890 and 2282 cases of ischaemic heart disease, respectively.MAIN OUTCOME: Blood pressure and prospectively assessed ischaemic heart disease.RESULTS: Estimates confirmed known observational associations between plasma uric acid and hyperuricaemia with risk of ischaemic heart disease and diastolic and systolic blood pressure. However, when using genotypic instruments for uric acid and hyperuricaemia, we saw no evidence for causal associations between uric acid, ischaemic heart disease, and blood pressure. We used genetic instruments to investigate body mass index as a potentially confounding factor in observational associations, and saw a causal effect on uric acid levels. Every four unit increase of body mass index saw a rise in uric acid of 0.03 mmol/L (95% confidence interval 0.02 to 0.04), and an increase in risk of hyperuricaemia of 7.5% (3.9% to 11.1%).CONCLUSION: By contrast with observational findings, there is no strong evidence for causal associations between uric acid and ischaemic heart disease or blood pressure. However, evidence supports a causal effect between body mass index and uric acid level and hyperuricaemia. This finding strongly suggests body mass index as a confounder in observational associations, and suggests a role for elevated body mass index or obesity in the development of uric acid related conditions.

KW - Adult

KW - Aged

KW - Blood Pressure

KW - Body Mass Index

KW - Denmark

KW - Female

KW - Humans

KW - Hyperuricemia

KW - Male

KW - Mendelian Randomization Analysis

KW - Middle Aged

KW - Myocardial Ischemia

KW - Prospective Studies

KW - Regression Analysis

KW - Uric Acid

M3 - Journal article

C2 - 23869090

VL - 347

JO - BMJ

JF - BMJ

SN - 0959-8138

M1 - f4262

ER -