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Literature DB >> 19820698

Genome-wide association study identifies variants in TMPRSS6 associated with hemoglobin levels.

John C Chambers¹, Weihua Zhang, Yun Li, Joban Sehmi, Mark N Wass, Delilah Zabaneh, Clive Hoggart, Henry Bayele, Mark I McCarthy, Leena Peltonen, Nelson B Freimer, Surjit K Srai, Patrick H Maxwell, Michael J E Sternberg, Aimo Ruokonen, Gonçalo Abecasis, Marjo-Riitta Jarvelin, James Scott, Paul Elliott, Jaspal S Kooner.

Abstract

We carried out a genome-wide association study of hemoglobin levels in 16,001 individuals of European and Indian Asian ancestry. The most closely associated SNP (rs855791) results in nonsynonymous (V736A) change in the serine protease domain of TMPRSS6 and a blood hemoglobin concentration 0.13 (95% CI 0.09-0.17) g/dl lower per copy of allele A (P = 1.6 x 10(-13)). Our findings suggest that TMPRSS6, a regulator of hepcidin synthesis and iron handling, is crucial in hemoglobin level maintenance.

Entities: Chemical Disease Gene Mutation Species

Mesh：

Substances：

Year: 2009 PMID： 19820698 PMCID： PMC3178047 DOI： 10.1038/ng.462

Source DB: PubMed Journal: Nat Genet ISSN： 1061-4036 Impact factor: 38.330

14 in total

Review 1. Red cells I: inherited anaemias.

Authors: D J Weatherall; A B Provan
Journal: Lancet Date: 2000-04-01 Impact factor: 79.321

2. Principal components analysis corrects for stratification in genome-wide association studies.

Authors: Alkes L Price; Nick J Patterson; Robert M Plenge; Michael E Weinblatt; Nancy A Shadick; David Reich
Journal: Nat Genet Date: 2006-07-23 Impact factor: 38.330

3. Estimation of the multiple testing burden for genomewide association studies of nearly all common variants.

Authors: Itsik Pe'er; Roman Yelensky; David Altshuler; Mark J Daly
Journal: Genet Epidemiol Date: 2008-05 Impact factor: 2.135

4. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization.

Authors: Elizabeta Nemeth; Marie S Tuttle; Julie Powelson; Michael B Vaughn; Adriana Donovan; Diane McVey Ward; Tomas Ganz; Jerry Kaplan
Journal: Science Date: 2004-10-28 Impact factor: 47.728

5. Haematological effects of the C282Y HFE mutation in homozygous and heterozygous states among subjects of northern and southern European ancestry.

Authors: Ernest Beutler; Vincent Felitti; Terri Gelbart; Jill Waalen
Journal: Br J Haematol Date: 2003-03 Impact factor: 6.998

Review 6. The type II transmembrane serine protease matriptase-2--identification, structural features, enzymology, expression pattern and potential roles.

Authors: Andrew J Ramsay; Janet C Reid; Gloria Velasco; James P Quigley; John D Hooper
Journal: Front Biosci Date: 2008-01-01

7. The serine protease TMPRSS6 is required to sense iron deficiency.

Authors: Xin Du; Ellen She; Terri Gelbart; Jaroslav Truksa; Pauline Lee; Yu Xia; Kevin Khovananth; Suzanne Mudd; Navjiwan Mann; Eva Marie Y Moresco; Ernest Beutler; Bruce Beutler
Journal: Science Date: 2008-05-01 Impact factor: 47.728

8. Membrane-bound serine protease matriptase-2 (Tmprss6) is an essential regulator of iron homeostasis.

Authors: Alicia R Folgueras; Fernando Martín de Lara; Alberto M Pendás; Cecilia Garabaya; Francisco Rodríguez; Aurora Astudillo; Teresa Bernal; Rubén Cabanillas; Carlos López-Otín; Gloria Velasco
Journal: Blood Date: 2008-06-03 Impact factor: 22.113

9. Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA).

Authors: Karin E Finberg; Matthew M Heeney; Dean R Campagna; Yeşim Aydinok; Howard A Pearson; Kip R Hartman; Mary M Mayo; Stewart M Samuel; John J Strouse; Kyriacos Markianos; Nancy C Andrews; Mark D Fleming
Journal: Nat Genet Date: 2008-04-13 Impact factor: 38.330

10. Genome-wide association study shows BCL11A associated with persistent fetal hemoglobin and amelioration of the phenotype of beta-thalassemia.

Authors: Manuela Uda; Renzo Galanello; Serena Sanna; Guillaume Lettre; Vijay G Sankaran; Weimin Chen; Gianluca Usala; Fabio Busonero; Andrea Maschio; Giuseppe Albai; Maria Grazia Piras; Natascia Sestu; Sandra Lai; Mariano Dei; Antonella Mulas; Laura Crisponi; Silvia Naitza; Isadora Asunis; Manila Deiana; Ramaiah Nagaraja; Lucia Perseu; Stefania Satta; Maria Dolores Cipollina; Carla Sollaino; Paolo Moi; Joel N Hirschhorn; Stuart H Orkin; Gonçalo R Abecasis; David Schlessinger; Antonio Cao
Journal: Proc Natl Acad Sci U S A Date: 2008-02-01 Impact factor: 11.205

94 in total

1. Natural selection on EPAS1 (HIF2alpha) associated with low hemoglobin concentration in Tibetan highlanders.

Authors: Cynthia M Beall; Gianpiero L Cavalleri; Libin Deng; Robert C Elston; Yang Gao; Jo Knight; Chaohua Li; Jiang Chuan Li; Yu Liang; Mark McCormack; Hugh E Montgomery; Hao Pan; Peter A Robbins; Kevin V Shianna; Siu Cheung Tam; Ngodrop Tsering; Krishna R Veeramah; Wei Wang; Puchung Wangdui; Michael E Weale; Yaomin Xu; Zhe Xu; Ling Yang; M Justin Zaman; Changqing Zeng; Li Zhang; Xianglong Zhang; Pingcuo Zhaxi; Yong Tang Zheng
Journal: Proc Natl Acad Sci U S A Date: 2010-06-07 Impact factor: 11.205

2. Identification of a common variant in the TFR2 gene implicated in the physiological regulation of serum iron levels.

Authors: Irene Pichler; Cosetta Minelli; Serena Sanna; Toshiko Tanaka; Christine Schwienbacher; Silvia Naitza; Eleonora Porcu; Cristian Pattaro; Fabio Busonero; Alessandra Zanon; Andrea Maschio; Scott A Melville; Maria Grazia Piras; Dan L Longo; Jack Guralnik; Dena Hernandez; Stefania Bandinelli; Elmar Aigner; Anthony T Murphy; Victor Wroblewski; Fabio Marroni; Igor Theurl; Carsten Gnewuch; Eric Schadt; Manfred Mitterer; David Schlessinger; Luigi Ferrucci; Derrick R Witcher; Andrew A Hicks; Günter Weiss; Manuela Uda; Peter P Pramstaller
Journal: Hum Mol Genet Date: 2010-12-28 Impact factor: 6.150

Review 3. Genome-wide significant associations for variants with minor allele frequency of 5% or less--an overview: A HuGE review.

Authors: Orestis A Panagiotou; Evangelos Evangelou; John P A Ioannidis
Journal: Am J Epidemiol Date: 2010-09-28 Impact factor: 4.897

Genome-wide association study identifies variants in TMPRSS6 associated with hemoglobin levels.

Review 1. Red cells I: inherited anaemias.

2. Principal components analysis corrects for stratification in genome-wide association studies.

3. Estimation of the multiple testing burden for genomewide association studies of nearly all common variants.

4. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization.

5. Haematological effects of the C282Y HFE mutation in homozygous and heterozygous states among subjects of northern and southern European ancestry.

Review 6. The type II transmembrane serine protease matriptase-2--identification, structural features, enzymology, expression pattern and potential roles.

7. The serine protease TMPRSS6 is required to sense iron deficiency.

8. Membrane-bound serine protease matriptase-2 (Tmprss6) is an essential regulator of iron homeostasis.

9. Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA).

10. Genome-wide association study shows BCL11A associated with persistent fetal hemoglobin and amelioration of the phenotype of beta-thalassemia.

1. Natural selection on EPAS1 (HIF2alpha) associated with low hemoglobin concentration in Tibetan highlanders.

2. Identification of a common variant in the TFR2 gene implicated in the physiological regulation of serum iron levels.

Review 3. Genome-wide significant associations for variants with minor allele frequency of 5% or less--an overview: A HuGE review.

4. Toenail iron, genetic determinants of iron status, and the risk of glioma.

Review 5. Liver iron sensing and body iron homeostasis.

Review 6. The liver: conductor of systemic iron balance.

7. Genes determining blood cell traits.

8. Genetic and behavioral modification of hemoglobin and iron status among first-time and high-intensity blood donors.

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

10. Targeting the hepcidin-ferroportin axis in the diagnosis and treatment of anemias.