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Abstract
Background: Obesity is a public health crisis in the US highlighting an urgent need to better understand obesity’s etiology to develop novel therapeutics against obesity. Leptin is a key hormone to suppress appetite, increase energy expenditure, and reduce body weight. However, obese individuals commonly resist to leptin. Leptin is also involved in lipid and glucose metabolisms, and leptin resistance leads to dyslipidemia and hyperglycemia. However, most studies of leptin resistance were conducted in animal models and/or cell lines, and the findings may not be applicable to humans. In human, genetic factors contribute to 15%-16% of the variations of leptin resistance. Goal: We aim to identify mechanisms underlying the leptin sensitivity of metabolic measures by genome-wide analyses among humans. Method: We conducted genome-wide gene-leptin interaction analyses on obesity and obesity-related metabolic measures among 8,431 participants of African, Chinese, European, and Hispanic ancestries from the Framingham Heart Study, Multi-Ethnic Study of Atherosclerosis, and Jackson Heart Study. Genes modifying the effect of leptin on obesity and its related traits contribute to leptin resistance. Both gene-based and single variant-base
analyses were conducted. All analyses were done separately in each cohort-ethnic group. Analyses results were combined using meta-analyses methods for each ethnic group across different cohorts and trans-ancestrally across all ethnicities. Result: Ancestry-specific interaction analyses identified PCTP rs78580870 (Meta P=1.60×10-9) among whites and MUC5AC rs28578580 (Meta P=3.59×10-10) and CPHL1P rs114959943 (Meta P=4.84×10-8) among blacks that modified the effect of leptin on obesity. Trans-ancestral analyses additionally identified rs11590104 in LOC102723321/ LOC105371230 (Meta P=2.82×10-8) interacting with leptin on obesity. Gene-based analyses found 6 functionally relevant novel genes contributing to leptin resistance. Meanwhile, PPP1R15A rs595474 (Meta P=5.56×10-9) interacted with leptin on blood glucose among blacks. Furthermore, GRM7 rs73013659 (Meta P=2.65×10-8), rs117478081 near NHLRC1 (Meta P=8.89×10-10) modified leptin-glucose associations among all ancestry groups. Finally, a novel variant rs74010747 in LOC105370802 (Meta P=8.08×10−9) interacted with leptin on high-density lipoprotein cholesterol among blacks. Conclusion: We identified 4 novel genomic loci modifying the association of leptin with obesity, 1 novel locus influencing leptin-lipid association and 3 novel loci changing leptin-blood glucose association through genome-wide studies among multiple ancestry groups.
analyses were conducted. All analyses were done separately in each cohort-ethnic group. Analyses results were combined using meta-analyses methods for each ethnic group across different cohorts and trans-ancestrally across all ethnicities. Result: Ancestry-specific interaction analyses identified PCTP rs78580870 (Meta P=1.60×10-9) among whites and MUC5AC rs28578580 (Meta P=3.59×10-10) and CPHL1P rs114959943 (Meta P=4.84×10-8) among blacks that modified the effect of leptin on obesity. Trans-ancestral analyses additionally identified rs11590104 in LOC102723321/ LOC105371230 (Meta P=2.82×10-8) interacting with leptin on obesity. Gene-based analyses found 6 functionally relevant novel genes contributing to leptin resistance. Meanwhile, PPP1R15A rs595474 (Meta P=5.56×10-9) interacted with leptin on blood glucose among blacks. Furthermore, GRM7 rs73013659 (Meta P=2.65×10-8), rs117478081 near NHLRC1 (Meta P=8.89×10-10) modified leptin-glucose associations among all ancestry groups. Finally, a novel variant rs74010747 in LOC105370802 (Meta P=8.08×10−9) interacted with leptin on high-density lipoprotein cholesterol among blacks. Conclusion: We identified 4 novel genomic loci modifying the association of leptin with obesity, 1 novel locus influencing leptin-lipid association and 3 novel loci changing leptin-blood glucose association through genome-wide studies among multiple ancestry groups.