Physiogenomic comparison of edema and BMI in patients receiving rosiglitazone or pioglitazone.
BACKGROUND
The thiazolidinediones (TZDs) improve tissue sensitivity to insulin in patients with type II diabetes, resulting in reduced levels of fasting blood glucose and glycated hemoglobin. However, TZDs unpredictably demonstrate adverse effects of increased body weight, fluid retention, and edema. The balance of efficacy and safety of TZD varies widely from patient to patient. Genetic variability may reveal pathophysiological pathways underlying weight gain associated with TZD therapy and due to adiposity and/or edema.


METHODS
We analyzed 384 single nucleotide polymorphisms (SNPs) from 222 cardiovascular and metabolic genes in 87 outpatients with type 2 diabetes receiving thiazolidinedione therapy. Physiogenomic analysis was used to discover associations with body mass index (BMI) and edema.


RESULTS
The 5 most significant gene associations found between BMI and SNPs were ADORA1, adenosine A1 receptor (rs903361, p<0.0003), PKM2, pyruvate kinase-muscle (rs2856929, p<0.002); ADIPOR2, adiponectin receptor 2 (rs7975375, p<0.007); UCP2, uncoupling protein 2 (rs660339, p<0.008); and APOH, apolipoprotein H (rs8178847, p<0.010). For edema, the 5 most significant gene associations were NPY, neuropeptide Y (rs1468271, p<0.006); GYS1, glycogen synthase 1-muscle (rs2287754, p<0.013); CCL2, chemokine C-C motif ligand 2 (rs3760396, p<0.015); OLR1, oxidized LDL receptor 1 (rs2742115, p<0.015); and GHRH, growth hormone releasing hormone (rs6032470, p<0.023). After accounting for multiple comparisons, ADORA1 was significantly associated with BMI at a false discovery rate (FDR) of <10%.


CONCLUSIONS
Physiogenomic associations were discovered suggesting mechanistic links between adenosine signaling and BMI, and between vascular permeability and drug-induced edema.
Ruaño
Gualberto
G
Genomas, Inc., 67 Jefferson St, Hartford, CT, United States. g.ruano@genomas.net
Bernene
James
J
Windemuth
Andreas
A
Bower
Bruce
B
Wencker
Detlef
D
Seip
Richard L
RL
Kocherla
Mohan
M
Holford
Theodore R
TR
Petit
William A
WA
Hanks
Steven
S
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015992:Body Mass Index; D003430:Cross-Sectional Studies; D064420:Drug-Related Side Effects and Adverse Reactions; D004487:Edema / Q000139:chemically induced* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D023281:Genomics; D005838:Genotype; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D000077205:Pioglitazone; D020641:Polymorphism, Single Nucleotide; D012189:Retrospective Studies; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000009:adverse effects*
D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D000077205:Pioglitazone