Page 21 - 2022_03-Haematologica-web

its function is lacking. TIMMDC1 is a membrane embed- ded mitochondrial complex factor, and is associated with mitochondrial disorders.32 The protein encoded by the CD80 gene functions as a membrane receptor being acti- vated by CTLA-4 or CD28, both of which are T-cell receptors. The downstream mechanisms are T-cell prolif- eration and cytokine production. CD80 and its receptors have been associated with focal segmental glomeruloscle- rosis33 and systemic lupus erythematosus.34,35 POGLUT1 (protein O-glucosyltransferase 1) is mutated in Dowling- Degos disease-4 (an autosomal dominant genodermatosis with progressive and disfiguring reticulate hyperpigmen- tation and muscular dystrophy, OMIM 615696) and POGLUT1 has been shown to catalyse O-glycosylation of epidermal growth factor (EGF)-like repeats.36,37 EGF- like repeats are well conserved structures, and highly rep- resented with proteins involved in coagulation.38,39 In vitro work has demonstrated POGLUT1 binds and glycosy- lates specific coagulation factors including factor VII and factor IX.37,40
The haploblock identified in this analysis of iTTP (which is tagged by rs9884090(A)) is associated with sig- nificantly decreased POGLUT1 expression by eQTL.41 Several other genetic variants contained within this hap- loblock have been associated with other autoimmune dis- eases, and the majority of these variants have been shown to be in linkage with our lead variant rs9884090 (see the Online Supplementary Appendix), supporting the findings described here.28,29,31,42,43,44 eQTL analysis is a robust tool, that can associate gene expression with spe-
cific genetic variants. Our analysis found rs9884090(A) to have a reduced frequency in iTTP, and rs9884090(A) was shown to be associated with significantly decreased POGLUT1 expression in different eQTL resources.18,22 In order to locate the underlying genetic variant implicated in this reduced POGLUT1 expression we used LD-link to identify additional variants, and located a 2-basepair dele- tion with the POGLUT1 upstream promoter region that is in tight linkage disequilibrium with the lead associated variant (R2/D’>0.80). As rs9884090(A) confers reduced risk of developing iTTP, we hypothesize that reduced expression of POGLUT1 leads to altered posttranslational modification (O-glycosylation) of key POGLUT1 targets to reduce the risk of iTTP. The evidence we present sup- ports POGLUT1 as the gene of interest, but we cannot exclude other genes within the associated haploblock. The pathway through which POGLUT1’s effects could be mediated remains to be determined. Given there are several reported variants with this haploblock associated with different autoimmune disease, it is likely the down- stream functional consequences medicated through POG- LUT1 influence immune-regulatory pathways which may generally increase the risk of other autoimmune dis- ease, in addition to iTTP, and may provide insights into potential therapies.45–56
In summary, we have identified a novel genetic variant, rs9884090(A), in two independent populations, which is associated with reduced risk of iTTP. Utilizing linkage disequilibrium we have identified a functional variant in tight LD with the lead SNP in the POGLUT1 promoter
Genome wide association study in Immune TTP
Figure 1. Manhattan plot of genome wide association analysis comparing UK immune thrombotic thrombocytopenic purpura discovery cohort compared with con- trols. The x-axis shows chromosome location, and the y-axis shows negative logarithmic P-values. Standardized genome wide significant 5x10-8 is depicted by the red line. The human leukocyte antigen peak is visualized on chromosome 6 (black), in addition to the novel chromosome 3 association (orange).
haematologica | 2022; 107(3)
577