Common variants at 10 genomic loci influence hemoglobin A₁(C) levels via glycemic and nonglycemic pathways.
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).
Soranzo
Nicole
N
Human Genetics, Wellcome Trust Sanger Institute, Hinxton, U.K.
Sanna
Serena
S
Wheeler
Eleanor
E
Gieger
Christian
C
Radke
Dörte
D
Dupuis
Josée
J
Bouatia-Naji
Nabila
N
Langenberg
Claudia
C
Prokopenko
Inga
I
Stolerman
Elliot
E
Sandhu
Manjinder S
MS
Heeney
Matthew M
MM
Devaney
Joseph M
JM
Reilly
Muredach P
MP
Ricketts
Sally L
SL
Stewart
Alexandre F R
AF
Voight
Benjamin F
BF
Willenborg
Christina
C
Wright
Benjamin
B
Altshuler
David
D
Arking
Dan
D
Balkau
Beverley
B
Barnes
Daniel
D
Boerwinkle
Eric
E
Böhm
Bernhard
B
Bonnefond
Amélie
A
Bonnycastle
Lori L
LL
Boomsma
Dorret I
DI
Bornstein
Stefan R
SR
Böttcher
Yvonne
Y
Bumpstead
Suzannah
S
Burnett-Miller
Mary Susan
MS
Campbell
Harry
H
Cao
Antonio
A
Chambers
John
J
Clark
Robert
R
Collins
Francis S
FS
Coresh
Josef
J
de Geus
Eco J C
EJ
Dei
Mariano
M
Deloukas
Panos
P
Döring
Angela
A
Egan
Josephine M
JM
Elosua
Roberto
R
Ferrucci
Luigi
L
Forouhi
Nita
N
Fox
Caroline S
CS
Franklin
Christopher
C
Franzosi
Maria Grazia
MG
Gallina
Sophie
S
Goel
Anuj
A
Graessler
Jürgen
J
Grallert
Harald
H
Greinacher
Andreas
A
Hadley
David
D
Hall
Alistair
A
Hamsten
Anders
A
Hayward
Caroline
C
Heath
Simon
S
Herder
Christian
C
Homuth
Georg
G
Hottenga
Jouke-Jan
JJ
Hunter-Merrill
Rachel
R
Illig
Thomas
T
Jackson
Anne U
AU
Jula
Antti
A
Kleber
Marcus
M
Knouff
Christopher W
CW
Kong
Augustine
A
Kooner
Jaspal
J
Köttgen
Anna
A
Kovacs
Peter
P
Krohn
Knut
K
Kühnel
Brigitte
B
Kuusisto
Johanna
J
Laakso
Markku
M
Lathrop
Mark
M
Lecoeur
Cécile
C
Li
Man
M
Li
Mingyao
M
Loos
Ruth J F
RJ
Luan
Jian'an
J
Lyssenko
Valeriya
V
Mägi
Reedik
R
Magnusson
Patrik K E
PK
Mälarstig
Anders
A
Mangino
Massimo
M
Martínez-Larrad
María Teresa
MT
März
Winfried
W
McArdle
Wendy L
WL
McPherson
Ruth
R
Meisinger
Christa
C
Meitinger
Thomas
T
Melander
Olle
O
Mohlke
Karen L
KL
Mooser
Vincent E
VE
Morken
Mario A
MA
Narisu
Narisu
N
Nathan
David M
DM
Nauck
Matthias
M
O'Donnell
Chris
C
Oexle
Konrad
K
Olla
Nazario
N
Pankow
James S
JS
Payne
Felicity
F
Peden
John F
JF
Pedersen
Nancy L
NL
Peltonen
Leena
L
Perola
Markus
M
Polasek
Ozren
O
Porcu
Eleonora
E
Rader
Daniel J
DJ
Rathmann
Wolfgang
W
Ripatti
Samuli
S
Rocheleau
Ghislain
G
Roden
Michael
M
Rudan
Igor
I
Salomaa
Veikko
V
Saxena
Richa
R
Schlessinger
David
D
Schunkert
Heribert
H
Schwarz
Peter
P
Seedorf
Udo
U
Selvin
Elizabeth
E
Serrano-Ríos
Manuel
M
Shrader
Peter
P
Silveira
Angela
A
Siscovick
David
D
Song
Kjioung
K
Spector
Timothy D
TD
Stefansson
Kari
K
Steinthorsdottir
Valgerdur
V
Strachan
David P
DP
Strawbridge
Rona
R
Stumvoll
Michael
M
Surakka
Ida
I
Swift
Amy J
AJ
Tanaka
Toshiko
T
Teumer
Alexander
A
Thorleifsson
Gudmar
G
Thorsteinsdottir
Unnur
U
Tönjes
Anke
A
Usala
Gianluca
G
Vitart
Veronique
V
Völzke
Henry
H
Wallaschofski
Henri
H
Waterworth
Dawn M
DM
Watkins
Hugh
H
Wichmann
H-Erich
HE
Wild
Sarah H
SH
Willemsen
Gonneke
G
Williams
Gordon H
GH
Wilson
James F
JF
Winkelmann
Juliane
J
Wright
Alan F
AF
Zabena
Carina
C
Zhao
Jing Hua
JH
Epstein
Stephen E
SE
Erdmann
Jeanette
J
Hakonarson
Hakon H
HH
Kathiresan
Sekar
S
Khaw
Kay-Tee
KT
Roberts
Robert
R
Samani
Nilesh J
NJ
Fleming
Mark D
MD
Sladek
Robert
R
Abecasis
Gonçalo
G
Boehnke
Michael
M
Froguel
Philippe
P
Groop
Leif
L
McCarthy
Mark I
MI
Kao
W H Linda
WH
Florez
Jose C
JC
Uda
Manuela
M
Wareham
Nicholas J
NJ
Barroso
Inês
I
Meigs
James B
JB
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
D001786:Blood Glucose; D006442:Glycated Hemoglobin; C517652:hemoglobin A1c protein, human