Lack of Significant Effects of the Type 2 Diabetes Susceptibility LociJAZF1,CDC123/CAMK1D,NOTCH2,ADAMTS9,THADA, andTSPAN8/LGR5on Diabetes and Quantitative Metabolic Traits

Abstract

Recently, several novel loci reaching genome-wide significance levels for type 2 diabetes (T2D) were identified through a meta-analysis of three genome-wide scans and large-scale follow-up. The aim of our study was to investigate the association of these loci with T2D and related subphenotypes in two cohorts from Germany. We performed an association study of 9 SNPs in or around JAZF1, CDC123/ CAMK1D, NOTCH2, BCL11A, ADAMTS9, VEGFA, DCD, THADA, and TSPAN8/ LGR5 with T2D and related quantitative traits (fasting insulin and glucose, indices derived from OGTT) in the isolated population of Sorbs (205 cases and 695 controls) and in a mixed German population (Leipzig) (938 subjects with and 918 without T2D). None of the variants was associated with T2D, but the meta-analysis of both cohorts revealed a modest trend of association of rs7578597 in THADA with T2D (p=0.055). Furthermore, Sorbian subjects homozygous for the rs7578597 T-allele had lower mean 30-minute plasma insulin when compared with carriers of the C-allele (p<0.05). The T-allele was also nominally associated with higher fasting plasma glucose in the Leipzig cohort (p<0.05). Although several other SNPs showed some evidence for association with T2D-related traits the effects were not replicated within our study. Associations of the T2D-risk alleles with T2D or related subphenotypes were overall very weak in the approximately 2 700 subjects studied. This is compatible with the modest effect size of these "second sweep" variants, which will require large-scale association studies on quantitative traits to clarify their role in the pathophysiology of T2D.

THADA Regulates the Organismal Balance between Energy Storage and Heat Production

“…Combined, these data suggest that the primary effect of altered THADA activity and calcium signaling is on lipid metabolism, and that a combination with high-fat feeding may be required to lead to type 2 diabetes over time. This could potentially explain why follow-up association studies did not find links between THADA and insulin sensitivity (Grarup et al., 2008, Sanghera et al., 2009, Schleinitz et al., 2010, Staiger et al., 2008, Stancakova et al., 2009) but did find links between THADA and adiposity (Gupta et al., 2013). …”

“…THADA was also identified as one of the top risk loci for type 2 diabetes by GWAS (Zeggini et al., 2008). Although follow-up studies could not confirm an association between THADA SNPs and various aspects of insulin release or insulin sensitivity (Grarup et al., 2008, Sanghera et al., 2009, Schleinitz et al., 2010, Staiger et al., 2008, Stancakova et al., 2009), some studies did find an association between THADA and pancreatic β-cell response (Simonis-Bik et al., 2010) or marginal evidence for an association with body mass index (Gupta et al., 2013). In sum, THADA has been connected to both metabolism and adaptation to climate.…”

Physiologic Characterization of Type 2 Diabetes–Related Loci

“…More recently, a variant located 500 kb upstream of IRS1 was demonstrated to increase risk of type 2 diabetes and decrease insulin sensitivity through lowering of expression of IRS1 and diminishing insulin signaling [52••]. The ADAMTS9 diabetes-associated allele has also been associated with decreased insulin sensitivity, as estimated from the euglycemic-hyperinsulinemic clamp [53]; however, others investigating fasting and OGTT-based insulin sensitivity indices have not been able to detect a significant effect [26, 33]. Future larger studies estimating tissue-specific insulin sensitivity and/or meta-analysis may clarify these inconsistencies.…”

Investigation into the promoter DNA methylation of three genes (CAMK1D, CRY2 and CALM2) in the peripheral blood of patients with type 2 diabetes

“…Single nucleotide polymorphisms (SNPs) in CAMK1D have been found to be associated with the susceptibility of developing T2D in an east Asian population (14). However, no significant association between the CAMK1D SNP and T2D was found in a study based on European populations (15). Thus, the role of the CAMK1D gene in the pathophysiology of T2D remains unclear (13).…”