Influence of renal function on association of CCR2-64I with mortality in the general
population
M.W. Zuurman1, R.Korstanje2, P.E. De Jong1, G.J.Navis1
1
2
Department of Nephrology, Internal Medicine, UMC Groningen, The Netherlands
Department of Medical Biology, University of Groningen, The Netherlands
Background (750 karakters)
Chemokines are small proteins that classically orchestrate the host immune response by
activating and inducing chemotaxis of leukocytes. The beta chemokine CCL2 has been
implicated in pathology such as atherosclerosis and progressive renal fibrosis. CCL2 signals
via the chemokine receptor CCR2 that exists in two isoforms, CCR2A and CCR2B. A single
nucleotide polymorphism in CCR2, CCR2-64I, substitutes a valine for an isoleucine in the
protein. CCR2-64I has been associated with increased risk of myocardial infarction, as well as
lower coronary artery calcification. Recently we have found an independent association with
mortality of the CCR2-64I allele in the general population. In the current study, we have
examined the differential effect of CCR2-64I on mortality in subjects classified by levels of
kidney function.
Methods (900)
Subjects were drawn from the PREVEND study cohort. All subjects were genotyped for
CCR2-64I. We excluded non-Caucasians, subjects positive for erythrocyturia or leukocyturia,
or missing values for any of the analysed parameters. Thus, 6931 individuals were eligible for
further study. Mortality was defined as all-cause death.
Creatinine clearance (CCR) was adjusted for body surface area (BSA). Subjects were divided
into three groups based on their state of filtration. Briefly, creatinine clearance was age- and
gender normalized by calculating a modeled CCR. Subjects were then classified into
diminished filtration (DF), normal filtration (NF) and elevated filtration (EF) according to 1
standard deviation from the mean residual. ANOVA and Pearson Chi-square analyses were
used to examine differences between genotype groups. Multivariate logistic and Cox
regression models were used to estimate odds ratios and survival. All models adjusted for age,
smoking status, UAE, body mass index (BMI), HT, mean arterial pressure, obesity and MI.
Results (2000)
N
Age (yrs)
Male (%)
BMI
Obesity (%)
MAP (mmHg)
Hypertension (%)
MI (%)
UAE (mg/24h)
CCR (ml/min/1.73 m2)
VV
5813
49.3 ± 12.6
50.7
26.0 ± 4.2
15.2
92.3 ± 12.3
31.3
4.3
9.3 (6.3-17.4)
92.6 ± 20.6
CCR2-64I genotype
VI
1065
49.0 ± 12.7
53.0
26.1 ± 4.1
14.6
93.0 ± 13.0
33.6
3.6
9.5 (6.5-17.1)
93.2 ± 21.1
II
53
51.5 ± 13.7
56.6
26.2 ± 3.5
18.9
92.4 ± 11.7
35.8
15.1a
9.9 (6.8-20.6)
92.6 ± 20.7
Smoking (%)
Deceased (%)
37.2
189 (3.3)
38.9
53 (5)
50.9
0 (0)
We found no differences in baseline characteristics between genotypes, except MI. Subjects
homozygous for CCR2-64I showed a higher incidence of MI (15.1%, p=0.004) compared to
other subjects. As we did not observe any death in the small group of CCR2-64I homozygous
subjects we compared only heterozygous individuals to CCR2-64V homozygotes in
subsequent analyses of mortality. We defined 796 DF, 4780 NF and 986 EF subjects.
Multivariate analysis showed significant less odds for mortality in subjects with EF compared
to those with DF (OR=0.56, p=0.037), while this was non-significant for NF individuals
(OR=0.78, p=0.185). In the same model, CCR2-64VI heterozygotes were at significant higher
odds of mortality compared to CCR2-64VV homozygotes (OR=1.55, p=0.015). Interestingly,
mortality rate diverged per lower category of filtration between homozygous CCR2-64VV
subjects and heterozygotes. Specifically, mortality rates were 1.3%, 4.5% and 8% in
heterozygous EF, NF and DF individuals respectively, compared to 2.4%, 3.1% and 5.4% in
CCR2-64VV homozygotes. Survival curves plotted using Cox regression confirmed the
observed results.
Conclusion (750)
Our current results suggest an additive effect of lower filtration on the previously observed
association of CCR2-64I with mortality. We showed that diminished filtration is a risk factor
for mortality in our study population. Second, carriers of the CCR2-64I minor allele show a
steeper decrease in survival per lower category of filtration.
The CCR2-C64I minor allele has been shown to alter the CCR2A isoform, stabilizing
expression and function. Its ligand, CCL2 has been implicated in renal disease. For instance,
it has been associated with progression of renal fibrosis and renal vasculitis. Thus, improved
CCR2A function in CCR2-64I subjects might lead to more pronounced renal inflammation
under pathological conditions, in turn leading to a faster progression to renal failure and
subsequent mortality. Further study is needed to confirm this hypothesis.
Categorie
Experimentele Nefrologie.