Genomewide scans of red cell indices suggest linkage on chromosome 6q23

Background

The red cell indices quantify the size, number and oxygen‐carrying ability of erythrocytes. Although the genetic basis of many monogenic forms of anaemia is well understood, comparatively little is known about the genes responsible for variation in the red cell indices among healthy participants.

Objective

To identify quantitative trait loci (QTLs) responsible for normal variation in the red cell indices of 391 pairs of dizygotic twins who were measured longitudinally at 12, 14 and 16 years of age.

Results

Evidence suggesting linkage of red cell indices to haemoglobin concentration (LOD  = 3.03) and haematocrit (LOD  = 2.95) on chromosome 6q23, a region previously identified as possibly harbouring a QTL for haematocrit, was found. Evidence for linkage to several other regions of the genome, including chromosome 4q32 for red cell count and 7q for mean cell volume, was also found. In contrast, there was little evidence of linkage to the chromosomal regions containing the genes for erythropoietin (7q21) and its receptor (19p13.2), nor to the regions containing the genes for the haemoglobin α (16p13.3) and β chains (11p15.5).

Conclusion

Findings provide additional evidence for a QTL affecting haemoglobin and haematocrit on chromosome 6q23. In contrast, polymorphisms in the genes coding for erythropoietin, its receptor and the haemoglobin α and β chains do not appear to contribute substantially to variation in the red cell indices between healthy persons.The red cell indices describe the size, number and oxygen‐carrying capacity of erythrocytes. Haemoglobin concentration indicates the amount of oxygen‐carrying protein haemoglobin in a given volume of blood; red blood cell count (RBC), the concentration of erythrocytes; mean corpuscular volume (MCV), the average volume of each red cell; and haematocrit (HCT), the proportion of blood that consists of erythrocytes. Together, these indices assist in the differential diagnosis of anaemia and are risk factors for a number of clinical conditions. For example, a high haematocrit is associated with increased risk of cerebrovascular^1,2 and coronary artery diseases.¹Approximately 7% of the world''s population are carriers for different inherited disorders of haemoglobin, making them one of the most prevalent Mendelian diseases.³ Although the genetic basis of many of these haemoglobinopathies is well understood, comparatively little is known regarding the genetic causes of variation in the normal range of red cell values. Studies on twins have shown that a substantial proportion of the variation between persons is due to genetic factors with heritability estimates ranging from 20% to 96%.^4,5,6,7,8,9 A recent genomewide linkage study by Lin et al⁷ identified a locus on chromosome 6q23–24 linked to HCT, and a pleiotropic locus affecting haemoglobin and HCT on chromosome 9q.⁷ Interestingly, the authors found no evidence of linkage to regions containing the genes for the α and β haemoglobin chains (on chromosomes 16p13.3 and 11p15.5), nor erythropoietin and its receptor (on chromosomes 7q21 and 19p13.2), which have all been implicated in Mendelian forms of anaemia. The implication is that the quantitative trait loci (QTLs) responsible for normal variation in the red cell indices might differ from the loci which cause monogenic forms of anaemia.In a previous study, we reported that variation in the red cell indices was highly heritable, with genetic factors explaining between 61% and 96% of the phenotypic variance in our sample of adolescent twins.⁵ In this paper, we extend these results by performing a genomewide linkage scan of the 391 dizygotic twin pairs from that study. We measured the red cell indices of twins at 12, 14 and 16 years of age and performed univariate multipoint sib‐pair linkage analyses across the genome. Our study is the first to report linkage results for RBC and MCV, and will hopefully constitute the first stage in the identification and subsequent positional cloning of QTLs responsible for normal variation in the red cell indices.