Serum uric acid and adiposity: deciphering causality using a bidirectional Mendelian randomization approach.
BACKGROUND
Although the relationship between serum uric acid (SUA) and adiposity is well established, the direction of the causality is still unclear in the presence of conflicting evidences. We used a bidirectional Mendelian randomization approach to explore the nature and direction of causality between SUA and adiposity in a population-based study of Caucasians aged 35 to 75 years.


RESULTS
We used, as instrumental variables, rs6855911 within the SUA gene SLC2A9 in one direction, and combinations of SNPs within the adiposity genes FTO, MC4R and TMEM18 in the other direction. Adiposity markers included weight, body mass index, waist circumference and fat mass. We applied a two-stage least squares regression: a regression of SUA/adiposity markers on our instruments in the first stage and a regression of the response of interest on the fitted values from the first stage regression in the second stage. SUA explained by the SLC2A9 instrument was not associated to fat mass (regression coefficient [95% confidence interval]: 0.05 [-0.10, 0.19] for fat mass) contrasting with the ordinary least square estimate (0.37 [0.34, 0.40]). By contrast, fat mass explained by genetic variants of the FTO, MC4R and TMEM18 genes was positively and significantly associated to SUA (0.31 [0.01, 0.62]), similar to the ordinary least square estimate (0.27 [0.25, 0.29]). Results were similar for the other adiposity markers.


CONCLUSIONS
Using a bidirectional Mendelian randomization approach in adult Caucasians, our findings suggest that elevated SUA is a consequence rather than a cause of adiposity.
Institute of Social and Preventive Medicine (IUMSP), Lausanne University Hospital, Lausanne, Switzerland.
Tanica
T
Lyngdoh
Philippe
P
Vuistiner
Pedro
P
Marques-Vidal
Valentin
V
Rousson
Gérard
G
Waeber
Peter
P
Vollenweider
Murielle
M
Bochud
D050154:Adiposity / Q000235:genetics*; D000328:Adult; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; D015984:Causality; D003430:Cross-Sectional Studies; D005260:Female; D005838:Genotype; D051246:Glucose Transport Proteins, Facilitative / Q000235:genetics; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics; D011897:Random Allocation; D044105:Receptor, Melanocortin, Type 4 / Q000235:genetics; D014527:Uric Acid / Q000097:blood*
D051246:Glucose Transport Proteins, Facilitative; D008565:Membrane Proteins; D011506:Proteins; D044105:Receptor, Melanocortin, Type 4; C411811:SLC2A9 protein, human; C530715:TMEM18 protein, human; D014527:Uric Acid; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; C526492:FTO protein, human