Evidence of Genetic Interaction between the β-Globin Complex and Chromosome 8q in the Expression of Fetal Hemoglobin

During human development, the switch from fetal to adult hemoglobin (Hb) is not complete with the residual γ-globin expression being restricted to a subset of erythrocytes termed “F cells” (FC). Statistical analyses have shown the FC trait to be influenced by a common sequence variant (C→T) at position −158 upstream of the Gγ-globin gene, termed the “XmnI-Gγ polymorphism.” The XmnI-Gγ site is believed to be involved in the expression of the Gγ-globin gene through interaction with transcription factors, and polymorphisms in the transcription factors could be influencing fetal Hb expression, conditional on the XmnI-Gγ site. Using a two-locus model, in which the second locus was the known quantitative-trait locus (QTL) at the XmnI-Gγ site, we showed suggestive linkage to chromosome 8q. A maximum single-point LOD score of 4.33 and a multipoint LOD score of 4.75 were found in a 15–20 cM region of chromosome 8q. A single-locus analysis failed to show linkage of FC to the region when the XmnI-Gγ site was accounted for by removing its effects from the data or including it as a covariate. Results of the single-locus analysis were significant when the effects of the XmnI-Gγ site were not accounted for in any way. The results of analysis in a large Indian kindred indicate that there is an interaction between the XmnI-Gγ site and a QTL on chromosome 8q that is influencing the production of fetal Hb