Lack of significant effects of the type 2 diabetes susceptibility loci JAZF1, CDC123/CAMK1D, NOTCH2, ADAMTS9, THADA, and TSPAN8/LGR5 on diabetes and quantitative metabolic traits.
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.
Schleinitz
D
D
Interdisciplinary Centre for Clinical Research, University of Leipzig, Leipzig 04109, Germany.
Tönjes
A
A
Böttcher
Y
Y
Dietrich
K
K
Enigk
B
B
Koriath
M
M
Scholz
G H
GH
Blüher
M
M
Zeggini
E
E
McCarthy
M I
MI
Kovacs
P
P
Stumvoll
M
M
D051722:ADAM Proteins / Q000235:genetics*; D000071119:ADAMTS9 Protein; D000328:Adult; D000951:Antigens, Neoplasm / Q000235:genetics; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1 / Q000235:genetics; D016022:Case-Control Studies; D018797:Cell Cycle Proteins / Q000235:genetics; D056970:Co-Repressor Proteins; D015331:Cohort Studies; D004268:DNA-Binding Proteins; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005858:Germany; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D051883:Receptor, Notch2 / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000235:genetics; D059470:Tetraspanins
D000951:Antigens, Neoplasm; D018797:Cell Cycle Proteins; D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins; D007328:Insulin; C430460:JAZF1 protein, human; C116884:LGR5 protein, human; D008562:Membrane Glycoproteins; C497764:NOTCH2 protein, human; D009363:Neoplasm Proteins; D051883:Receptor, Notch2; D043562:Receptors, G-Protein-Coupled; C477698:THADA protein, human; C065609:TSPAN8 protein, human; D059470:Tetraspanins; C098828:CDC123 protein, human; C517601:CAMK1D protein, human; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1; D051722:ADAM Proteins; D000071119:ADAMTS9 Protein; C412869:ADAMTS9 protein, human; D005947:Glucose