Genome-Wide Genele-Ptin Interaction Study Identifies Loci Contributing To Leptin Resistance

Background: In a preliminary candidate genes study, we robustly identified that the nicotinic acetylcholine receptor genes modified obesity’s sensitivity to leptin. However, the finding only explained a small proportion of the heritability of leptin resistance. Therefore, the current study expanded our preliminary work to the entire human genome to identify additional novel mechanisms of leptin resistance in humans. Methods: Discovery stage analyses were conducted among 3,838 White participants of the Framingham Heart Study (FHS) 3 rd generation. SNPs contributing to leptin resistance were identified by examining interactions between the SNPs and leptin on body mass index (BMI) and waist circumference (WC), controlling for age, gender, and the first 3 genetic principal components. Gene-based analyses were conducted by combining SNP-based p values using the GATES method. Promising SNPs ( P <1х10 -6 ) and genes ( P <1х10 -4 ) of the FHS were further evaluated for replication among 667 White participants of the Multi-Ethnic Study of Atherosclerosis (MESA) study. Analysis results of the FHS and MESA were combined using inverse-variance-weighted meta-analysis method for SNPs and Fisher’s method for genes. Genomic control was applied before meta-analysis. Results: Single SNP-based analyses identified that PCTP rs78580870, 17:53899497 (FHS P =1.90х10 -8 , MESA P =0.01, Meta P =8.23х10 -10 ) interacted with leptin on BMI. Gene-based analyses robustly identified 4 genes interacting with leptin on WC, including MED9 (FHS P =5.60х10 -6 , MESA P =1.79х10 -3 , Meta P =1.95х10 -7 ) at 17p11.2, RASD1 (FHS P =3.92х10 -6 , FHS P =1.33х10 -3 , Meta P =1.05х10 -7 ) at 17p11.2, DTX3 (FHS P =5.27х10 -7 , MESA P =3.57х10 -2 , Meta P =3.53х10 -7 ) at 12q13.3, and ARHGEF25 (FHS P =7.55х10 -7 , MESA P =4.96х10 -2 , Meta P =6.79х10 -7 ) at 12q13.3. These 4 genes have related biological functions of leptin or obesity. Conclusion: We identified 1 novel genomic locus and 4 novel genes explaining leptin resistance among White. Future large scale genomic studies of leptin resistance among multiple ethnic groups are warranted.