Polymorphisms near EXOC4 and LRGUK on chromosome 7q32 are associated with Type 2 Diabetes and fasting glucose; the NHLBI Family Heart Study.

BACKGROUND: The chromosome 7q32 region is linked to metabolic syndrome and obesity related traits in the Family Heart Study. As part of a fine mapping study of the region, we evaluated the relationship of polymorphisms to fasting glucose levels and Type 2 diabetes. METHODS: Thirty-nine HapMap defined tag SNPs in a 1.08 Mb region and a novel deletion polymorphism were genotyped in 2,603 participants of the NHLBI Family Heart Study (FHS). Regression modeling, adjusting for BMI, age, sex, smoking and the TCF7L2 polymorphism, was used to evaluate the association of these polymorphisms with T2D and fasting glucoses levels. RESULTS: The deletion polymorphism confers a protective effect for T2D, with homozygous deletion carriers having a 53% reduced risk compared to non-deleted carriers. Among non-diabetics, the deletion was significantly associated with lower fasting glucose levels in men (p = 0.038) but not women (p = 0.118). In addition, seven SNPs near the deletion were significantly associated (p < 0.01) to diabetes. CONCLUSION: Chromosome 7q32 contains both SNPs and a deletion that were associated to T2D. Although the deletion region contains several islands of strongly conserved sequence, it is not known to contain a transcribed gene. The closest nearby gene, EXOC4, is involved in insulin-stimulated glucose transport and may be a candidate for this association. Further work is needed to determine if the deletion represents a functional variant or may be in linkage disequilibrium with a functional mutation influencing EXOC4 or another nearby gene.

Postmortem Interval Influences α-Synuclein Expression in Parkinson Disease Brain.

Duplications and triplications of the α-synuclein (SNCA) gene increase risk for PD, suggesting increased expression levels of the gene to be associated with increased PD risk. However, past SNCA expression studies in brain tissue report inconsistent results. We examined expression of the full-length SNCA transcript (140 amino acid protein isoform), as well as total SNCA mRNA levels in 165 frontal cortex samples (101 PD, 64 control) using quantitative real-time polymerase chain reaction. Additionally, we evaluated the relationship of eight SNPs in both 5' and 3' regions of SNCA with the gene expression levels. The association between postmortem interval (PMI) and SNCA expression was different for PD and control samples: SNCA expression decreased with increasing PMI in cases, while staying relatively constant in controls. For short PMI, SNCA expression was increased in PD relative to control samples, whereas for long PMI, SNCA expression in PD was decreased relative to control samples.

Multiple genes influence BMI on chromosome 7q31-34: the NHLBI Family Heart Study.

The National Heart, Lung, and Blood Institute Family Heart Study (FHS) genome-wide linkage scan identified a region of chromosome 7q31-34 with a lod score of 4.9 for BMI at D7S1804 (131.9 Mb). We report the results of linkage and association to BMI in this region for two independent FHS samples. The first sample includes 225 FHS pedigrees with evidence of linkage to 7q31-34, using 1,132 single-nucleotide polymorphisms (SNPs) and 7 microsatellites. The second represents a case-control sample (318 cases; BMI >25 and 325 controls; BMI <25) derived from unrelated FHS participants who were not part of the genome scan. The latter set was genotyped for 606 SNPs, including 37 SNPs with prior evidence for association in the linked families. Although variance components linkage analysis using only SNPs generated a peak lod score that coincided with the original linkage scan at 131.9 Mb, a conditional linkage analysis showed evidence of a second quantitative trait locus (QTL) near 143 cM influencing BMI. Three SNPs (rs161339, rs12673281, and rs1993068) located near the three genes pleiotrophin (PTN), diacylglycerol (DAG) kinase iota (DGK iota), and cholinergic receptor, muscarinic 2 (CHRM2) demonstrated significant association in both linked families (P = 0.0005, 0.002, and 0.03, respectively) and the case-control sample (P = 0.01, 0.0003, and 0.03, respectively), regardless of the genetic model tested. These findings suggest that several genes may be associated with BMI in the 7q31-34 region.