title: Common variants at 10 genomic loci influence hemoglobin A₁(C) levels via glycemic and nonglycemic pathways.
abstract: OBJECTIVE
  Glycated hemoglobin (HbA₁(c)), used to monitor and diagnose diabetes, is influenced by average glycemia over a 2- to 3-month period. Genetic factors affecting expression, turnover, and abnormal glycation of hemoglobin could also be associated with increased levels of HbA₁(c). We aimed to identify such genetic factors and investigate the extent to which they influence diabetes classification based on HbA₁(c) levels.
  
  
  METHODS
  We studied associations with HbA₁(c) in up to 46,368 nondiabetic adults of European descent from 23 genome-wide association studies (GWAS) and 8 cohorts with de novo genotyped single nucleotide polymorphisms (SNPs). We combined studies using inverse-variance meta-analysis and tested mediation by glycemia using conditional analyses. We estimated the global effect of HbA₁(c) loci using a multilocus risk score, and used net reclassification to estimate genetic effects on diabetes screening.
  
  
  RESULTS
  Ten loci reached genome-wide significant association with HbA(1c), including six new loci near FN3K (lead SNP/P value, rs1046896/P = 1.6 × 10⁻²⁶), HFE (rs1800562/P = 2.6 × 10⁻²⁰), TMPRSS6 (rs855791/P = 2.7 × 10⁻¹⁴), ANK1 (rs4737009/P = 6.1 × 10⁻¹²), SPTA1 (rs2779116/P = 2.8 × 10⁻⁹) and ATP11A/TUBGCP3 (rs7998202/P = 5.2 × 10⁻⁹), and four known HbA₁(c) loci: HK1 (rs16926246/P = 3.1 × 10⁻⁵⁴), MTNR1B (rs1387153/P = 4.0 × 10⁻¹¹), GCK (rs1799884/P = 1.5 × 10⁻²⁰) and G6PC2/ABCB11 (rs552976/P = 8.2 × 10⁻¹⁸). We show that associations with HbA₁(c) are partly a function of hyperglycemia associated with 3 of the 10 loci (GCK, G6PC2 and MTNR1B). The seven nonglycemic loci accounted for a 0.19 (% HbA₁(c)) difference between the extreme 10% tails of the risk score, and would reclassify ∼2% of a general white population screened for diabetes with HbA₁(c).
  
  
  CONCLUSIONS
  GWAS identified 10 genetic loci reproducibly associated with HbA₁(c). Six are novel and seven map to loci where rarer variants cause hereditary anemias and iron storage disorders. Common variants at these loci likely influence HbA₁(c) levels via erythrocyte biology, and confer a small but detectable reclassification of diabetes diagnosis by HbA₁(c).
authors.affiliation: Human Genetics, Wellcome Trust Sanger Institute, Hinxton, U.K.
authors.forename: Nicole
authors.initials: N
authors.lastname: Soranzo
authors.forename: Serena
authors.initials: S
authors.lastname: Sanna
authors.forename: Eleanor
authors.initials: E
authors.lastname: Wheeler
authors.forename: Christian
authors.initials: C
authors.lastname: Gieger
authors.forename: Dörte
authors.initials: D
authors.lastname: Radke
authors.forename: Josée
authors.initials: J
authors.lastname: Dupuis
authors.forename: Nabila
authors.initials: N
authors.lastname: Bouatia-Naji
authors.forename: Claudia
authors.initials: C
authors.lastname: Langenberg
authors.forename: Inga
authors.initials: I
authors.lastname: Prokopenko
authors.forename: Elliot
authors.initials: E
authors.lastname: Stolerman
authors.forename: Manjinder S
authors.initials: MS
authors.lastname: Sandhu
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Heeney
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Devaney
authors.forename: Muredach P
authors.initials: MP
authors.lastname: Reilly
authors.forename: Sally L
authors.initials: SL
authors.lastname: Ricketts
authors.forename: Alexandre F R
authors.initials: AF
authors.lastname: Stewart
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Voight
authors.forename: Christina
authors.initials: C
authors.lastname: Willenborg
authors.forename: Benjamin
authors.initials: B
authors.lastname: Wright
authors.forename: David
authors.initials: D
authors.lastname: Altshuler
authors.forename: Dan
authors.initials: D
authors.lastname: Arking
authors.forename: Beverley
authors.initials: B
authors.lastname: Balkau
authors.forename: Daniel
authors.initials: D
authors.lastname: Barnes
authors.forename: Eric
authors.initials: E
authors.lastname: Boerwinkle
authors.forename: Bernhard
authors.initials: B
authors.lastname: Böhm
authors.forename: Amélie
authors.initials: A
authors.lastname: Bonnefond
authors.forename: Lori L
authors.initials: LL
authors.lastname: Bonnycastle
authors.forename: Dorret I
authors.initials: DI
authors.lastname: Boomsma
authors.forename: Stefan R
authors.initials: SR
authors.lastname: Bornstein
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Böttcher
authors.forename: Suzannah
authors.initials: S
authors.lastname: Bumpstead
authors.forename: Mary Susan
authors.initials: MS
authors.lastname: Burnett-Miller
authors.forename: Harry
authors.initials: H
authors.lastname: Campbell
authors.forename: Antonio
authors.initials: A
authors.lastname: Cao
authors.forename: John
authors.initials: J
authors.lastname: Chambers
authors.forename: Robert
authors.initials: R
authors.lastname: Clark
authors.forename: Francis S
authors.initials: FS
authors.lastname: Collins
authors.forename: Josef
authors.initials: J
authors.lastname: Coresh
authors.forename: Eco J C
authors.initials: EJ
authors.lastname: de Geus
authors.forename: Mariano
authors.initials: M
authors.lastname: Dei
authors.forename: Panos
authors.initials: P
authors.lastname: Deloukas
authors.forename: Angela
authors.initials: A
authors.lastname: Döring
authors.forename: Josephine M
authors.initials: JM
authors.lastname: Egan
authors.forename: Roberto
authors.initials: R
authors.lastname: Elosua
authors.forename: Luigi
authors.initials: L
authors.lastname: Ferrucci
authors.forename: Nita
authors.initials: N
authors.lastname: Forouhi
authors.forename: Caroline S
authors.initials: CS
authors.lastname: Fox
authors.forename: Christopher
authors.initials: C
authors.lastname: Franklin
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Franzosi
authors.forename: Sophie
authors.initials: S
authors.lastname: Gallina
authors.forename: Anuj
authors.initials: A
authors.lastname: Goel
authors.forename: Jürgen
authors.initials: J
authors.lastname: Graessler
authors.forename: Harald
authors.initials: H
authors.lastname: Grallert
authors.forename: Andreas
authors.initials: A
authors.lastname: Greinacher
authors.forename: David
authors.initials: D
authors.lastname: Hadley
authors.forename: Alistair
authors.initials: A
authors.lastname: Hall
authors.forename: Anders
authors.initials: A
authors.lastname: Hamsten
authors.forename: Caroline
authors.initials: C
authors.lastname: Hayward
authors.forename: Simon
authors.initials: S
authors.lastname: Heath
authors.forename: Christian
authors.initials: C
authors.lastname: Herder
authors.forename: Georg
authors.initials: G
authors.lastname: Homuth
authors.forename: Jouke-Jan
authors.initials: JJ
authors.lastname: Hottenga
authors.forename: Rachel
authors.initials: R
authors.lastname: Hunter-Merrill
authors.forename: Thomas
authors.initials: T
authors.lastname: Illig
authors.forename: Anne U
authors.initials: AU
authors.lastname: Jackson
authors.forename: Antti
authors.initials: A
authors.lastname: Jula
authors.forename: Marcus
authors.initials: M
authors.lastname: Kleber
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Knouff
authors.forename: Augustine
authors.initials: A
authors.lastname: Kong
authors.forename: Jaspal
authors.initials: J
authors.lastname: Kooner
authors.forename: Anna
authors.initials: A
authors.lastname: Köttgen
authors.forename: Peter
authors.initials: P
authors.lastname: Kovacs
authors.forename: Knut
authors.initials: K
authors.lastname: Krohn
authors.forename: Brigitte
authors.initials: B
authors.lastname: Kühnel
authors.forename: Johanna
authors.initials: J
authors.lastname: Kuusisto
authors.forename: Markku
authors.initials: M
authors.lastname: Laakso
authors.forename: Mark
authors.initials: M
authors.lastname: Lathrop
authors.forename: Cécile
authors.initials: C
authors.lastname: Lecoeur
authors.forename: Man
authors.initials: M
authors.lastname: Li
authors.forename: Mingyao
authors.initials: M
authors.lastname: Li
authors.forename: Ruth J F
authors.initials: RJ
authors.lastname: Loos
authors.forename: Jian'an
authors.initials: J
authors.lastname: Luan
authors.forename: Valeriya
authors.initials: V
authors.lastname: Lyssenko
authors.forename: Reedik
authors.initials: R
authors.lastname: Mägi
authors.forename: Patrik K E
authors.initials: PK
authors.lastname: Magnusson
authors.forename: Anders
authors.initials: A
authors.lastname: Mälarstig
authors.forename: Massimo
authors.initials: M
authors.lastname: Mangino
authors.forename: María Teresa
authors.initials: MT
authors.lastname: Martínez-Larrad
authors.forename: Winfried
authors.initials: W
authors.lastname: März
authors.forename: Wendy L
authors.initials: WL
authors.lastname: McArdle
authors.forename: Ruth
authors.initials: R
authors.lastname: McPherson
authors.forename: Christa
authors.initials: C
authors.lastname: Meisinger
authors.forename: Thomas
authors.initials: T
authors.lastname: Meitinger
authors.forename: Olle
authors.initials: O
authors.lastname: Melander
authors.forename: Karen L
authors.initials: KL
authors.lastname: Mohlke
authors.forename: Vincent E
authors.initials: VE
authors.lastname: Mooser
authors.forename: Mario A
authors.initials: MA
authors.lastname: Morken
authors.forename: Narisu
authors.initials: N
authors.lastname: Narisu
authors.forename: David M
authors.initials: DM
authors.lastname: Nathan
authors.forename: Matthias
authors.initials: M
authors.lastname: Nauck
authors.forename: Chris
authors.initials: C
authors.lastname: O'Donnell
authors.forename: Konrad
authors.initials: K
authors.lastname: Oexle
authors.forename: Nazario
authors.initials: N
authors.lastname: Olla
authors.forename: James S
authors.initials: JS
authors.lastname: Pankow
authors.forename: Felicity
authors.initials: F
authors.lastname: Payne
authors.forename: John F
authors.initials: JF
authors.lastname: Peden
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Pedersen
authors.forename: Leena
authors.initials: L
authors.lastname: Peltonen
authors.forename: Markus
authors.initials: M
authors.lastname: Perola
authors.forename: Ozren
authors.initials: O
authors.lastname: Polasek
authors.forename: Eleonora
authors.initials: E
authors.lastname: Porcu
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Rader
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Rathmann
authors.forename: Samuli
authors.initials: S
authors.lastname: Ripatti
authors.forename: Ghislain
authors.initials: G
authors.lastname: Rocheleau
authors.forename: Michael
authors.initials: M
authors.lastname: Roden
authors.forename: Igor
authors.initials: I
authors.lastname: Rudan
authors.forename: Veikko
authors.initials: V
authors.lastname: Salomaa
authors.forename: Richa
authors.initials: R
authors.lastname: Saxena
authors.forename: David
authors.initials: D
authors.lastname: Schlessinger
authors.forename: Heribert
authors.initials: H
authors.lastname: Schunkert
authors.forename: Peter
authors.initials: P
authors.lastname: Schwarz
authors.forename: Udo
authors.initials: U
authors.lastname: Seedorf
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Selvin
authors.forename: Manuel
authors.initials: M
authors.lastname: Serrano-Ríos
authors.forename: Peter
authors.initials: P
authors.lastname: Shrader
authors.forename: Angela
authors.initials: A
authors.lastname: Silveira
authors.forename: David
authors.initials: D
authors.lastname: Siscovick
authors.forename: Kjioung
authors.initials: K
authors.lastname: Song
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Spector
authors.forename: Kari
authors.initials: K
authors.lastname: Stefansson
authors.forename: Valgerdur
authors.initials: V
authors.lastname: Steinthorsdottir
authors.forename: David P
authors.initials: DP
authors.lastname: Strachan
authors.forename: Rona
authors.initials: R
authors.lastname: Strawbridge
authors.forename: Michael
authors.initials: M
authors.lastname: Stumvoll
authors.forename: Ida
authors.initials: I
authors.lastname: Surakka
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Swift
authors.forename: Toshiko
authors.initials: T
authors.lastname: Tanaka
authors.forename: Alexander
authors.initials: A
authors.lastname: Teumer
authors.forename: Gudmar
authors.initials: G
authors.lastname: Thorleifsson
authors.forename: Unnur
authors.initials: U
authors.lastname: Thorsteinsdottir
authors.forename: Anke
authors.initials: A
authors.lastname: Tönjes
authors.forename: Gianluca
authors.initials: G
authors.lastname: Usala
authors.forename: Veronique
authors.initials: V
authors.lastname: Vitart
authors.forename: Henry
authors.initials: H
authors.lastname: Völzke
authors.forename: Henri
authors.initials: H
authors.lastname: Wallaschofski
authors.forename: Dawn M
authors.initials: DM
authors.lastname: Waterworth
authors.forename: Hugh
authors.initials: H
authors.lastname: Watkins
authors.forename: H-Erich
authors.initials: HE
authors.lastname: Wichmann
authors.forename: Sarah H
authors.initials: SH
authors.lastname: Wild
authors.forename: Gonneke
authors.initials: G
authors.lastname: Willemsen
authors.forename: Gordon H
authors.initials: GH
authors.lastname: Williams
authors.forename: James F
authors.initials: JF
authors.lastname: Wilson
authors.forename: Juliane
authors.initials: J
authors.lastname: Winkelmann
authors.forename: Alan F
authors.initials: AF
authors.lastname: Wright
authors.forename: Carina
authors.initials: C
authors.lastname: Zabena
authors.forename: Jing Hua
authors.initials: JH
authors.lastname: Zhao
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Epstein
authors.forename: Jeanette
authors.initials: J
authors.lastname: Erdmann
authors.forename: Hakon H
authors.initials: HH
authors.lastname: Hakonarson
authors.forename: Sekar
authors.initials: S
authors.lastname: Kathiresan
authors.forename: Kay-Tee
authors.initials: KT
authors.lastname: Khaw
authors.forename: Robert
authors.initials: R
authors.lastname: Roberts
authors.forename: Nilesh J
authors.initials: NJ
authors.lastname: Samani
authors.forename: Mark D
authors.initials: MD
authors.lastname: Fleming
authors.forename: Robert
authors.initials: R
authors.lastname: Sladek
authors.forename: Gonçalo
authors.initials: G
authors.lastname: Abecasis
authors.forename: Michael
authors.initials: M
authors.lastname: Boehnke
authors.forename: Philippe
authors.initials: P
authors.lastname: Froguel
authors.forename: Leif
authors.initials: L
authors.lastname: Groop
authors.forename: Mark I
authors.initials: MI
authors.lastname: McCarthy
authors.forename: W H Linda
authors.initials: WH
authors.lastname: Kao
authors.forename: Jose C
authors.initials: JC
authors.lastname: Florez
authors.forename: Manuela
authors.initials: M
authors.lastname: Uda
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Wareham
authors.forename: Inês
authors.initials: I
authors.lastname: Barroso
authors.forename: James B
authors.initials: JB
authors.lastname: Meigs
mesh_terms: D000328:Adult; D001786:Blood Glucose / Q000378:metabolism; D015992:Body Mass Index; D002874:Chromosome Mapping; D015331:Cohort Studies; D005260:Female; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006442:Glycated Hemoglobin / Q000235:genetics*; D006801:Humans; D008297:Male; D015201:Meta-Analysis as Topic; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D044465:White People / Q000235:genetics
chemical_list: D001786:Blood Glucose; D006442:Glycated Hemoglobin; C517652:hemoglobin A1c protein, human