Association of Gγ-158C > T XmnI polymorphism with elevated HbF percentage in Sickle Cell Anemia patients: Evidence from a case-control study and meta-analysis

Abstract

Background

Sickle Cell Anemia (SCA) is a monogenic disorder characterized by significant clinical heterogeneity, much of which is modulated by fetal hemoglobin (HbF) levels. The -158C > T XmnI polymorphism (rs7482144) in the Gγ-globin gene promoter is a known genetic determinant of HbF expression. This study investigates the association of the Gγ-158C > T XmnI polymorphism with HbF levels in SCA patients from Eastern India and global evidence through a meta-analysis.

Methods

A case-control study was conducted involving 100 SCA patients and 50 healthy controls from Eastern India. Genotyping for the Gγ-158C > T XmnI polymorphism was performed using PCR-RFLP. Clinical and hematological parameters, including HbF percentage, were assessed. Genotype and allele frequencies were compared between cases and controls. A meta-analysis was performed, incorporating 591 SCA cases and 531 controls were included from 10 published studies satisfying the criteria, including the present investigation, evaluating various genetic models (T vs C, TT vs CC, TT vs CC + CT, CT vs CC, TT + CT vs CC). Heterogeneity and publication bias were assessed using standard statistical methods.

Results

SCA patients exhibited significantly higher frequencies of the T allele (76.5 %) and TT genotype (66 %) compared to controls (T allele: 37 %, TT genotype: 22 %). HbF levels were significantly elevated in TT homozygotes (21.8 ± 8.57 %) compared to CT (17.5 ± 9.51 %) and CC (13.01 ± 5.35 %) genotypes (p < 0.003). The T allele and TT genotype were strongly associated with SCA, with odds ratios (OR) of 0.18 (95 % CI: 0.11–0.30, p < 0.0001) and 0.09 (95 % CI: 0.04–0.23, p < 0.0001), respectively. Meta-analysis confirmed a significant association between the T allele and increased HbF levels in SCA across populations (T vs C: pooled OR = 0.359, 95 % CI: 0.200–0.643, p = 0.001; TT vs CC: pooled OR = 0.186, 95 % CI: 0.107–0.321, p = 0.000). Moderate heterogeneity was observed for some comparisons (I² up to 77.6 %), but no significant publication bias was detected.

Conclusion

The Gγ-158C > T XmnI polymorphism is significantly associated with increased HbF levels and a protective effect in SCA patients, both in the Eastern Indian population and globally. These findings highlight the importance of this genetic marker for prognostication and potential therapeutic targeting in SCA.