The question that the investigators were examining was, "Is uric acid a cause of hypertension?" The data supporting this is largely epidemiologic, with a smattering of interventional trials. The largest criticism of the epidemiological trials has been the issue of causality and directionality, i.e. does the hypertension cause the high uric acid or does high uric acid cause the hypertension? |
| this is how I show the directionality debate in my presentation |
Previous interventions involved using allopurinol to decrease uric acid. However there are questions of whether allopurinol may have some magical anti-hypertensive effect outside of its ability to lower uric acid. The investigators discovered a cohort of Amish with a variant of GLUT9, a urate transporter. This variant, an ILE for VAL at amino acid 259, lowers the uric acid level by about 0.5 mg/dL in women and 0.25 in men. The lowered uric acid is likely due to enhanced renal clearance.
Mendelian randomization (MR) is a concept I had not come across before. Here is a video of Wayne State University researcher, Dr Anthony Ference, who used MR to study LDL. He does a nice job of describing the concept.
The authors of the uric acid acid trial describe mendelian randomization thusly:
The mendelian randomization principle relies on the tenet that alleles, and hence genotypes, are randomly assigned during gamete formation. The main advantage of this method is that gamete formation occurs before birth and is therefore unaffected by traditional confounders that occur after conception, such as diet, socioeconomic status, access to healthcare, and all other environmental factors. Because relationships between genotypes and outcomes have only limited susceptibility to confounding and are not subject to reverse causality, genetic variation may be used to establish directionality and infer causality between a certain gene product and a specific outcome. Therefore, Mendelian randomization is akin to a randomized trial design, inheritance of the GLUT9 ILE allele would be analogous to randomly being assigned probenecid, a uricosuric agent, from birth, whereas inheritance of the wild-type genotype would be analogous to receiving placebo.The cohort was a group of 868 participants of the HAPI (Hereditary and Phenotype Intervention) study. Ninety-eight of these people had GLUT9 variants. Patients' blood pressures recorded in clinic on a liberal (standard) diet and then checked with 24-hour ambulatory monitoring following a week on a high-sodium diet (280 meq/day) and again after a week on a low-sodium diet (40 meq/day). The diets had fixed carbohydrates and potassium.
The blood pressure spread is impressive and statistically significant in both the high- and low-sodium diets. The authors summary was for every 1 mg/dl decrease in uric acid the systolic blood pressure fell by 3-5 mmHg.
I thought this study was an original approach to the question of fructose and uric acid. They found an experimental method that allowed them to look at different levels of uric acid without confounding the results with the pleiotropic effects of allopurinol.
