Genetic association analysis of LARS2 with type 2 diabetes.
OBJECTIVE
LARS2 has been previously identified as a potential type 2 diabetes susceptibility gene through the low-frequency H324Q (rs71645922) variant (minor allele frequency [MAF] 3.0%). However, this association did not achieve genome-wide levels of significance. The aim of this study was to establish the true contribution of this variant and common variants in LARS2 (MAF > 5%) to type 2 diabetes risk.


METHODS
We combined genome-wide association data (n = 10,128) from the DIAGRAM consortium with independent data derived from a tagging single nucleotide polymorphism (SNP) approach in Dutch individuals (n = 999) and took forward two SNPs of interest to replication in up to 11,163 Dutch participants (rs17637703 and rs952621). In addition, because inspection of genome-wide association study data identified a cluster of low-frequency variants with evidence of type 2 diabetes association, we attempted replication of rs9825041 (a proxy for this group) and the previously identified H324Q variant in up to 35,715 participants of European descent.


RESULTS
No association between the common SNPs in LARS2 and type 2 diabetes was found. Our replication studies for the two low-frequency variants, rs9825041 and H324Q, failed to confirm an association with type 2 diabetes in Dutch, Scandinavian and UK samples (OR 1.03 [95% CI 0.95-1.12], p = 0.45, n = 31,962 and OR 0.99 [0.90-1.08], p = 0.78, n = 35,715 respectively).


CONCLUSIONS
In this study, the largest study examining the role of sequence variants in LARS2 in type 2 diabetes susceptibility, we found no evidence to support previous data indicating a role in type 2 diabetes susceptibility.
Department of Molecular Cell Biology, Leiden University Medical Center (LUMC), 2300RC Leiden, the Netherlands.
E
E
Reiling
B
B
Jafar-Mohammadi
E
E
van 't Riet
M N
MN
Weedon
J V
JV
van Vliet-Ostaptchouk
T
T
Hansen
R
R
Saxena
T W
TW
van Haeften
P A
PA
Arp
S
S
Das
G
G
Nijpels
M J
MJ
Groenewoud
E C
EC
van Hove
A G
AG
Uitterlinden
J W A
JW
Smit
A D
AD
Morris
A S F
AS
Doney
C N A
CN
Palmer
C
C
Guiducci
A T
AT
Hattersley
T M
TM
Frayling
O
O
Pedersen
P E
PE
Slagboom
D M
DM
Altshuler
L
L
Groop
J A
JA
Romijn
J A
JA
Maassen
M H
MH
Hofker
J M
JM
Dekker
M I
MI
McCarthy
L M
LM
't Hart
D000368:Aged; D019943:Amino Acid Substitution; D000604:Amino Acyl-tRNA Synthetases / Q000235:genetics* / Q000378:metabolism; D015992:Body Mass Index; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology* / Q000235:genetics; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D015810:Linkage Disequilibrium; D024101:Mitochondrial Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide
D024101:Mitochondrial Proteins; D000604:Amino Acyl-tRNA Synthetases; C549096:LARS2 protein, human