Abstract 2325: Family Based Linkage Disequilibrium Mapping On Human Chromosome Region 2q34 For Total Cholesterol In An Obesity Cohort
Cardiovascular diseases (CVD) is among the leading causes of death. Decades of references demonstrated that dyslipidemia and obesity are major risk factors of CVD. Based on our genome scan data in an obesity cohort (382 microsatellite markers, 320 nuclear families), we carried out quantitative linkage analyses for lipid related phenotypes, including total cholesterol, triglyceride, LDL, HDL and cholesterol/HDL ratio. Using the family regression method, we found significant linkage (LOD=4.36, p<0.00001) on the 2q34 region for total cholesterol (TC) and suggestive linkage of LDL (LOD = 1.65, p=0.003) on the marker D2S2944 (210.4 cM). Based on the linkage mapping result, we focused on a 6Mb (213.5–219.5 Mb) region for linkage disequilibrium (LD) analyses. Sixty-five nuclear families (382 individuals) were selected based on the ranking of family-specific LOD scores of the 2q34 region. We selected 125 SNPs (single nucleotide polymorphisms) in the 6 Mb genome region. Most of these 125 SNPs were gene-centered, thus, close to genes and their flanking regions. Genes including ZNFN1A2, SPAG16, LOC402117, ABCA12, IGFBP2, IGFBP5, TNS1, MR-1, PTPRN and IRS1 were covered in this study. The average interval between SNPs was less than 20Kb within gene coding regions and about 45Kb in the whole 6Mb region. We employed a high-throughput Illumina system (San Diego, CA) for SNP genotyping. We performed family-based association studies by two methods: QTDT and FBAT. Significant associations were found between the gene ABCA12 (ATP-binding Cassette, Superfamily A, Member 12) SNPs and serum cholesterol. Using QTDT, we got p=0.0001 on the SNP rs1980846, other 4 flanking SNPs also showed associations (P<0.01). Analyses done by FBAT yielded p=0.0009 (additive model) on the same SNP rs1980846. A five-SNP haplotype in the ABCA12 gene region was found associated with total cholesterol (p=0.019, hbat). Furthermore, we got a significant association (p=0.00009, recessive model) between fasting glucose and the SNP rs4673937 within the gene ABCA12.