The molecular basis of β thalassaemia in Punjabi and Maharashtran Indians includes a multilocus aetiology involving triplicated α‐globin loci

Abstract

We have analysed 201 beta-thalassaemia (beta-thal) genes from natives of the Punjab (156) and Maharashtra states of India and found the causative mutation in 200 of them. The most common beta-globin gene mutations differed significantly between these two groups and between these groups and Indian immigrants in the U.S.A. and the U.K. In the Punjabi Indians the IVS-1, nt 1 (G-T) mutation accounted for nearly one-quarter of beta-thal genes, whereas it was 5% or less in the other groups. Likewise, the cap + 1 mutation was much more prevalent in the Punjabis, whereas the nonsense codon 15 allele had a higher frequency in the Maharashtrans of the Bombay region. The common IVS-1, nt5 allele had a frequency of 60% of beta-thal genes in the Maharastrans, 35% in North American immigrants, and only 23% in the Punjabis. Two-thirds of all beta-thal genes in Punjab were found in the merchant caste (Khatri-Arora), whereas the menial caste (Shudra) was highly represented among those with beta-thal genes in Maharashtra. Two novel beta-globin alleles were each found once; a frameshift codon 55 (+A) in Maharashtrans and a frameshift codons 47-48 (+ATCT) in Punjabis. Of three Punjabi patients with beta-thal intermedia in whom only a single severe beta-globin gene mutation was found, two had six alpha-globin genes (homozygosity for a triplicated alpha-globin locus) instead of the normal alpha-globin gene number of four. Thus, these two individuals had a multilocus aetiology of beta-thal and their parents have the unusual recurrence risk of 1 in 8 for conceiving a third with beta-thal intermedia. Since 15% of 126 alpha-globin clusters studies in Punjabis contained either single (10%) or triplicated (5%) alpha-globin genes, the alpha-globin gene number is a frequent modifier of the phenotype of beta-thal in this ethnic group.

Nucleotide −88 (C-T) promoter mutation is a common β-thalassemia mutation in the Jat Sikhs of Punjab, India

“…Surprisingly, none of the individuals with the À88 (C-T) mutation or for that matter even those who were compound heterozygous for À88 (C-T) and another b-gene mutation had a-thalassemia. This in spite of the fact that a-thalassemia is common in this region, as reported by us earlier [10,15]. It appears that this group of patients with the À88 (C-T) is a more homogenous group in whom a-thalassemia is uncommon or absent.…”

“…There are many farmers from Punjab (Jat Sikhs) settled in Haryana and UP, and so the possibility of these individuals being Jat Sikhs by caste remains. In our earlier report [15], we noted that both the individuals with the À88 (C-T) mutation were Jat Sikhs by caste. This observation is significant and should help in analyzing similar cases in the Jat Sikhs who reside not only in Punjab but also in other parts of India and have migrated to other countries, particularly to the United Kingdom, Unites States of America, and Canada.…”

“…The À88 (C-T) mutation has been reported in Africans and Asian Indians [1,2], although the number of cases reported so far in Asian Indians are very few, as all are heterozygous and the reported prevalence has been less than 2% [3,4,13]. The reports of this mutation in Asian Indians have mostly been in individuals originating from Punjab [3,14,15]. Verma et al in 1997 [3] reported this mutation in individuals from Punjab, Haryana, and Uttar Pradesh (UP).…”

Controlling -globin: a review of -globin expression and its impact on -thalassemia

“…79 Conversely, the inheritance of extra copies of α-globin can also convert the normally clinically silent phenotype of heterozygous β-thalassemia to a clinically significant anemia. 55,[80][81][82][83][84][85] In extreme cases where homozygous triplicated or quadruplicated α-globin are present, a relatively severe transfusion-dependent phenotype can emerge. 80 Hence, alterations in α-globin synthesis have considerable effect on β-thalassemic phenotypes; increased α-globin expression in heterozygous β-thalassemia leads to greater imbalance and converts a silent carrier state to a clinically significant anemia while reduced α-globin synthesis in homozygous β-thalassemia reduces the severity of anemia by restoring globin balance.…”

Correspondence

“…We did not encounter a single case of homozygosity for agene triplication with heterozygous b-thalassaemia. However, Garewal et al (1994) have reported two such cases with a clinical presentation of thalassaemia intermedia from North India. (Chang et al, 1994).…”