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

Lin, Jianghai

doi:10.1136/jmg.2004.021097

Cited by 19 publications

(21 citation statements)

References 35 publications

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“…Consistent with present observations, recent genomewide scans report significant linkages of MCV [36], transferrin saturation [37], and hematocrit [38] with a locus or loci at 6p23-24. …”

Section: Acknowledgmentssupporting

confidence: 91%

Determinants and characteristics of mean corpuscular volume and hemoglobin concentration in white HFE C282Y homozygotes in the hemochromatosis and iron overload screening study

McLaren

Barton²,

et al. 2007

American J Hematol

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Elevated mean corpuscular volume (MCV) is common in persons with hemochromatosis associated with HFE C282Y homozygosity. We evaluated data from the subset of non-Hispanic white participants in the Hemochromatosis and Iron Overload Screening Study to determine if elevated MCV in C282Y homozygotes is related to this genotype or to serum iron measures. Regression analysis was used to model MCV and Hb from transferrin saturation (TfSat), serum ferritin (SF), mean corpuscular hemoglobin concentration, red blood cell count, age, HFE genotype, Field Center, and presence of liver-related abnormalities in C282Y homozygotes and control subjects without HFE mutations (wt/wt genotype). Mean MCV was higher in C282Y homozygotes than in HFE wt/wt controls (94.4 vs. 89.7 fL in women; 95.3 vs. 91.2 fL in men; P < 0.0001 for both). These differences were largely associated with increased mean TfSat and SF in C282Y homozygotes. Adjusted mean MCV was 92.0 fL (95% confidence interval, 91.1, 92.9) in female C282Y homozygotes and 90.9 fL (90.3, 91.5) in controls. Among women with SF in the reference range 20-200 lg/L, adjusted mean MCV was 92.9 fL, (91.7, 94.2) in C282Y homozygotes, 1.8 fL higher than in controls (P 5 0.013). The adjusted mean MCV of male C282Y homozygotes and controls was similar (P 5 0.30). Adjusted mean Hb was 0.2 g/dL higher in women with C282Y/C282Y than in controls. Greater mean MCV in C282Y homozygosity reflects increased mean TfSat and mean SF in men and women; an additional effect of genotype on MCV and Hb was detected in women. Am. J. Hematol. 82:898-905, 2007. V V C 2007 Wiley-Liss, Inc. IntroductionElevated values of mean corpuscular volume (MCV) are common in persons with hemochromatosis. In early series of hemochromatosis cases, this was attributed to hepatic cirrhosis [1], a then-current diagnostic criterion of hemochromatosis and a common sequel of severe iron overload [1,2]. In Alabama hemochromatosis probands diagnosed in medical care, mean MCV and hemoglobin concentration (Hb) were significantly greater in HFE C282Y homozygotes than in probands with other HFE genotypes or in control subjects, and 44% of all probands had prephlebotomy values of MCV greater than the upper reference limit [3]. Further, there was a significant positive association of MCV in HFE C282Y homozygotes with serum transferrin saturation (TfSat) at diagnosis and with quantities of iron removed by phlebotomy to achieve iron depletion, but not with the presence of human leukocyte antigen-A*03 [3]. In a southern California hemochromatosis screening program that evaluated persons who attended a health appraisal clinic, mean TfSat, mean serum ferritin concentration (SF), mean MCV, and mean Hb were higher than the corresponding measures in participants without common HFE mutations [4].

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“…Consistent with present observations, recent genomewide scans report significant linkages of MCV [36], transferrin saturation [37], and hematocrit [38] with a locus or loci at 6p23-24. …”

Section: Acknowledgmentssupporting

confidence: 91%

Determinants and characteristics of mean corpuscular volume and hemoglobin concentration in white HFE C282Y homozygotes in the hemochromatosis and iron overload screening study

McLaren

Barton²,

et al. 2007

American J Hematol

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“…In addition, the heritability estimate from the Framingham Offspring Study of 1,444 persons aged 10-64 (mean: 33 years) was 0.45. 13 Other erythrocyte indices also have significant heritability. Overall, these data indicate that variation in hemoglobin concentration is significantly influenced by genetic factors; however, the combinations of genes that regulate hemoglobin level remain to be identified.…”

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confidence: 99%

Variability and heritability of hemoglobin concentration: an opportunity to improve understanding of anemia in older adults

Patel¹

2008

Haematologica

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“…However, other QTL that map to the 80-90 Mbp chromosome 4 interval include loci that control the immune response (Ifa and Ifb), splenomegaly (Sbw2, Orgwg6 and Spm1), and anti-red blood cell IgG antibodies (Arigg3), which have been implicated in mouse models of autoimmune haemolytic anaemia and systemic lupus erythrematosus [7][8][9]. Significantly, a mouse anti-erythrocyte autoantibody modifier locus (Aem3) and anti-nuclear autoantibody locus (Bana2) co-localise to the suggestive E/NE bone marrow cell ratio QTL on chromosome 10, and a human haematocrit level QTL has also been mapped to chromosome 6q23-24, syntenic to mouse chromosome 10 QTL [1].…”

Section: Discussionmentioning

confidence: 99%

“…Thus, low peripheral red blood cell (pRBC) counts cause anaemia, whereas a high haematocrit increases the risk of cerebral infarction, cardiovascular disease and hypertension [1,2]. Maturation of erythrocytes is crucially dependent upon production of erythropoietin (epo) in response to tissue hypoxia.…”

Section: Introductionmentioning

confidence: 99%

“…There have not, up until now, been QTL studies reported using RBC counts as the phenotype, but Lin et al carried out a study using families from the Framingham Heart Study with haematocrit and haemoglobin levels as the phenotypes [1]. The study found evidence for a haematocrit QTL on chromosome 6q23-24 (mouse Chr10, 18-25Mb) and one effecting haematocrit and total haemoglobin on 9q34 (mouse Chr1, 65-70Mb).…”

Section: Introductionmentioning

confidence: 99%

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Mouse bone marrow and peripheral blood erythroid cell counts are regulated by different autosomal genetic loci

Jawad¹,

Giotopoulos²,

Fitch³

et al. 2007

Blood Cells, Molecules, and Diseases

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1 SummaryErythropoiesis is under fine control and genetic loci that effect it are likely to be important in a range of conditions. To assess the relative contributions of different genetic loci to parameters of erythropoiesis we have measured RBC counts in the peripheral circulation and committed erythroid cells (RBC and small normoblasts) in the bone marrow in a cohort of (CBA/H x C57BL/6) F2 mice to map quantitative trait loci (QTL). Candidate genes were assessed using bioinformatics and DNA sequencing.Different autosomal loci affect bone marrow (chromosomes 5, 11, and 19) and peripheral blood (chromosome 4) erythroid cell counts but there may be a common chromosome X locus. Spleen weight QTL were found on chromosomes 3, 15 and 17. Surprisingly, erythropoietin (EPO) is the best candidate quantitative trait gene (QTG) in the chromosome 5 locus that affects bone marrow but not peripheral blood erythroid cell counts. Epo gene expression is known to be genetically regulated in mice, but our data suggests a tissue-specific role for epo in mouse erythropoiesis that is also genetically determined. The identity of the other QTG will be important both to further knowledge of the control of erythropoiesis and as potential modifier genes for haematological disorders.

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

Cited by 19 publications

References 35 publications

Determinants and characteristics of mean corpuscular volume and hemoglobin concentration in white HFE C282Y homozygotes in the hemochromatosis and iron overload screening study

Determinants and characteristics of mean corpuscular volume and hemoglobin concentration in white HFE C282Y homozygotes in the hemochromatosis and iron overload screening study

Variability and heritability of hemoglobin concentration: an opportunity to improve understanding of anemia in older adults

Mouse bone marrow and peripheral blood erythroid cell counts are regulated by different autosomal genetic loci

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