Genome-wide association study of hematological and biochemical traits in a Japanese population

Kamatani, Yoichiro; Matsuda, Koichi; Okada, Yukinori; Kubo, Michiaki; Hosono, Naoya; Daigo, Yataro; Nakamura, Yusuke; Kamatani, Naoyuki

doi:10.1038/ng.531

Cited by 470 publications

(488 citation statements)

References 39 publications

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“…The genetic modifier of ALP is reported to have a potential influence on serum ALP activity. 17 Total ALP value is also elevated by some environmental factors, in vitamin D deficiency 2 or in the third trimester of gestation by the increasing placental ALP, which is not affected by TNSALP. 18 Recently, it was shown that patients who are homozygous for the c.1559delT mutation differed in the severity of HPP, including both their symptoms and serum ALP activity.…”

Section: Discussionmentioning

confidence: 97%

Prevalence of c.1559delT in ALPL, a common mutation resulting in the perinatal (lethal) form of hypophosphatasia in Japanese and effects of the mutation on heterozygous carriers

et al. 2010

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Hypophosphatasia (HPP) is an inherited disorder caused by mutations in ALPL that encodes an isozyme of alkaline phosphatase (ALP), TNSALP. One of the most frequent ALPL mutations is c.1559delT, which causes the most severe HPP, the perinatal (lethal) form (pl-HPP). c.1559delT has been found only in Japanese and its prevalence is suspected to be high; however, the allele frequency of c.1559delT in Japanese remains unknown. We designed a screening system for the mutation based on high-resolution melting curve analysis, and examined the frequency of c.1559delT. We found that the c.1559delT carrier frequency is 1/480 (95% confidence interval, 1/1562-1/284). This indicates that B1 in 900 000 individuals to have pl-HPP caused by a homozygous c.1559delT mutation. In our analysis, the majority of c.1559delT carriers had normal values of HPP biochemical markers, such as serum ALP and urine phosphoethanolamine. Our results indicate that the only way to reliably detect whether individuals are pl-HPP carriers is to perform the ALPL mutation analysis.

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Section: Discussionmentioning

confidence: 97%

Prevalence of c.1559delT in ALPL, a common mutation resulting in the perinatal (lethal) form of hypophosphatasia in Japanese and effects of the mutation on heterozygous carriers

et al. 2010

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“…GWAS have suggested a correlation between the TFR2 genomic region and various hematological traits [16][17][18][19]. Recent studies using mouse models of anemia have suggested that loss of Tfr2 in the erythroid compartment could be responsible for either increased RBC counts [21,22,24] or a block in the development of erythroblasts [23].…”

Section: Discussionmentioning

confidence: 99%

“…These observations are suggestive of a relation between TFR2 and erythropoiesis. This concept is also supported by recent genome wide association studies (GWAS) which found an association between TFR2 and various hematological parameters [16][17][18][19]. In one GWAS, an association was found between red blood cell (RBC) number and a SNP centered on the TFR2 gene [16], although the authors did mention that another candidate for this association could be erythropoietin (EPO) [16,18].…”

Section: Introductionmentioning

confidence: 86%

Hematopoietic deletion of transferrin receptor 2 in mice leads to a block in erythroid differentiation during iron‐deficient anemia

et al. 2016

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Iron metabolism and erythropoiesis are inherently interlinked physiological processes. Regulation of iron metabolism is mediated by the iron-regulatory hormone hepcidin. Hepcidin limits the amount of iron released into the blood by binding to and causing the internalization of the iron exporter, ferroportin. A number of molecules and physiological stimuli, including erythropoiesis, are known to regulate hepcidin. An increase in erythropoietic demand decreases hepcidin, resulting in increased bioavailable iron in the blood. Transferrin receptor 2 (TFR2) is involved in the systemic regulation of iron metabolism. Patients and mice with mutations in TFR2 develop hemochromatosis due to inappropriate hepcidin levels relative to body iron. Recent studies from our laboratory and others have suggested an additional role for TFR2 in response to iron-restricted erythropoiesis. These studies used mouse models with perturbed systemic iron metabolism: anemic mice lacking matriptase-2 and Tfr2, or bone marrow transplants from iron-loaded Tfr2 null mice. We developed a novel transgenic mouse model which lacks Tfr2 in the hematopoietic compartment, enabling the delineation of the role of Tfr2 in erythroid development without interfering with its role in systemic iron metabolism. We show that in the absence of hematopoietic Tfr2 immature polychromatic erythroblasts accumulate with a concordant reduction in the percentage of mature erythroid cells in the spleen and bone marrow of anemic mice. These results demonstrate that erythroid Tfr2 is essential for an appropriate erythropoietic response in iron-deficient anemia. These findings may be of relevance in clinical situations in which an immediate and efficient erythropoietic response is required.

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“…b On a given chromosome locus, we tabulated genes separately if they were located in different linkage disequilibrium blocks (see the "Methods" section). c P value is from Ganesh et al 4 d P value is from Kamatani et al 8 e P values were not available. f P value is from Soranzo et al 5 Chromosome 15q22.…”

Section: New Loci Associated With Rbc Traits In Individuals Of Europementioning

confidence: 99%

“…2 The RBC traits have a substantial genetic component, with heritabilities of 0.56, 0.52, and 0.52 reported for RBC count, mean corpuscular volume (MCV), and mean corpuscular hemoglobin (MCH), respectively. 3 Recently, genomewide association studies (GWAS) in cohorts of European ancestry, [4][5][6][7] as well as in a Japanese cohort, 8 have reported multiple quantitative trait loci associated with one or more RBC traits.…”

mentioning

confidence: 99%

Genetic Loci Implicated in Erythroid Differentiation and Cell Cycle Regulation Are Associated With Red Blood Cell Traits

Ding

Shameer

Jouni

et al. 2012

Mayo Clinic Proceedings

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Objective: To identify common genetic variants influencing red blood cell (RBC) traits. Patients and Methods: We performed a genomewide association study from June 2008 through July 2011 of hemoglobin, hematocrit, RBC count, mean corpuscular volume, mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration in 12,486 patients of European ancestry from the electronic MEdical Records and Genomics (eMERGE) network. We developed an electronic medical record-based algorithm that included individuals who had RBC measurements obtained for clinical care and excluded values measured in the setting of hematopoietic disorders, comorbid conditions, or medications known to affect RBC production or a recent history of blood loss. Results: We identified 4 new genetic loci and replicated 11 loci previously reported to be associated with one or more RBC traits in individuals of European ancestry. Notably, genes present in 3 of the 4 newly identified loci (THRB, PTPLAD1, CDT1) and in 6 of the 11 replicated loci (KLF1, ALDH8A1, CCND3, SPTA1, FBXO7, TFR2/EPO) are implicated in erythroid differentiation and regulation of cell cycle in hematopoietic stem cells. Conclusion: Genes in the erythroid differentiation and cell cycle regulation pathways influence interindividual variation in RBC indices. Our results provide insights into the molecular basis underlying variation in RBC traits.

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Genome-wide association study of hematological and biochemical traits in a Japanese population

Cited by 470 publications

References 39 publications

Prevalence of c.1559delT in ALPL, a common mutation resulting in the perinatal (lethal) form of hypophosphatasia in Japanese and effects of the mutation on heterozygous carriers

Prevalence of c.1559delT in ALPL, a common mutation resulting in the perinatal (lethal) form of hypophosphatasia in Japanese and effects of the mutation on heterozygous carriers

Hematopoietic deletion of transferrin receptor 2 in mice leads to a block in erythroid differentiation during iron‐deficient anemia

Genetic Loci Implicated in Erythroid Differentiation and Cell Cycle Regulation Are Associated With Red Blood Cell Traits

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