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

Nur-Aisyah Aziz,Hamid Ali Nagi Al-Jamal,Nur-Khairunnisa Kharolazaman,Nadiah Wan-Arfah Wan Abdul Jamil,Wan-Rohani Wan Taib,Imilia Ismail,Hishamshah Ibrahim,Ezalia Esa

doi:10.1038/s41598-021-96018-y

Nur-Aisyah Aziz, Hamid Ali Nagi Al-Jamal + Show 6 more

Open Access

https://doi.org/10.1038/s41598-021-96018-y

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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.

Highlights

Haemoglobin disorders are the most common monogenic disease w orldwide[1,2]
We explored a single-based and haplotype association of five intragenic HBB polymorphisms in beta-thalassemia cases from Malaysia
From the analysis of single-based association, two intronic polymorphisms; IVS2-16G>C, and IVS2-666C>T, and one variant at 3’ untranslated region to HBB gene assigned as 3’UTR + 314G>A were found significantly associated with beta-thalassemia

Summary

Introduction

Haemoglobin disorders are the most common monogenic disease w orldwide[1,2]. These inherited autosomal recessive disorders are classified according to the haemoglobin expression or synthesis. Have been done previously in the East and West Malaysia, genetic heterogeneity is more observed in multiracial population in Malaysia with a diverse spectrum of alpha (α-), beta (β-) and delta (δ-) globin genes mutations among the patients with thalassemia syndromes[7,8,9,10,11]. The identification of nucleic acid variations in the HBB gene has improved our understanding of underlying causal mutations of beta-thalassemia in Malaysia. Genetic heterogeneity is more observed among different ethnicity in Malaysia with a diverse spectrum of HBB gene mutations. Five single nucleotide polymorphisms (SNPs) within the HBB gene were evaluated to determine its significance and haplotype structure inference with beta-thalassemia in Malaysia, which was the first study conducted in Malaysia to the best of our knowledge

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