Brief Genetics Report A Common Stromal Cell–Derived Factor-1 Chemokine Gene Variant is Associated With the Early Onset of Type 1 Diabetes

Type 1 diabetes results from the autoimmune destruction of pancreatic b-cells. Although the disease shows a strong association with HLA class II alleles, other genes may influence the initiation or the rate of progression of the autoimmune process. The recruitment of mononuclear cells within the islets of Langerhans is a critical step in the pathogenesis of the disease. Because chemokines are cytokines that promote migration of mononuclear cells, we hypothesized that polymorphisms in chemokine receptor or chemokine genes, CCR5 and SDF1, may be involved in susceptibility to or clinical expression of type 1 diabetes. The frequencies of the CCR5-D32 and SDF1-3*A (801G3A in the 3* untranslated region) variants were similar in 208 unrelated Caucasian patients with type 1 diabetes and in 120 Caucasian control subjects. They were not modified after stratification for the predisposing HLA-DR3 and -DR4 haplotypes. However, the SDF1-3*A variant was strongly associated with early onset (<15 years) of the disease (odds ratio 2.6, P 5 0.0019). On average, the presence of the SDF1-3*A allele was associated with a 5-year reduction in the age at onset of diabetes (P 5 0.0067). Our results suggest that stromal cell–derived factor-1 may be implicated in the aggressiveness of the autoimmune process leading to type 1 diabetes. These preliminary data require replication in other populations. Diabetes 50:1211–1213, 2001 Type one diabetes is an autoimmune disease that is clinically heterogeneous with regard to the great variability of age at onset, its possible association with organ-specific autoimmune diseases, and its occurrence as a sporadic or a familial disease. The genes involved in susceptibility to type 1 diabetes remain largely unidentified. Apart from major histocompatibility complex (MHC) class II genes (IDDM1) and the insulin gene region (IDDM2), many other putative loci have been proposed but not confirmed by recent genome scan studies (1,2). Genetics may also influence the rate of progression or the aggressiveness of the disease. HLA DR3/DR4 heterozygosity is more frequent among patients with early rather than late-onset type 1 diabetes (3), and patients bearing the HLA class I A24 allele have more complete (4) or rapid (5) pancreatic b-cell destruction than patients who do not express this allele. The recruitment of activated mononuclear cells within pancreatic islets (i.e., insulitis) is a critical step in the pathogenesis of type 1 diabetes (6). Chemokines are cytokines that promote the migration of leukocytes into inflammatory sites and differentiation or activation. In recent years, their role in the pathogenesis of several immune-mediated diseases has been recognized (7). Moreover, polymorphisms in genes encoding chemokines or their receptors, such as stromal cell–derived factor (SDF)-1, CCR5, and CCR2 have been shown to influence the course of HIV infection or inflammatory diseases (8–10). We thus hypothesized that such polymorphisms may participate in susceptibility to or clinical presentation of type 1 diabetes. The frequencies of the CCR5-D32 and SDF1-39A (801G3A in the 39 untranslated region) variants were assessed in 208 unrelated Caucasian patients with type 1 diabetes and 120 Caucasian control subjects. Allelic and genotypic frequencies of the CCR5-D32 and SDF1-39A variants were similar in the two groups (Table 1). The observed frequencies in control subjects were the same as that previously reported in French subjects (11). The CCR5-D32 and the SDF1-39A alleles were present in 11.5 and 34.1% of the patients, respectively. These frequencies were not modified when the patients were stratified according to presence or absence of the predisposing HLA-DR3 and/or -DR4 haplotypes (data not shown). To test whether the two From the Unité de Diabétologie, Service d’Immunologie Clinique and the Laboratory of Immunology, Hôpital Necker-Enfants Malades; the Unité de Physiologie Cellulaire, Université Pierre et Marie Curie; the Institut National de la Sante et de la Recherche Medicale (INSERM) U 342, Institut Cochin de Génétique Moléculaire, Hôpital Cochin-Saint-Vincent de Paul, Paris, France; and the Laboratory of Genomic Diversity, National Cancer Institute, Frederick, Maryland. Address correspondence and reprint requests to Dr. José Timsit, Unité de Diabétologie, Service d’Immunologie Clinique, Hôpital Necker, 161 rue de Sèvres, 75015 Paris, France. E-mail: [email protected]. Received for publication 19 September 2000 and accepted in revised form 23 January 2001. The content of this publication does not necessarily reflect the views and policies of the Department of Health and Human Services, nor does the mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. MHC, major histocompatibility complex; OR, odds ratio; PCR, polymerse chain reaction; SDF, stromal cell–derived factor.