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- Title
A SNP Within a Gene Desert on Chromosome 11q23-24 Partially Explains the Genetic Linkage to BMI in this Region in Pima Indians: Evidence that this SNP Regulates Gene Expression In Vitro.
- Authors
Traurig, Michael; Kobes, Sayuko; Hanson, Rob; Bogardus, Clifton; Baler, Leslie
- Abstract
A prior genome linkage scan in Pima Indians indicated an obesity/type 2 diabetes (T2D) susceptibility locus (LOD = 3.6 and 1.7 respectively) on chromosome 11q23-24. To narrow this 24Mb region of linkage, single nucleotide polymorphisms (SNPs) were genotyped at a 10kb density for association mapping. To date, 3368 SNPs have been individually genotyped and tested for association with body mass index (BMI) and T2D in the same subjects that were part of the linkage study (n = 1229). Ten SNPs spanning a 39kb region located = 147-186kb centromeric to ETS-1 show evidence for association with BMI (p = 10-² to 10[sup -3]); and, the association became stronger (p = 10[sup -3] to 10[sup -6]) when the analysis is restricted to the 430 individuals from families with a positive LOD score for BMI (p values adjusted for age, gender, nuclear family membership, full Pima heritage, and birth year). Adjustment of the linkage peak for the effect of the SNPs most strongly associated with BMI reduced the evidence for linkage around 25%. The difference in mean BMI among individuals homozygous for the major versus minor alleles for any of these SNPs was ≈ 5 kg/m². The ten SNPs are located in a large gene desert covering nearly 1.7Mb. There are no known genes in this region but the density of conserved non-coding elements is remarkably high. To determine whether any of these SNPs have functional relevance (i. e. located within a long-range enhancer demerit or in a promoter of a novel gene), we cloned the regions (500-800bps) encompassing the SNPs (both alleles) into the appropriate pGL3 reporter vectors. The clones were then transfected into human subcutaneous preadipocytes and luciferase activities were measured. The vector containing a region encompassing rs1125253 (T/G variant) displayed higher luciferase activity with the T allele as compared to the G allele, but both of these vectors had higher activity when compared to a no-insert control vector. We are currently planning DNA footprinting experiments to determine if rs1125253 is located in a putative DNA binding site. ADA-Funded Research
- Subjects
GENETIC polymorphisms; CHROMOSOMES; BODY mass index; GENETIC regulation; OBESITY; GENETICS of type 2 diabetes; PIMA (North American people); BINDING sites; DISEASES
- Publication
Diabetes, 2007, Vol 56, pA296
- ISSN
0012-1797
- Publication type
Article