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Association of stromal cell-derived factor 1 genotype with diabetic foot syndrome and macrovascular disease in patients with type 2 diabetes.

To the Editor:

Stromal cell-derived factor 1 (SDF-1) is a highly active chemokine that influences migration and trafficking of leukocytes (1) and hematopoietic progenitor cells (2). Patients with type 2 diabetes (T2DM) who carry the heterozygous SDF-1 3'A genotype (801G/A in the 3' untranslated region) have increased insulin-dependent mobilization of adult progenitor cells (3), which are known to participate in angiogenesis and vascular repair (4). In contrast, homing of progenitor cells has been shown to contribute to diabetes-related vascular complications (5, 6). Because carriers of the SDF-1 3'A genotype have increased SDF-1 mRNA in peripheral blood mononuclear cells (7), genetic variations in SDF-1 expression might affect trafficking of inflammatory cells or dysfunctional precursors and thus predispose to diabetic complications. To investigate a possible influence of the SDF-1 genotype on the development of late vascular diabetic complications, we performed a case-control study in T2DM patients suffering from diabetic foot syndrome (DFS) and a cohort of T2DM patients almost free of late complications.

All patients were recruited from the diabetes outpatient departments of the University of Heidelberg Diabetes Clinics in Mannheim and Heidelberg and gave written consent according to the requirements of the local Ethics Committee. Eighty-five Caucasian T2DM patients with DFS and a control group of 81 T2DM patients without macrovascular disease were included. Characteristics of the study population are given in Table 1. Diagnostic criteria for DFS, polyneuropathy, and peripheral artery disease were applied according to the guidelines of the German Diabetes Association (8) as part of routine clinical care. Of the 85 patients with DFS, 62.4% had peripheral artery disease, 94.1% had diabetic polyneuropathy, and 72.9% had macrovascular disease, including stroke (10.6%) and coronary artery disease (42.3%). Of the controls, 29.6% had diabetic polyneuropathy and 3.7% had diabetic retinopathy. The SDF-1 genotype was detected by PCR and subsequent cleavage with the restriction enzyme Msp1 as described previously (9). For statistical analysis, differences in genotype distribution were compared by the [chi square] test. For each test, two-tailed probability and 95% confidence intervals (CIS) were calculated. Odds ratios (ORs) were calculated as an index of the association of the SDF-1 genotypes with DFS. SPSS, Ver. 13.0, was used for all statistical testing.

The overall frequency of the heterozygous SDF-1 3'A genotype in DFS patients and controls (n = 166) was 36.4%, higher than the previously reported 27.9% in Caucasian patients with type 1 diabetes (10). DFS patients had a nonsignificant increase in the heterozygous SDF-1 3'A genotype (42.4% vs 29.6% of controls; OR = 1.7; 95% CI, 0.9-3.5; P = 0.09; Table 1). The frequency of the heterozygous SDF-1 3'A genotype was significantly higher in patients with DFS and macrovascular disease (50%; OR = 2.4; 95% CI, 1.1-5.0; [chi square]=6.2; P = 0.01; Table 1]. Because DFS patients in this subgroup had a significantly longer duration of diabetes (Table 1), we calculated sensitivity with a logistic regression model including diabetes duration categorized in 3 additional variables (by quartiles). This analysis indicated an association of the heterozygous SDF-1 3'A genotype with DFS in patients with macrovascular disease that just missed statistical significance [OR = 1.9 (0.9-3.7); P = 0.07]. The distribution of the heterozygous SDF-1 3'A genotype in T2DM patients with neuropathic DFS and without macrovascular disease did not differ from that in controls (31.3%; data not shown).

DFS is a complication marking a subgroup of patients with a very high cardiovascular mortality rate (11). The finding of increased heterozygous SDF-1 3'A in patients with macrovascular disease indicates a possible role of this genotype in the development of late macrovascular complications. SDF-1 has consistently been shown to induce platelet aggregation and to be highly expressed in human atherosclerotic plaques (12). Previous studies indicated an important role of SDF-1 for the homing of angiogenic progenitor cells to sites of vascular injury (5, 6,13, 14). This might have deleterious effects in diabetes, possibly because of a change in progenitor cell phenotype and depending on the site of injury (4-6). It is beyond the scope of the pilot study presented here to clarify the underlying mechanisms. Remarkably, there were no carriers of the homozygous SDF-1 3'A genotype in the DFS patients. The frequency of this genotype in the entire cohort of T2DM patients was 1.8%, lower than published previously (9,10). We speculate that this finding is caused by natural selection and an increased risk of premature cardiovascular death in high-risk diabetic carriers of the homozygous genotype. However, this hypothesis and the value of SDF-1 genotyping for identifying diabetic patients at cardiovascular risk will have to be assessed in additional cohorts as well as prospective studies.

This work was supported in part by grants from the Lautenschldger Stiftung (to P.P.N. and A.B.), a European Foundation for the Study of Diabetes Eli Lilly Research Grant (to A.B.), and the Juvenile Diabetes Research Foundation (to A.B. and P.P.N.). A.B. and P.M.H. were supported by Deutsche Diabetes-Gesellschaft. We thank C. Comtesse for excellent technical assistance.

References

(1.) Bleul CC, Fuhlbrigge RC, Casasnovas JM, Aiuti A, Springer TA. A highly efficacious lymphocyte chemoattractant, stromal cell-derived factor 1 (SDF-1). J Exp Med 1996;184:1101-9.

(2.) Aiuti A, Webb IJ, Bleul C, Springer T, Gutierrez-Ramos JC. The chemokine SDF-1 is a chemo-attractant for human CD34+ hematopoietic progenitor cells and provides a new mechanism to explain the mobilization of CD34+ progenitors to peripheral blood. J Exp Med 1997;185:111-20.

(3.) Humpert PM, Neuwirth R, Battista MJ, Voronko 0, von Eynatten M, Konrade I, et al. SDF-1 genotype influences insulin-dependent mobilization of adult progenitor cells in type 2 diabetes. Diabetes Care 2005;28:934-6.

(4.) Humpert PM, Eichler H, Lammert A, Hammes HP, Nawroth PP, Bierhaus A. Adult vascular progenitor cells and tissue regeneration in metabolic syndrome. Vasa 2005;34:73-8, 80.

(5.) Zheng F, Comacchia F, Schulman I, Banerjee A, Cheng QL, Potier M, et al. Development of albuminuria and glomerular lesions in normoglycemic B6 recipients of db/db mice bone marrow: the role of mesangial cell progenitors. Diabetes 2004;53:2420-7.

(6.) Butler JIM, Guthrie SM, Koc M, Afzal A, Caballero S, Brooks HL, et al. SDF-1 is both necessary and sufficient to promote proliferative retinopathy. J Clin Invest 2005;115:86-93.

(7.) Sei S, O'Neill DP, Stewart SK, Yang Q, Kumagai M, Boler AM, et al. Increased level of stromal cell-derived factor-1 mRNA in peripheral blood mononuclear cells from children with AIDSrelated lymphoma. Cancer Res 2001;61:502837.

(8.) Morbach S, Mueller E, Reike H, Risse A, Spraul M. Diagnostik, Therapie, Verlaufskontrolle and Pravention des diabetischen Fusssyndroms. Evidenzbasierte DiabetesLeitlinie DDG. Diabetes and Stoffwechsel 2004;13(Su ppl 2):9-30.

(9.) Winkler C, Modi W, Smith MW, Nelson GW, Wu X, Carrington M, et al. Genetic restriction of AIDS pathogenesis by an SDF-1 chemokine gene variant. ALIVE Study, Hemophilia Growth and Development Study (HGDS), Multicenter AIDS Cohort Study (MACS), Multicenter Hemophilia Cohort Study (MHCS), San Francisco City Cohort (SFCC). Science 1998; 279:389-93.

(10.) Dubois-Laforgue D, Hendel H, Caillat-Zucman S, Zagury JF, Winkler C, Boitard C, et al. A common stromal cell-derived factor-1 chemokine gene variant is associated with the early onset of type 1 diabetes. Diabetes 2001;50: 1211-3.

(11.) Moulik PK, Mtonga R, Gill GV. Amputation and mortality in new-onset diabetic foot ulcers stratified by etiology. Diabetes Care 2003;26: 491-4.

(12.) Abi-Younes S, Sauty A, Mach F, Sukhova GK, Libby P, Luster AD. The stromal cell-derived factor-1 chemokine is a potent platelet agonist highly expressed in atherosclerotic plaques. Circ Res 2000;86:131-8.

(13.) Ceradini DJ, Kulkarni AR, Callaghan MJ, Tepper OM, Bastidas N, Kleinman ME, et al. Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med 2004;10:858-64.

(14.) Yamaguchi J, Kusano KF, Masuo 0, Kawamoto A, Silver M, Murasawa S, et al. Stromal cell-derived factor-1 effects on ex vivo expanded endothelial progenitor cell recruitment for ischemic neovascularization. Circulation 2003;107: 1322-8.

Per M. Humpertl *

Marco J. Battista [1]

Alexander Lammert [2]

Peter Reismann [1]

Zdenka Djuric [1]

Gottfried Rudofsky, Jr. [1]

Markus Zorn [3]

Michael Morcos [1]

Hans-Peter Hammes [2]

Peter P. Nawroth [1,3]

Angelika Bierhaus [1]

[1] Medizinische Klinik I

University of Heidelberg

Heidelberg, Germany

[2] V. Medizinische Klinik

University Clinics Mannheim

Mannheim, Germany

[3] Sektion Laboratoriumsmedizin der Inneren Medizin I

Heidelberg, Germany

* Address correspondence to this author at: Medizinische Klinik I, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany. Fax 49-622156-4233; e-mail per.humpert@med.uniheidelberg.de.

DOI: 10.1373/clinchem.2005.065482
Table 1. Characteristics of the study cohort and genotype
distribution.

 Controls DFS
 (n = 81) (n = 85)

Mean (SD) age, years 67.3 (9.7) 69.0 (10.0)
Sex, F/M 38/42 33/52
Mean (SD) duration of
 diabetes, years 12.2 (6.3) 13.7 (9.6)
Mean (SD) Hb [A.sub.1c],
 (b) % 7.4 (1.5) 7.3 (1.4)
Mean (SD) cholesterol
 mmol/L 4.98 (0.98) 4.88 (1.31)
 mg/dL 192.4 (37.8) 188.3 (50.5)
Mean (SD) BMI, kg/[m.sup.2] 30.0 (4.6) 30.4 (6.3)
SDF-1 genotype, n (%)
 GG 54 (66.7) 49 (57.6)
 AA 3 (3.7) 0
 AG 24 (29.6) 36 (42.4)

 DFS and any
 macrovascular
 OR (95% CI) disease (n = 62)

Mean (SD) age, years 70.0 (9.5)
Sex, F/M 27/31
Mean (SD) duration of
 diabetes, years 14.9 (9.2) (a)
Mean (SD) Hb [A.sub.1c],
 (b) % 7.3 (1.3)
Mean (SD) cholesterol
 mmol/L 4.93 (1.41)
 mg/dL 190.3 (54.3)
Mean (SD) BMI, kg/[m.sup.2] 30.4 (7.0)
SDF-1 genotype, n (%)
 GG 31 (50.0)
 AA 0
 AG 1.7 (0.9-3.5) (c) 31 (50.0)

 OR (95% CI)
 vs controls

Mean (SD) age, years
Sex, F/M
Mean (SD) duration of
 diabetes, years
Mean (SD) Hb [A.sub.1c],
 (b) %
Mean (SD) cholesterol
 mmol/L
 mg/dL
Mean (SD) BMI, kg/[m.sup.2]
SDF-1 genotype, n (%)
 GG
 AA
 AG 2.4 (1.1-5.0) (d)

(a) P = 0.05, t-test.

(b) Hb [A.sub.1c], hemoglobin mass index.

(c,d) [chi square] test: (c) P = 0.09; (d) P = 0.01.
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Title Annotation:Letters
Author:Humpert, Per M.; Battista, Marco J.; Lammert, Alexander; Reismann, Peter; Djuric, Zdenka; Rudofsky,
Publication:Clinical Chemistry
Article Type:Letter to the editor
Date:Jun 1, 2006
Words:1725
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