Evidence of genetic interaction between the beta-globin complex and chromosome 8q in the expression of fetal hemoglobin

Abstract

During human development, the switch from fetal to adult hemoglobin (Hb) is not complete with the residual gamma-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 Ggamma-globin gene, termed the "XmnI-Ggamma polymorphism." The XmnI-Ggamma site is believed to be involved in the expression of the Ggamma-globin gene through interaction with transcription factors, and polymorphisms in the transcription factors could be influencing fetal Hb expression, conditional on the XmnI-Ggamma site. Using a two-locus model, in which the second locus was the known quantitative-trait locus (QTL) at the XmnI-Ggamma 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-Ggamma 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-Ggamma 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-Ggamma site and a QTL on chromosome 8q that is influencing the production of fetal Hb.

Figure 1

Null distribution of LOD scores computed under the unrestricted two-locus models. The distribution was generated from 50,000 replicates, in which a simulated marker was unlinked to QTL2. The pedigree structure, trait values, and XmnI-Gγ genotypes were identical to the analyzed data. A gene-dropping algorithm written by C.G. generated the replicate marker data.

Figure 2

Multipoint LOD scores for two groups of four markers (orders 1 and 2) computed under the unrestricted two-locus model. The two marker orders were chosen so that when combined, multipoint LOD scores would be computed approximately every 2 cM across the chromosome 8q region. Marker names are shown above the line for order 1 and below the line for order 2. Locations are given in centimorgans, starting from the most centromeric location tested. The distances between the markers were estimated using the program CRIMAP (Green et al. 1990) and by comparison with the published Généthon map (Dib et al. 1996). Likelihoods were computed using the program VITESSE (O'Connell and Weeks 1995).