Allelic imbalance of multiple sclerosis susceptibility genes IKZF3 and IQGAP1 in human peripheral blood

Abstract

BackgroundMultiple sclerosis is a chronic inflammatory, demyelinating disease of the central nervous system. Recent genome-wide studies have revealed more than 110 single nucleotide polymorphisms as associated with susceptibility to multiple sclerosis, but their functional contribution to disease development is mostly unknown.ResultsConsistent allelic imbalance was observed for rs907091 in IKZF3 and rs11609 in IQGAP1, which are in strong linkage disequilibrium with the multiple sclerosis associated single nucleotide polymorphisms rs12946510 and rs8042861, respectively. Using multiple sclerosis patients and healthy controls heterozygous for rs907091 and rs11609, we showed that the multiple sclerosis risk alleles at IKZF3 and IQGAP1 are expressed at higher levels as compared to the protective allele. Furthermore, individuals homozygous for the multiple sclerosis risk allele at IQGAP1 had a significantly higher total expression of IQGAP1 compared to individuals homozygous for the protective allele.ConclusionsOur data indicate a possible regulatory role for the multiple sclerosis-associated IKZF3 and IQGAP1 variants. We suggest that such cis-acting mechanisms may contribute to the multiple sclerosis association of single nucleotide polymorphisms at IKZF3 and IQGAP1.Electronic supplementary materialThe online version of this article (doi:10.1186/s12863-016-0367-4) contains supplementary material, which is available to authorized users.

Polymorphisms of IKZF3 Gene and Autoimmune Thyroid Diseases: Associated with Graves’ Disease but Not with Hashimoto’s Thyroiditis

“…This SNP has been indicated as a susceptible factor for multiple sclerosis and SLE. It has been observed in Keshari’s research that rs907091 was in strong linkage with the multiple sclerosis in Norwegian patients [26]. In consistent with our research, a study confirmed rs907091 was associated with SLE in the Chinese Han population.…”

Transcript specific regulation of expression influences susceptibility to multiple sclerosis

“…This is most evident in the IKAROS family zinc finger 3 ( IKZF3 ) - ORMDL sphingolipid biosynthesis regulator 3 ( ORMDL3 ) region on chromosome 17q12-q21 in the region implicated by the MS associated variant rs12946510 (NC_000017.11:g.39756124C>T). Two previous studies in MS have explored this region and reported correlation of the disease associated variant with either IKZF3 42 or gasdermin B ( GSDMB ) 43 but neither study explored the other genes in the region. In our study we identified ASE for all three tested genes in the region, IKZF3 , GSDMB and the zona pellucida binding protein gene 2 ( ZPBP2 ), with the greatest ASE bias observed in GSDMB .…”

Allele-specific expression of Parkinson’s disease susceptibility genes in human brain

“…First, every selected transcribed SNP was genotyped, and the heterozygous samples were further analysed for allele-specific expression by quantification of the alleles in cDNA. The cDNA ratio was then normalized to the mean gDNA allelic ratio as gDNA from the heterozygous donors determine the difference between signals when the alleles are equally represented 18 .…”

“…To analyse the allelic expression measurements of heterozygous donors, the relative allelic expression of the two alleles was calculated as delta Ct (ΔCt) = Ct (FAM) − Ct (VIC). Then, the normalized ΔCt (nΔCt) was calculated by determining the difference between the allelic ratios (ΔCt) for cDNA and the mean ΔCt of all gDNA samples 18 . Samples with Ct values > 36 were excluded from further analysis as it indicates very low gene expression levels.…”

“…By measuring transcripts from each allele of a gene using a transcribed SNP as a marker to differentiate between the two mRNA copies of heterozygous individuals, the effect of trans -acting factors on gene expression is essentially removed since the output from one allele serves as a within-sample control for the other 17 . When allele-specific expression is detected, it indicates the presence of cis -regulatory variation in high LD with the transcribed marker used to differentiate between alleles 18 .…”