Evidence of new intragenic HBB haplotypes model for the prediction of beta-thalassemia in the Malaysian population

Abstract

This study sought to determine the potential role of HBB haplotypes to predict beta-thalassemia in the Malaysian population. A total of 543 archived samples were selected for this study. Five tagging SNPs in the beta-globin gene (HBB; NG_000007.3) were analyzed for SNP-based and haplotype association using SHEsis online software. Single-SNP-based association analysis showed three SNPs have a statistically significant association with beta-thalassemia. When Bonferroni correction was applied, four SNPs were found statistically significant with beta-thalassemia; IVS2-74T>G (padj = 0.047), IVS2-16G>C (padj = 0.017), IVS2-666C>T (padj = 0.017) and 3’UTR + 314G>A (padj = 0.002). However, 3'UTR + 233G>C did not yield a significant association with padj value = 0.076. Further investigation using combined five SNPs for haplotype association analysis revealed three susceptible haplotypes with significant p values of which, haplotypes 1-2-2-1-1 (p = 6.49 × 10−7, OR = 10.371 [3.345–32.148]), 1-2-1-1-1 (p = 0.009, OR = 1.423 [1.095–1.850] and 1-1-1-1-1 (p = 1.39 × 10−4, OR = 10.221 [2.345–44.555]). Three haplotypes showed protective effect with significant p value of which, 2-2-1-1-1 (p = 0.006, OR = 0.668 [0.500–0.893]), 1-1-2-2-1 (p = 0.013, OR = 0.357 [0.153–0.830]) and 1-1-2-1-1 (p = 0.033, OR = 0.745 [0.567–0.977]). This study has identified the potential use of intragenic polymorphic markers in the HBB gene, which were significantly associated with beta-thalassemia. Combining these five SNPs defined a new haplotype model for beta-thalassemia and further evaluation for predicting severity in beta-thalassemia.

Genetic Background Studies of Eight Common Beta Thalassemia Mutations in Thailand Using β-Globin Gene Haplotype and Phylogenetic Analysis

“…In the Thai population, the wild type was found to have high levels of heterogeneity in codon 2 (C/T), IVS II-16 (C/G) and the Hinf I polymorphism, with a minor allele frequency (MAF) of more than 30%, whereas IVS II-74 (G/T) and IVS II-81 (C/T) were found to have the least heterogeneity (MAF < 5%). However, two intragenic polymorphisms (IVS II-74 (G/T) and IVS II-81 (C/T)) have been found to have high levels of heterogeneity in other populations [ 13 , 14 , 23 ]. We compared the β-thalassemia genotype and wild type in each DAF of polymorphisms using the Fisher’s exact test.…”

“…Only two DNA polymorphisms on 3′ haplotypes are useful for studying the genetic background of β-globin genes: Ava II (IVS II-16) (rs10768683; C > G), located on the β-globin gene, and Hinf I (rs10837631; T > A), located on the 3′ β-globin gene [ 11 , 12 ]. Newly intragenic polymorphisms of the β-globin gene are informative polymorphisms in haplotype analysis associated with genetic background and clinical linkage studies of β-thalassemia mutations [ 13 , 14 , 15 ]. However, studies of these intergenic polymorphisms have yet to be comprehensively reported for the Thai population [ 16 ].…”

Activation of STAT and SMAD Signaling Induces Hepcidin Re-Expression as a Therapeutic Target for β-Thalassemia Patients

“…Thalassemia is an inherited autosomal recessive blood disorder that can be divided into either alpha (α) or beta (β) depending on the affected α or β globin chain [ 1 ]. The adult hemoglobin (HbA) consists of two α and two β (α2β2) chains in each HbA molecule [ 2 , 3 ]. Alpha-thalassemia occurs if one or more of the four alleles that code for α globin is missing or damaged [ 4 ].…”

HBB Gene Mutations and Their Pathological Impacts on HbE/β-Thalassaemia in Kuala Terengganu, Malaysia

“…Thalassaemia is a group of inherited haematologic disorders caused by defects in the synthesis of one or more of the haemoglobin chains. These are among the most common genetic diseases globally, occurring more frequently in the Mediterranean, Indian subcontinent, Southeast Asia, and West Africa [1,2].…”