Study of the Association Between the CAPSL-IL7R Locus and Type 1 Diabetes

Overview

Journal Diabetologia

Specialty Endocrinology

Date 2008 Jun 20

PMID 18563381

Citations 24

Authors

J L Santiago

B Z Alizadeh

A Martinez

L Espino

H de la Calle

M Fernandez-Arquero

M A Figueredo

E G de la Concha

B O Roep

B P C Koeleman

E Urcelay

Affiliations

Soon will be listed here.

Abstract

Aims/hypothesis: In the past few years, several genes outside the MHC region have been described as new susceptibility genetic factors to type 1 diabetes. An association between CAPSL-rs1445898 and type 1 diabetes was reported in a large white population and corroborated in a genome-wide analysis, which also found an association with IL7R, which is located adjacent to CAPSL. The aim of this study was to replicate the aforementioned associations in independent cohorts.

Methods: We analysed two CAPSL (rs1010601 and rs1445898) and three IL7R (rs6897932, rs987106 and rs3194051) polymorphisms. All these single nucleotide polymorphisms (SNPs) were genotyped using TaqMan minor groove binder chemistry in 301 unrelated Spanish type 1 diabetes patients and 646 healthy controls. Additionally, the associated CAPSL SNP rs1445898 was genotyped in a Dutch cohort consisting of 429 type 1 diabetes patients and 720 healthy controls.

Results: The homozygous mutant genotype of the CAPSL SNP rs1445898 showed a trend towards a protective effect in the overall Spanish cohort (OR [95% CI] 0.70 [0.44-1.09]; p = 0.09) and in the Dutch cohort (OR [95% CI] 0.74 [0.51-1.05]; p = 0.09). Pooling of both cohorts was performed, yielding a statistically significant difference (Mantel-Haenszel OR 0.71; p = 0.005). This protective effect was significantly different in early-onset vs late-onset Spanish patients (OR [95% CI] 0.26 [0.10-0.65]; p = 0.001). Similarly, in the early-onset subgroup, the homozygous mutant genotype of the IL7R SNP rs6897932 showed a similar protective effect (OR [95% CI] 0.18 [0.02-0.94]; p = 0.02).

Conclusions/interpretation: In summary, we describe an independent replication of the association between the CAPSL-IL7R locus and type 1 diabetes, especially for early-onset type 1 diabetes patients.

Citing Articles

Genome-wide KAS-Seq mapping of leukocytes in ischemia-reperfusion model reveals IL7R as a potential therapeutic target for ischemia-reperfusion injury.

Zhang L, Duolikun M, Chen H, Wang Z, Li X, Xiao H Sci Rep. 2025; 15(1):6165.

PMID: 39979392 PMC: 11842730. DOI: 10.1038/s41598-025-90457-7.

Prevalence of Selected Polymorphisms of Il7R, CD226, CAPSL, and CLEC16A Genes in Children and Adolescents with Autoimmune Thyroid Diseases.

Borysewicz-Sanczyk H, Wawrusiewicz-Kurylonek N, Goscik J, Sawicka B, Bossowski F, Corica D Int J Mol Sci. 2024; 25(7).

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single nucleotide polymorphisms are associated with the size and function of the MAIT cell population in treated HIV-1 infection.

Han F, Gulam M, Zheng Y, Zulhaimi N, Sia W, He D Front Immunol. 2022; 13:985385.

PMID: 36341446 PMC: 9632172. DOI: 10.3389/fimmu.2022.985385.

Soluble IL-7Rα/sCD127 in Health, Disease, and Its Potential Role as a Therapeutic Agent.

Barros P, Berthoud T, Aloufi N, Angel J Immunotargets Ther. 2021; 10:47-62.

PMID: 33728276 PMC: 7954429. DOI: 10.2147/ITT.S264149.

IL7RA genetic variants differentially affect IL-7Rα expression and alternative splicing: a role in autoimmune and infectious diseases?.

Lundtoft C, Seyfarth J, Jacobsen M Genes Immun. 2020; 21(2):83-90.

PMID: 31929513 DOI: 10.1038/s41435-019-0091-y.

References

Giliani S, Mori L, de Saint Basile G, Le Deist F, Rodriguez-Perez C, Forino C . Interleukin-7 receptor alpha (IL-7Ralpha) deficiency: cellular and molecular bases. Analysis of clinical, immunological, and molecular features in 16 novel patients. Immunol Rev. 2005; 203:110-26. DOI: 10.1111/j.0105-2896.2005.00234.x. View

Barratt B, Payne F, Lowe C, Hermann R, Healy B, Harold D . Remapping the insulin gene/IDDM2 locus in type 1 diabetes. Diabetes. 2004; 53(7):1884-9. DOI: 10.2337/diabetes.53.7.1884. View

Ueda H, Howson J, Esposito L, Heward J, Snook H, Chamberlain G . Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature. 2003; 423(6939):506-11. DOI: 10.1038/nature01621. View

Gabriel S, Schaffner S, Nguyen H, Moore J, Roy J, Blumenstiel B . The structure of haplotype blocks in the human genome. Science. 2002; 296(5576):2225-9. DOI: 10.1126/science.1069424. View

Nistico L, Buzzetti R, Pritchard L, Van der Auwera B, Giovannini C, Bosi E . The CTLA-4 gene region of chromosome 2q33 is linked to, and associated with, type 1 diabetes. Belgian Diabetes Registry. Hum Mol Genet. 1996; 5(7):1075-80. DOI: 10.1093/hmg/5.7.1075. View

Kondo M, Takeshita T, Higuchi M, Nakamura M, Sudo T, Nishikawa S . Functional participation of the IL-2 receptor gamma chain in IL-7 receptor complexes. Science. 1994; 263(5152):1453-4. DOI: 10.1126/science.8128231. View

Machen J, Harnaha J, Lakomy R, Styche A, Trucco M, Giannoukakis N . Antisense oligonucleotides down-regulating costimulation confer diabetes-preventive properties to nonobese diabetic mouse dendritic cells. J Immunol. 2004; 173(7):4331-41. DOI: 10.4049/jimmunol.173.7.4331. View

. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature. 2007; 447(7145):661-78. PMC: 2719288. DOI: 10.1038/nature05911. View

Hafler D, Compston A, Sawcer S, Lander E, Daly M, De Jager P . Risk alleles for multiple sclerosis identified by a genomewide study. N Engl J Med. 2007; 357(9):851-62. DOI: 10.1056/NEJMoa073493. View

10.

Bottini N, Musumeci L, Alonso A, Rahmouni S, Nika K, Rostamkhani M . A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. Nat Genet. 2004; 36(4):337-8. DOI: 10.1038/ng1323. View

11.

Todd J, Walker N, Cooper J, Smyth D, Downes K, Plagnol V . Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes. Nat Genet. 2007; 39(7):857-64. PMC: 2492393. DOI: 10.1038/ng2068. View

12.

Concannon P, Erlich H, Julier C, Morahan G, Nerup J, Pociot F . Type 1 diabetes: evidence for susceptibility loci from four genome-wide linkage scans in 1,435 multiplex families. Diabetes. 2005; 54(10):2995-3001. DOI: 10.2337/diabetes.54.10.2995. View

13.

Roifman C, Zhang J, Chitayat D, Sharfe N . A partial deficiency of interleukin-7R alpha is sufficient to abrogate T-cell development and cause severe combined immunodeficiency. Blood. 2000; 96(8):2803-7. View

14.

Pociot F, McDermott M . Genetics of type 1 diabetes mellitus. Genes Immun. 2002; 3(5):235-49. DOI: 10.1038/sj.gene.6363875. View

15.

Watanabe M, Ueno Y, Yajima T, Iwao Y, Tsuchiya M, Ishikawa H . Interleukin 7 is produced by human intestinal epithelial cells and regulates the proliferation of intestinal mucosal lymphocytes. J Clin Invest. 1995; 95(6):2945-53. PMC: 295983. DOI: 10.1172/JCI118002. View

16.

Barrett J, Fry B, Maller J, Daly M . Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics. 2004; 21(2):263-5. DOI: 10.1093/bioinformatics/bth457. View

17.

Smyth D, Cooper J, Bailey R, Field S, Burren O, Smink L . A genome-wide association study of nonsynonymous SNPs identifies a type 1 diabetes locus in the interferon-induced helicase (IFIH1) region. Nat Genet. 2006; 38(6):617-9. DOI: 10.1038/ng1800. View

18.

Bell G, Horita S, KARAM J . A polymorphic locus near the human insulin gene is associated with insulin-dependent diabetes mellitus. Diabetes. 1984; 33(2):176-83. DOI: 10.2337/diab.33.2.176. View

19.

Harnaha J, Machen J, Wright M, Lakomy R, Styche A, Trucco M . Interleukin-7 is a survival factor for CD4+ CD25+ T-cells and is expressed by diabetes-suppressive dendritic cells. Diabetes. 2005; 55(1):158-70. View