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Reiling, E.; Jafar-Mohammadi, B.; van't Riet, E.; Weedon, M.N.; Vliet-Ostaptchouk, J.V. van; Hansen, T.; ... ; Hart, L.M. 't (2010)

Genetic association analysis of LARS2 with type 2 diabetes

Article / Letter to editor
AIMS/HYPOTHESIS: 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...Show moreAIMS/HYPOTHESIS: 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/INTERPRETATION: 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.Show less
All authors
Reiling, E.; Jafar-Mohammadi, B.; van't Riet, E.; Weedon, M.N.; Vliet-Ostaptchouk, J.V. van; Hansen, T.; Saxena, R.; Haeften, T.W. van; Arp, P.A.; S. das; Nijpels, G.; Groenewoud, M.J.; Hove, E.C. van; Uitterlinden, A.G.; Smit, J.W.A.; Morris, A.D.; Doney, A.S.F.; Palmer, C.N.A.; Guiducci, C.; Hattersley, A.T.; Frayling, T.M.; Pedersen, O.; Slagboom, P.E.; Altshuler, D.M.; Groop, L.; Romijn, J.A.; Maassen, J.A.; Hofker, M.H.; Dekker, J.M.; McCarthy, M.I.; Hart, L.M. 't
Date
2010-01-31
Journal
Diabetologia
Volume
53
Issue
1
Pages
103 - 10
DOI
doi:10.1007/s00125-009-1557-7