Evidence for a gene influencing haematocrit on chromosome 6q23-24: genomewide scan in the Framingham Heart Study.

F or more than 40 years, a number of studies have revealed that high haematocrit (HCT) levels are associated with increased risk for cerebrovascular disease, cardiovascular disease (CVD), peripheral vascular disease, and all cause mortality. 10–11 During 34 years of follow up in more than 5200 individuals, a Framingham investigation demonstrated that increased HCT was significantly associated with increased risks for CVD, coronary heart disease, and myocardial infarction in both men and women. A significant increase in all cause mortality for individuals with very low or high HCT was also observed. Although HCT levels were related to other vascular risk factors, the risk associated with an elevated HCT persisted after accounting for other risk factors for cardiovascular and cerebrovascular events, and for all cause mortality. 12 HCT is the percentage of whole blood that is comprised of red blood cells, and is a compound measure of red blood cell number and size. HGB is an abundant protein within red blood cells and serves as the main oxygen carrying component of red blood cells, therefore HCT and HGB are strongly correlated. From the rheological viewpoint, blood viscosity depends largely on HCT value. There is an inverse relationship between viscosity and vascular blood flow; high HCT hampers organ perfusion. Twin studies in healthy humans have suggested that HCT variation is partly determined by genetic factors with heritability estimated at 40265%. A number of gene products are known to be involved in erythropoiesis, most notably erythropoietin. However, the genes that determine an individual’s normal HCT level in the general population are unknown. A genome scan to map genes controlling HCT in the spontaneously hypertensive rat indicated a significant association between a marker on chromosome 4 and the observed variability of HCT. No association was found between HCT and erythropoietin, which was mapped to chromosome 12 in rat. So far, no linkage analysis of HCT in humans has been reported. We thus report one of the first linkage studies of HCT in the Framingham Heart Study, with the goal of identifying chromosomal regions that may contain quantitative trait loci (QTL) involved in controlling HCT. Because HCT and HGB are strongly correlated, we also carried out a genome scan on HGB. Finally, we conducted a bivariate linkage analysis of HCT and HGB.