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.


Available from: Peter Henneman
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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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    ABSTRACT: Substantial evidence suggests that type 2 diabetes mellitus (T2DM) is a multi-factorial disease with a strong genetic component. A list of genetic susceptibility loci in populations of European and Asian ancestry has been established in the literature. Little is known on the inter-ethnic contribution of such established functional polymorphic variants. We performed a case-control study to explore the genetic susceptibility of 16 selected T2DM-related SNPs in a cohort of 102 Uyghur objects (51 cases and 51 controls). Three of the 16 SNPs showed significant association with T2DM in the Uyghur population. There were significant differences between the T2DM and control groups in frequencies of the risk allelic distributions of rs7754840 (CDKAL1) (p=0.014), rs864745 (JAZF1) (p=0.032), and rs35767 (IGF1) (p=0.044). Carriers of rs7754840-C, rs35767-A, and rs864745-C risk alleles had a 2.32-fold [OR (95% CI): 1.19-4.54], 2.06-fold [OR (95% CI): 1.02-4.17], 0.48-fold [OR (95% CI): 0.24-0.94] increased risk for T2DM, respectively. The cumulative risk allelic scores of these 16 SNPs differed significantly between the T2DM patients and the controls [17.1±8.1 vs. 15.4±7.3; OR (95%CI): 1.27(1.07-1.50), p=0.007]. This is the first study to evaluate genomic variation at 16 SNPs in respective T2DM candidate genes for the Uyghur population compared with other ethnic groups. The SNP rs7754840 in CDKAL1, rs864745 in JAZF1, and rs35767 in IGF1 might serve as potential susceptibility loci for T2DM in Uyghurs. We suggest a broader capture and study of the world populations, including who that are hitherto understudied, are essential for a comprehensive understanding of the genetic/genomic basis of T2DM.
    Omics: a journal of integrative biology 03/2015; 19(4). DOI:10.1089/omi.2014.0162 · 2.36 Impact Factor
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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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    ABSTRACT: The genetic basis of type 2 diabetes remains incompletely defined despite the use of multiple genetic strategies. Multiparental populations such as heterogeneous stocks (HS) facilitate gene discovery by allowing fine mapping to only a few megabases, significantly decreasing the number of potential candidate genes compared to traditional mapping strategies. In the present work, we employed expression and sequence analysis in HS rats (Rattus norvegicus) to identify Tpcn2 as a likely causal gene underlying a 3.1-Mb locus for glucose and insulin levels. Global gene expression analysis on liver identified Tpcn2 as the only gene in the region that is differentially expressed between HS rats with glucose intolerance and those with normal glucose regulation. Tpcn2 also maps as a cis-regulating expression QTL and is negatively correlated with fasting glucose levels. We used founder sequence to identify variants within this region and assessed association between 18 variants and diabetic traits by conducting a mixed-model analysis, accounting for the complex family structure of the HS. We found that two variants were significantly associated with fasting glucose levels, including a nonsynonymous coding variant within Tpcn2. Studies in Tpcn2 knockout mice demonstrated a significant decrease in fasting glucose levels and insulin response to a glucose challenge relative to those in wild-type mice. Finally, we identified variants within Tpcn2 that are associated with fasting insulin in humans. These studies indicate that Tpcn2 is a likely causal gene that may play a role in human diabetes and demonstrate the utility of multiparental populations for positionally cloning genes within complex loci.
    Genetics 09/2014; 198(1):17-29. DOI:10.1534/genetics.114.162982 · 5.96 Impact Factor
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    • "From a panel of known isletspecific transcripts, the authors identified GLIS3 as a downstream target of HI-LNC25, a lncRNA that shares a regulatory domain with MAFB. Variants at the GLIS3 locus are associated with different risks for T1D (Barrett et al., 2009), elevated fasting glucose levels (Dupuis et al., 2010), as well as T2D (Cho et al., 2012). Lossof function studies suggest that GLIS3 encodes a transcription factor critical for regulating the expression of insulin and several key islet-transcription factors, and may confer risk for both T1D and T2D by resulting in diminished β-cell numbers and by promoting the formation of a pro-apoptotic splice variant of the protein Bim (Kang et al., 2009; Nogueira et al., 2013; ZeRuth et al., 2013). "
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    ABSTRACT: Diabetes mellitus represents a group of complex metabolic diseases that result in impaired glucose homeostasis, which includes destruction of β-cells or the failure of these insulin-secreting cells to compensate for increased metabolic demand. Despite a strong interest in characterizing the transcriptome of the different human islet cell types to understand the molecular basis of diabetes, very little attention has been paid to the role of long non-coding RNAs (lncRNAs) and their contribution to this disease. Here we summarize the growing evidence for the potential role of these lncRNAs in β-cell function and dysregulation in diabetes, with a focus on imprinted genomic loci.
    Frontiers in Genetics 07/2014; 5:200. DOI:10.3389/fgene.2014.00200
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