<b><i>ANTXR1</i></b> Intronic Variants Are Associated with Fetal Hemoglobin in the Arab-Indian Haplotype of Sickle Cell Disease

Abstract

Disease severity of sickle cell anemia is highly variable, and it is commonly accepted that fetal hemoglobin (HbF) levels play a major role as an ameliorating factor. Investigation of genetic variants have identified several genes to be the principal influencers of HbF regulation. Here, we further elucidated the association of rs4527238 and rs35685045 of ANTXR1 genes in the context of HbF level variance in sickle cell anemia patients of the Arab-Indian haplotype. Samples from 630 sickle cell anemia patients were analyzed for the mutations at 2 specific locations of the ANTXR1 gene by TaqMan®-based real-time PCR. The CC genotype (p = 0.018) of rs4527238 and the TT genotype (p = 0.048) of rs35685045 of ANTXR1 were found to be significantly associated with low HbF expression. The frequency of the CC genotype of rs4527238 was observed to be high in the low HbF patient group compared to the high HbF group (p = 0.009). Likewise, the frequency of the TT genotype of rs35685045 was also high among the low HbF group (p = 0.017). The ANTXR1 genetic mutations and the association with HbF expression in the Arab-Indian haplotype sickle cell patients revealed that the ANTXR1 gene may be a major HbF modulator leading to potential therapeutic options that should be further explored.

Transmembrane Protein ANTXR1 Regulates γ-Globin Expression by Targeting the Wnt/β-Catenin Signaling Pathway

“…Anthrax toxin receptor 1 (ANTXR1), a type I transmembrane protein, also known as tumor endothelial marker 8 (TEM8), was initially identified because of its overexpression in the endothelial cells (ECs) that is associated with human colorectal cancer [ 9 – 12 ] Previous studies had not shown an association between ANTXR1 and hematological phenotypes until the recent finding that a single nucleotide polymorphism (SNP, rs4527238, T>C) in intron 9 of the ANTXR1 gene was associated with the regulation of HbF levels in Saudi patients with SCD [ 13 ]. Several other studies and our research reconfirmed that the genotypes of two SNPs (rs4527238 and rs35685045) in the ANTXR1 gene were associated with HbF levels in individuals with β -thalassemia minor and sickle cell anemia [ 14 ]. These findings suggest that ANTXR1 is involved in the regulation of γ -globin gene expression.…”

Protocol for “Genetic composition of sickle cell disease in the Arab population: A systematic review”

“…El‐Hazmi et al described the genotypes and phenotypes of SCD in the Arab population in 2011 8 . Since then, there have been many new studies describing variants of SCD genotypes and phenotypes, and with the emerging era of gene therapy for SCD, it is essential to compile the current evidence, especially in the last 5 years 22‐44 . We will pool all data describing the genotypic and phenotypic variants of SCD in the Arab population to date in a systematic review.…”

A New <b><i>Trans</i></b>-Acting Modulator of Fetal Hemoglobin?

“…In the last issue of Acta Haematologica, Al-Ali et al [7] replicated the original observations in 630 new AI haplotype homozygotes and used different methods of genotyping and analysis, thereby lending further credence to this association. Unfortunately, association provides no information about causation.…”