New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk

Department of Biostatistics, Boston University School of Public Health, Massachusetts, USA.
Nature Genetics (Impact Factor: 29.35). 02/2010; 42(2):105-16. DOI: 10.1038/ng.520
Source: PubMed


Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.

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    • "Some variants were associated with T2DM in one ethnic group of subjects but not in others. SNPs in PPARG, CDKAL1, CDKN2A/B, SLC30A8, IGF2BP2, TCF7L2, ADRA2A, FADS1, DGKB, IGF1, CDC123/CAMK1D, TSPAN8, and JAZF1 were identified to be associated with T2DM in European populations by GWAS (Dupuis et al., 2010; Saxena et al.,2007; Zeggini et al., 2008). These SNPs have been confirmed by multiple studies in various populations, such as Danes, Han Chinese, and Japanese (Grarup et al., 2008; Hu et al., 2009; 2010; Liu et al., 2011; Ohshige et al., 2011; Wen et al., 2010; Zhou et al., 2010). "
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    • " ; Voight et al . 2010 ) , with 34 , 840 cases and 114 , 981 controls recently genotyped on the custom Metabochip ( Morris et al . 2012 ) . The Meta - Analyses of Glucose and Insulin - related traits Consortium ( MAGIC ) has collected phenotypic informa - tion for quantitative glycemic traits such as glucose and insulin in . 40 , 000 individuals ( Dupuis et al . 2010 ) , with 133 , 010 individuals genotyped on the custom Metabochip ( Scott et al . 2012"
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