The PPAR Gamma Pro12Ala variant: association with type 2 diabetes, trait differences,
and interaction with the ?3-adrenergic receptor

Erdos, M.R. (2), Douglas, J.A. (1), Watanabe, R.M. (1), Braun, A. (3), Oeth, P. (3), 
Mohlke, K. (2), Valle, T. (4), Buchanan, T.A. (5), Bergman, R.N. (6), Collins, F.S. (2), 
Boehnke, M. (1), and Tuomilehto, J. (4)

(1) University of Michigan,Ann Arbor, MI 48109-2029 U.S.A.
(2) National Human Genome Research Institute, Bethesda, MD 20892 U.S.A.
(3) Sequenom Industrial Genomics, San Diego, CA 92121-1331 U.S.A.
(4) National Public Health Institute, Helsinki, Finland
(5) University of Southern California, Los Angeles, CA 90033 U.S.A.

Recent studies have identified a common proline-to-alanine substitution (Pro12Ala) in 
the peroxisome proliferator-activated receptor-?2 (PPAR-?2), a nuclear receptor that 
regulates adipocyte differentiation and possibly insulin sensitivity.  The Pro12Ala variant 
has been associated in some studies with type 2 diabetes and/or diabetes-related traits.  
We examined this variant in 1618 Finnish subjects: 785 index cases with type 2 diabetes, 
193 non-diabetic spouses, 420 non-diabetic offspring, and 220 elderly non-diabetic 
controls.  The frequency of the Pro12Ala variant was significantly lower in diabetic 
compared to non-diabetic subjects (0.15 versus 0.21; p<0.001). 

We also compared diabetes-related traits between subjects with and without the Pro12Ala 
variant within clinical subgroups.  Among subjects with type 2 diabetes, the variant was 
associated with greater weight gain relative to weight at age 20 (p=0.023) and lower 
triglycerides (p=0.033).  The variant was associated with higher diastolic blood pressure 
(DBP) only for severely obese (BMI>40 kg/m2) diabetic subjects.  A similar association 
with DBP and systolic blood pressure (SBP) was also observed among very obese non-
diabetic offspring.  In non-diabetic spouses, the variant was associated with higher fasting 
insulin (p=0.033), SBP (p=0.021), and DBP (p=0.045).

Among type 2 diabetic subjects also genotyped for the Trp64Arg variant of the ?3-
adrenergic receptor (ADRB3) (n=468), presence of the Pro12Ala variant and the 
Trp64Arg variant was associated with higher waist-to-hip ratio (p=0.025), lower HDL 
cholesterol (p=0.025), higher triglycerides (p=0.043), and higher SBP (p=0.030).  These 
findings support a role for the PPAR-?2 Pro12Ala variant in the etiology of type 2 
diabetes.