New loci associated with blood measurements

23 October 2009

Blood measurements are commonly used clinical parameters, with abnormal results potentially indicative of many different diseases including anaemia, cancer, cardiovascular, metabolic, infectious and immune conditions. Blood measurements such as the number and volume of cells are highly heritable, and vary widely between individuals. The HaemGen consortium was established to search for genetic loci that contribute to variation in blood parameters, and to assess potential correlations with disease outcomes. Soranzo et al. recently reported the findings of the first systematic genome-wide meta-analysis of eight clinically relevant haematological traits [Soranzo et al. Nat Genet (2009) doi:10.1038/ng.467]. The consortium measured six parameters directly (concentration of haemoglobin, the numbers of red blood cells, white blood cells and platelets, and the volumes of red blood cells and platelets) and derived the two red cell measures of mean corpuscular haemoglobin content and concentration.

The first stage of their study made use of more than 4,500 healthy individuals of British and European ancestry with genotyping data for over 2 million SNPs. Using a meta-analysis to combine the results, the most promising 89 SNPs were then analysed in a further 9,000 individuals of European ancestry. In all, 23 of these SNPs were found to reach genome-wide significance in the combined sample of almost 14,000 individuals. Of the 22 loci represented by these 23 SNPs – of which 15 were novel discoveries – six loci were strongly associated with red blood cell parameters, 15 with platelet parameters and only one with total white blood cell count. No loci linked to haemoglobin concentration or mean corpuscular haemoglobin concentration were identified at genome-wide significance level.

The 23 SNPs were then examined for associations with coronary disease, because of known associations between several blood traits and coronary artery disease or myocardial infarction. An initial stage tested association with 4,000 cases and almost 6,000 controls of European ancestry, identifying two SNPs (both from the 12q24 region) of nominal significance (p<0.05) that were further tested in an additional 5,500 cases and 4,500 controls. Both SNPs, which are in high linkage disequilibrium, also showed association in this second stage. Further investigations identified these genetic variants as unique to individuals of European ancestry. The authors suggest that they may have conferred a selective advantage thousands of years ago for their increased protection against infection, but may now contribute to an increased risk of heart disease, coeliac disease and type 1 diabetes.

Comment: Blood measurements are an important clinical tool. This study has discovered novel genetic determinants of blood cell parameters ’providing important insights into novel biological mechanisms underlying the formation of blood cells by the blood stem cells and their role in disease’. A greater understanding of the genetics underlying blood parameter variation may lead to more refined disease risk stratification and disease prognosis for conditions such as blood cell cancer.

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