In our 1 M GWAS, among the top GWAS signals for BMI were 3 variants that mapped within the lysophosphatidylglycerol acyltransferase 1 (LPGAT1) gene. LPGAT1 belongs to a large family of acyltransferases which are involved in a variety of biological processes including pathways that regulate energy homeostasis and body weight. Therefore LPGAT1 was analyzed as a candidate gene for obesity in Pima Indians. Variants (n = 26) located within and adjacent to LPGAT1 including a novel 27 bp deletion identified by sequencing were genotyped in a population-based sample of 3391 full-heritage Pima Indians living in the Gila River Indian Community. Replication of selected variants was assessed in a second sample of 3327 mixed-heritage Native Americans from the same community. Variants with nominal associations with body mass index (BMI) in each of the two independent samples (tagged by rs112662024 and rs12058008) had associations of P = 1-4 x 10-5 in the combined sample (n = 6718). A haplotype that included a novel 27 bp deletion, which does not occur in Caucasians, showed the strongest association with BMI in full heritage Pima Indians. In vitro functional analysis provided suggestive evidence that this 27 bp deletion in the 5-UTR may affect transcriptional or post-transcriptional regulation. Analysis of LPGAT1 cDNA from human preadipocytes identified an additional exon whose sequence could potentially serve as a mitochondrial targeting peptide. In our 1 million SNP GWAS for type 2 diabetes, our strongest finding was with a SNP (rs1861612) in DNER that was associated with type 2 diabetes at genome-wide significance (odds ratio = 1.29 per copy of the T allele, P = 6.6 x 10-8). DNER (delta/notch-like EGF repeat containing) is expressed in islets and mediates notch signaling via cell-cell interaction. Notch signaling is critical for pancreatic development. We assessed the physiologic role of DNER in a mouse -cell line in which DNER was both over-expressed and knocked down by siRNA targeting. Notch pathway specific genes, Notch1, Hes1, and Neurog3 were significantly regulated by DNER (P <0.001), suggesting that alterations in DNER mediate an effect on T2D susceptibility through the notch signaling pathway. Although DNER has not been previously reported in GWASs for type 2 diabetes, NOTCH2 is a highly reproducible type 2 diabetes gene in other ethnicities. In our 1 million SNP GWAS for BMI, one of our strongest findings was identifying MAP2K3 as a new gene for obesity. This gene had not been reported as being among the top signals in published GWASs from other ethnic groups, however, we requested that the GIANT study of BMI in Caucasians look at specific SNPs in their GWAS data and several SNPs did have significant associations with BMI (P = 2 x 10-4). The effect of these variants was larger in American Indians as compared to Caucasians. Combining our American Indian data with the Caucasian data provided strong associations (P = 4 x 10-9). Functional studies on MAP2K3 showed that this gene has a role in adipogenesis, which is consistent with what is currently known about MAP signaling pathways. However, we also show that constitutive expression of MAP2K3 in the hypothalamus, a key tissue for modulating food intake, is associated with an up-regulation of genes involved in inflammation. This is an intriguing finding because several recent reports have proposed a causal role of hypothalamic inflammation in high fat induced obesity, as well as cytokines eliciting effects on feeding behavior.
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