Earlier in our class, Dr. Cohen discussed the Chemokine receptor 5 (CCR5) and it’s effect on resistence and progression to AIDS for individuals with a mutant version of this gene. One project that I participated on was looking at CCR5 and any observable effects on patients with Type I diabetes.
As briefly mentioned in class, there is a mutant form of the CCR5 gene in which a 32bp deletion results in a truncated non-functional protein that is not expressed on the cell surface of mononuclear cells. A number of studies have looked at the association of CCR5D32 and it’s effects on disease. Individuals with CCR5D32 have either strong resistance to HIV infection (homozygous) or delayed progression to AIDS (heterozygous). In rheumatoid arthritis there is a negative association of the polymorphism suggesting that it influences the development of RA, as well as the clinical course and severity. For the study I participated on, we wanted to see what (if any) effects that this gene polymorphism has on Type I diabetes. Specifically, if it influences the development of persistent islet autoimmunity (IA) and/or the progression to T1D. Other studies looking at this with limited/specific populations have mixed results. A small report from Hungary shows no association while to others with larger cohorts report partial protection from progression to T1D.
In our study, we genotyped children with the high risk HLA DR3/4-DQ8 genotype as well as the offspring of T1D parents. Included in the cohort were high-risk T1D individuals, siblings and offspring of relatives of T1D individuals, as well as general population newborns. This information was coupled with the IA information for all. (Type 1 diabetes is usually preceded by the presence of autoantibodies directed toward pancreatic islet cell antigens. These antibodies can be present months to years before the actual clinical diagnosis of diabetes and can serve as predictive markers of T1D).
The data for persistent IA and progression to T1D was grouped by genotypes and analyzed by survival analysis. The comparisons for the development of persistent IA showed significant levels of protection from having at least one D32 allele for both high-risk T1D individuals as well as the normal population group. The data also suggest that there is protection from the progression to T1D, however the sample size was too small for this result to have statistical significance.
Although not yet published, this study showed an association with the CCR5 polymorphism and the clinical course of T1D and also agreed with two other published studies. Combined with other genetic markers, perhaps the CCR5 gene could prove to be of benefit in disease prediction.
Sources:
1. Steck, AK. Chemokine Receptor CCR5D32 is associated with protection from persistent Islet Autoimmunity. Not published.
2. Int J Mol Med. 2008 Nov;22(5):669-75. Frequency of CCR5-Delta32 deletion in human immunodeficiency virus type 1 (HIV-1) in healthy blood donors, HIV-1-exposed seronegative and HIV-1-seropositive individuals of southern Brazilian population.
3. J Diabetes Complications. 2003 Nov-Dec;17(6):387-91. CC-chemokine receptor CCR5-del32 mutation as a modifying pathogenetic factor in type I diabetes.
4. Pediatr Res. 1999 Jul;46(1):82-4. Chemokine receptor CCR2 and CCR5 polymorphisms in children with insulin-dependent diabetes mellitus.
5. Diabetes Care. 2004 Feb;27(2):497-502. Is presence of islet autoantibodies at birth associated with development of persistent islet autoimmunity? The Diabetes Autoimmunity Study in the Young (DAISY).
Hi Randy, very cool study! Too bad your "n" was too small, if this was published, other groups could initialize some very interesting preliminary studies to understand the mechanism of protection. Were there any hints at delayed onset of T1D associated with the CCR5 deletion? Did you guys test pre-diabetic serum or sibs who did develop T1D and follow the patients through clinical diagnosis and progression of T1D. Is there any or higher association of the CCR5del32 with the high risk haplotypes?
ReplyDeleteIt seems that the CCR5 gene doesn't have a direct association with the etiology of T1 and T2D. Could you suggest some mechanisms at how the CCR5del32 protects?
Julie Wu IMMU7630
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ReplyDeleteHi Randy, I am glad to read about what you guys were working on upstairs! I am also curious as to the mechanism by which the delta32 allele affects the progression to T1D, and why anyone would think to test this theory in the first place! Is it a direct mechanism of protection against developing autoantibodies, or is it associated with another protecting factor? Also, how great was the protection effect? Did you have anyone in your study with homozygous delta32, and if so, was the protection greater?
ReplyDeleteFor this study there were over 500 subjects, of which about 150 were het CCR5d32. There was only one homozygous CCR5d32. This one subject never developed T1D. All the het subjects had delayed IA development and did develop T1D (also delayed).
ReplyDeleteOne observation is that the reduced number of CCR5+ cells results in a reduced recruitment of macrophages, CD4 and CD8 T cells, resulting in a less beta cell destruction, and thus prolonging IA levels and progression to T1D. However, it seems that other chemokine receptors (CCR1, 3, and 9) compensate for the loss of CCR5 expression and offer alternative pathways for recruitment.