PPARγ2
polymorphism and diabetic nephropathy
Original article:
Peroxisome proliferator-activated receptor-γ2
polymorphism Pro12Ala is associated with nephropathy in type 2 diabetes. The
Berlin Diabetes Mellitus (BeDiaM) study. Herrmann S-M, Ringel J, Wang
J-G, Staessen JA, Brand E. Diabetes 2002; 51: 2653–7.
Summary
Nephropathy associated with type 2 diabetes is a complex trait. The
contribution of genetic markers is supported by familial studies.
Segregation analyses performed in Pima Indians as well as in Caucasian
families are in favour of a monogenic or oligogenic disease. Many candidate
genes have been examined. In this report the authors describe the effect of
a Pro12Ala polymorphism in the peroxisome proliferator-activated receptor (PPAR)
gene in patients with type 2 diabetes and nephropathy.
A total of 445 patients (220 men and 225 women) of Caucasian ethnicity with
type 2 diabetes and nephropathy were recruited to this German multicentre
study. Nephropathy was classified according to urinary albumin excretion (UAE)
or the presence of endstage renal failure. The phenotype was very accurately
reported with collection of data on coronary artery disease and retinopathy
(stages III or IV on funduscopy or a history of laser treatment).
Retinopathy was found in 16% of patients; UAE was 24.8 mg/min and 21.8
mg/min in men and women, respectively.
The distribution of the PPARg2 Pro12Ala gene polymorphism was in
Hardy-Weinberg equilibrium. Ala12 allele carriers had lower UAE compared
with non-carriers (17.1 vs. 25.8 mg/min; p = 0.01). After adjustment for
sex, age, BMI, hypertension, hyperlipidemia, duration of diabetes and
diabetes treatment, Ala12 allele carriers still had lower UAE in comparison
with non-carriers. After adjustment, the odds ratio of having proteinuria
was 0.66 for Ala12 allele carriers compared with non-carriers (Fig. 1).
Fig. 1: Odds ratios of having macroalbuminuria in
PPARg2 Ala12 allele carriers vs. non-carriers for all patients and subgroups
according to duration of diabetes. Vertical lines denote 95% CI. The size of
the symbols is proportional to the number of cases given alongside the
squares. Number of patients (n) and significance levels for odds ratios (p)
and for the interaction (pint) between the genetic polymorphism and duration
of diabetes are given.
Interestingly, there was a significant interaction between the Pro12Ala
polymorphism and duration of diabetes (Fig. 2). The longer the duration of
diabetes, the stronger the protective effect of the Ala12 allele.
Fig.
2: Percentage difference in UAE between PPARg2 Ala12 allele carriers and
non-carriers for all patients and for subgroups according to duration of
diabetes. Vertical lines denote 95% CI. For each subgroup, the number of
subjects is given (bottom). Number of patients (n) and significance levels
for the difference (p) and for the interaction (pint) between the genetic
polymorphism and duration of diabetes are given.
Comment
The authors examined the effect of a common polymorphism on the incidence of
diabetic nephropathy. The role of this polymorphism on the genesis of renal
disease might be due to the effect of insulin resistance. In type 1
diabetes, insulin resistance has been recently shown to be higher in
patients who eventually progress to proteinuria [1]. However, in the present
study, the authors did not measure insulin resistance. They stated that the
Pro12Ala polymorphism was a good candidate gene, as treatment
with glitazones could modify the course of diabetic nephropathy.
However, one of the main difficulties with regard to the analysis of this
polymorphism is that we do not have any intermediate phenotype. The exact
mechanism by which the gene may be involved in diabetic nephropathy is not
known. Of interest, Herrmann et al. did not analyse the contribution of the
genotype to the different stages of nephropathy but to a continuous trait,
namely UAE. However, we do not have any data on the patients with endstage
renal failure. As diabetic retinopathy was rarely found, UAE might also be
related to non-diabetic renal disease.
The main point in this study is that the positive correlation continued even
after adjusting for confounding factors. However, other studies examining
the same question have failed to produce such positive results. Additional
investigations must therefore be carried out to confirm the risk of
nephropathy associated with the PPARγ2
Pro12Ala polymorphism.
Reference
1. Orchard TJ, Chang YF, Ferrell RE et al. Nephropathy in
type 1 diabetes: a manifestation of insulin resistance and multiple genetic
susceptibilities? Further evidence from the Pittsburgh Epidemiology of
Diabetes Complications Study. Kidney Int 2002; 62: 963–70.
Summary and Comment:
Samy Hadjadj, Poitiers, France