Association study of IL2/IL21 and FcgRIIa: significant association with the IL2/IL21 region in Scandinavian coeliac disease families

Abstract

The first genome-wide association study performed in a UK coeliac disease (CD) case-control cohort revealed association with a linkage disequilibrium block containing the KIAA1109/Tenr/IL2/IL21 genes. Also recently, an association with a nonsynonymous polymorphism in FcgRIIa (CD32a) was reported in CD with an unusually strong P-value. We aimed to replicate the reported associations with the single nucleotide polymorphisms rs13119723 A4G and rs6822844 G4T in the KIAA1109/Tenr/ IL2/IL21 region and rs1801274 G4A in the FcgRIIa gene in a family sample consisting of 325 Swedish/Norwegian families using the robust transmission disequilibrium test. The family sample used in this study included 100 families with two or more children affected by CD and 225 families with one affected child. We could confirm significant association between the polymorphisms rs13119723 A4G and rs6822844 G4T located in the KIAA1109/Tenr/IL2/IL21 region and CD (P-value 0.001 and 0.002, respectively). However, we found no association with the FcgRIIa rs1801274 G4A polymorphism (P-value ¼ 0.3). In conclusion, our results support the KIAA1109/Tenr/IL2/IL21 region as a true CD susceptibility region.

Four novel coeliac disease regions replicated in an association study of a Swedish–Norwegian family cohort

“…Hence, successful replication in families substantiates the notion of true initial findings. We have earlier replicated the association with 4q27 (IL2/IL21), 7 and in this study we were able to replicate association with SNPs tagging four of the additional disease regions: 1q31 (RGS1), 3p21 (CCR1/CCR3/CCR2), 3q25-26 (IL12A/SCHIP1) and 3q28 (LPP). We were unable to analyse rs3184504 at 12q24 (SH2B3) because of assay failure.…”

“…Association between the 4q27 region and CD has been confirmed in independent CD populations, including our own. 7,8 In a follow-up study of the GWAS, 1020 SNPs with the lowest P-values were genotyped in a larger CD cohort, and significant associations were found for seven novel regions. 9 In the same study, the genetic CD risk accounted for by the eight non-HLA chromosomal regions was estimated to be B3-4%, whereas the risk attributed to DQ2 and DQ8 could explain B35% of the heritability.…”

Association between IL2/IL21 and SH2B3 polymorphisms and risk of celiac disease: a meta-analysis

“…IL2 is critical in cellular activation, and primary and secondary T-cell responses (Bachmann and Oxenius, 2007). In addition, it promotes the proliferation of T-cells, B-cells, and natural killer cells (Adamovic et al, 2008), and may, therefore, promote both the Th-1 and Th-2 cell responses, which induce the apoptotic death of enterocytes and/or enterocyte cytoskeleton changes. Moreover, IL21 can prolong chronic inflammation and favor tissue damage by promoting the recruitment of immune cells, the increase of autoreactive T cells, and the synthesis of extracellular matrix metalloproteinases (Fina et al, 2008).…”

“…The exact role played by rs6822844 G>T and rs6840978 C>T in CD is unclear, but both SNPs, located in the inter-gene region of IL2 and IL21, are convincing candidates for CD pathogenesis (Romanos et al, 2009). Both IL2 and IL21 cytokines are T-cell-derived and stimulate T-cell maturation and proliferation (Adamovic et al, 2008). More importantly, IL21 cooperates with IL2 to promote IFN-γ synthesis, thereby amplifying T helper cell type 1 (Th1) responses, which leads to enterocyte apoptosis by the Fas/Fas ligand (FasL) system, or interleukin 15 (IL-15)-induced perforin-granzyme and NFG2D-MIC signaling pathways (Kasaian et al, 2002).…”

“…Both IL2 and IL21 are highly interesting candidate genes for CD susceptibility, because the cytokines they encode are T-cell-derived and promote autocrine T-cell activation and proliferation (Adamovic et al, 2008). IL21 cooperates with IL2 to promote interferon gamma (IFN-γ) synthesis (Kasaian et al, 2002).…”