Association and evolutionary studies of the melatonin receptor 1B gene (MTNR1B) in the self-contained population of Sorbs from Germany.

AIMS: Several polymorphisms of the melatonin receptor 1B gene (MTNR1B) have been shown to be associated with elevated fasting plasma glucose and impaired early insulin release. The aim of this study was to assess the effects of MTNR1B variants on traits related to the metabolic syndrome in the self-contained population of Sorbs from Germany. As comprehensive studies concerning the conservation of MTNR1B are lacking, we also evaluated natural selection in vertebrates and human populations at this locus. METHODS: Five single nucleotide polymorphisms representing all blocks of linkage disequilibrium within and surrounding the MTNR1B locus were genotyped in 937 Sorbs for association analyses on metabolic traits related to Type 2 diabetes. The associations were assessed by regression analyses, the conservation between species was investigated with phylogenetic analysis by maximum likelihood (PAML). In addition, various tests of population genetic measures (e.g. fixation index, Tajima's D) were performed. RESULTS: Previously reported association between MTNR1B variants (rs10830963, rs4753426) and oral glucose tolerance test-derived indices of ß-cell function (homeostasis model assessment-B, P = 3.7 × 10⁻6 and P = 0.004, respectively), as well as insulin (fasting insulin: P=2×10⁻³ and P=0.02; 30-min insulin: P = 2.1 × 10⁻4 and P=0.03, respectively) and fasting glucose (rs10830963, P=1.2×10⁻6) parameters could be replicated in the present study. Phylogenetic analysis by maximum likelihood analyses showed that the gene was strongly conserved between species (ω=0.2583). Structures important for the receptor function are also conserved. On the lineage leading to human adaptive selection was present (ω=1.1030). Population genetic measures further indicated natural selection. CONCLUSIONS: Our data support the physiologic importance of MTNR1B in the context of glucose homeostasis and suggest evidence of selection at this locus.

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.

A SNP haplotype of the forkhead transcription factor FOXO1A gene may have a protective effect against type 2 diabetes in German Caucasians.

AIM: The human protein encoded by the FOXO1A gene functions as a transcription factor of insulin signaling key genes. In this study we investigated the role of genetic variation in the FOXO1A gene in susceptibility to type 2 diabetes (T2D) and relevant metabolic traits. METHODS: We genotyped six haplotype tagging single nucleotide polymorphisms (SNPs) for association analyses in German Caucasians (593 patients with T2D and 760 non-diabetics, who included 594 normoglycemics and 166 individuals with impaired glucose tolerance). RESULTS: In a case control study involving all type 2 diabetics and healthy controls with normal glucose tolerance, none of the FOXO1A SNPs showed any association with T2D. However, the frequency of the [C-C-G-A-A-A] haplotype comprising six FOXO1A SNPs was 36.5% in normoglycemic non-diabetic controls compared to 31.0% in type 2 diabetic patients (P=0.004). Consistent with this, the same haplotype was significantly associated with lower fasting plasma insulin, BMI, HbA(1C), free fatty acids and % body fat in all non-diabetic subjects (all adjusted P<0.05). CONCLUSION: In conclusion, our study suggests a protective effect of FOXO1A haplotype [C-C-G-A-A-A] on T2D development and relevant intermediate phenotypes which predispose for T2D.