Ann Hematol (2006) 85: 25–28 DOI 10.1007/s00277-005-1092-7 ORIGINAL ARTICLE Angel F. Remacha . Joan C. Souto . José Manuel Soria . Alfonso Buil . M. Pilar Sardà . Mark Lathrop . John Blangero . Laura Almasy . Jordi Fontcuberta Genomewide linkage analysis of soluble transferrin receptor plasma levels Received: 29 March 2005 / Accepted: 12 July 2005 / Published online: 23 August 2005 # Springer-Verlag 2005 Abstract Genetic control of soluble transferrin receptor (sTfR) levels was demonstrated using family-based studies (GAIT, Genetic Analysis of Idiopathic Thrombophilia project); moreover, a genetic relationship was observed between sTfR and the risk for thrombosis, suggesting that these phenotypes shared genetic determinants. We studied the regions that control sTfR. To assess such regions, a full genome scan was carried out using 604 highly polymor- phic deoxyribonucleic acid markers (resolution 7.3 cM) in 21 extended pedigrees (358 individuals). Then, a quanti- tative trait linkage analysis was performed using variance components methods. The genomewide scan linkage anal- ysis showed two regions (quantitative trait locus or QTL) with significant limit of detection (LOD) scores (2q23.14, LOD score=2.64, nominal p=0.00024; 3q21.2, LOD score=1.94, nominal p=0.0014). There were no obvious candidate genes in these regions. In conclusion, this linkage analysis suggested the existence of a QTL in 2q23.14 that probably harbored a gene (or genes) controlling sTfR lev- els. Moreover, a second linkage signal was observed in 3q21.2; albeit the evidence for this second locus was lower. The next step will be to identify the gene(s) and its possible involvement in thrombosis and iron homeostasis. Keywords Iron metabolism . Thrombosis . Transferrin receptor . Family studies . Heritability . Linkage study Introduction The most common human diseases (e.g., diabetes and thrombophilia) are complex diseases, which are caused by a combination of genetics and environmental factors. To investigate genetic factors in these complex diseases, two strategies have been developed. Generally, most studies on complex diseases have been association studies because their samples are much easier to recruit. Nevertheless, these association studies present a number of drawbacks (knowl- edge on candidate genes, false-positive results, and impossi- bility to establish causality) [1, 2]. In contrast, family-based studies are less often carried out owing to recruitment dif- ficulty. However, family-based studies are statistically ro- bust; they do not need knowledge on genes and they are capable of establishing causality [1, 2]. In studying complex diseases, it is easy and fruitful to investigate intermediate phenotypes that are potentially related to the disease (e.g., glucose level and diabetes mellitus). Family studies could be divided into different stages. The first stage is the assessment of genetic and environmental influences. Genetic influence is expressed as heritability (h 2 ), which is the proportion of the variability of a phenotype controlled by genes. As a result of this first analysis, the relationship between the intermediate pheno- types and the risk for the complex disease is established [1, 3]. The second stage is the identification of the regions of the genome (quantitative trait locus or QTL) that in- fluence the variability of the phenotype by linkage anal- ysis [4–7]. The third stage is the identification of genes in the region [7, 8]. The last stage is the determination of functional polymorphism within these genes [7, 9, 10]. The Genetic Analysis of Idiopathic Thrombophilia (GAIT) project was designed to look for genetic risk factors for thrombosis through analyses of intermediate phenotypes. Well-established intermediate phenotypes (Factor VIII, Fac- tor II, or homocysteine) have been included [11]; moreover, other intermediate phenotypes, such as iron-related param- eters, were added, given that a relationship between iron and thrombosis had been hypothesized [12, 13]. The esti- mate for thrombosis heritability was very high (0.61±0.16; A. F. Remacha (*) . J. C. Souto . J. M. Soria . A. Buil . M. P. Sardà . J. Fontcuberta Hematology Department, Hospital de Sant Pau, Avda Padre Claret 167, Barcelona, 08025, Spain e-mail: aremacha@hsp.santpau.es Tel.: +34-93-2919290 Fax: +34-93-2919192 M. Lathrop Centre National de Genotypage, Evry, France J. Blangero . L. Almasy Southwest Foundation for Biomedical Research, San Antonio, TX, USA