In our 1 M GWAS, 4 of the 10 SNPs most significantly associated with body mass index (BMI) mapped near or within the MAP2K3 gene. Fine mapping of this region revealed that specific regions of this locus were duplicated, and a large number of the database SNPs from this region were false SNPs. Validated SNPs that mapped uniquely to the MAP2K3 locus were genotyped in 3500 full-heritage Pima Indians and replication was assessed in a second sample of 3800 American Indians. Two tag SNPs were associated with BMI in the full-heritage Pima sample and the associations replicated in the second sample. The effect of specific variants on BMI in Caucasians was evaluated using genotypic data from the GIANT consortium. One of the tag SNPs was additionally associated with BMI among 123,800 Caucasians, suggesting that variation in MAP2K3 affects BMI in multiple ethnic groups. Our prior 100K GWAS identified a SNP associated with decreased insulin-stimulated glucose disposal. This SNP mapped within an intron of MAP3K5 which encodes the apoptosis signal-regulating kinase 1 (ASK1). ASK1 is required for the TNF-induced activation of JNK and p38 pathways and may play a pivotal role in the development of insulin resistance and type 2 diabetes. Seven tag SNPs were genotyped in the population-based sample of 3500 full-heritage Pima Indians, among which 415 non-diabetic subjects had been metabolically phenotyped. One SNP was modestly associated with diabetes where the risk allele was associated with reduced insulin sensitivity among the non-diabetic subjects. SNPs in this region genotyped in a GWAS in Caucasians were similarly associated with diabetes, where the risk alleles were consistent between the Caucasians and Pima Indians. Most of the associated SNPs mapped with intron 1 or 2 of MAP3K5, suggesting that the functional variant may affect gene expression. In our recent global gene expression study of muscle biopsies from 125 non-diabetic Pima Indians, the MAP3K5 transcript was indeed positively correlated with the rate of insulin-stimulated glucose disposal and the transcript level was also negatively correlated with SNP genotype. Therefore we propose that a functional variant within the proximal promoter or introns 1 or 2 of MAP3K5 reduces expression of this gene which leads to impaired insulin sensitivity and type 2 diabetes. Among the top signals for percentage of body fat in our GWAS were 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. Variants located within and adjacent to LPGAT1, including 2 novel variants identified by sequencing, were genotyped in the sample of 3500 full-heritage Pima Indians and the second sample of 3800 American Indians. Two tag SNPs were significantly associated with BMI in both samples. Analysis of LPGAT1 cDNA from human preadipocytes identified an additional exon whose sequence could potentially serve as a mitochondrial targeting peptide. In vitro functional analysis of two variants provided suggestive evidence that a 27 bp deletion in the 5-UTR may affect transcriptional or post-transcriptional regulation.
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