Shared Genetic Architecture and Casual Relationship Between Leptin Levels and Type 2 Diabetes: Large-scale Cross-trait Meta-analysis and Mendelian Randomization Analysis

Overview

Journal BMJ Open Diabetes Res Care

Specialty Endocrinology

Date 2020 Apr 29

PMID 32341051

Citations 12

Authors

Xinpei Wang

Jinzhu Jia

Tao Huang

Affiliations

Soon will be listed here.

Abstract

Objective: We aimed to estimate genetic correlation, identify shared loci and test causality between leptin levels and type 2 diabetes (T2D).

Research Design And Methods: Our study consists of three parts. First, we calculated the genetic correlation of leptin levels and T2D or glycemic traits by using linkage disequilibrium score regression analysis. Second, we conducted a large-scale genome-wide cross-trait meta-analysis using cross-phenotype association to identify shared loci between trait pairs that showed significant genetic correlations in the first part. In the end, we carried out a bidirectional MR analysis to find out whether there is a causal relationship between leptin levels and T2D or glycemic traits.

Results: We found positive genetic correlations between leptin levels and T2D (R=0.3165, p=0.0227), fasting insulin (FI) (R=0.517, p=0.0076), homeostasis model assessment-insulin resistance (HOMA-IR) (R=0.4785, p=0.0196), as well as surrogate estimates of β-cell function (HOMA-β) (R=0.4456, p=0.0214). We identified 12 shared loci between leptin levels and T2D, 1 locus between leptin levels and FI, 1 locus between leptin levels and HOMA-IR, and 1 locus between leptin levels and HOMA-β. We newly identified eight loci that did not achieve genome-wide significance in trait-specific genome-wide association studies. These shared genes were enriched in pancreas, thyroid gland, skeletal muscle, placenta, liver and cerebral cortex. In addition, we found that 1-SD increase in HOMA-IR was causally associated with a 0.329 ng/mL increase in leptin levels (β=0.329, p=0.001).

Conclusions: Our results have shown the shared genetic architecture between leptin levels and T2D and found causality of HOMA-IR on leptin levels, shedding light on the molecular mechanisms underlying the association between leptin levels and T2D.

Citing Articles

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Brito Nunes C, Borges M, Freathy R, Lawlor D, Qvigstad E, Evans D Metabolites. 2024; 14(9).

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Comprehensive insights into berberine's hypoglycemic mechanisms: A focus on ileocecal microbiome in db/db mice.

Chen X, Mei X, Ren Z, Chen S, Tong Y, Zhang C Heliyon. 2024; 10(13):e33704.

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Genome-wide association study and polygenic score assessment of insulin resistance.

Aliyu U, Ismail Umlai U, Toor S, Elashi A, Al-Sarraj Y, Abou Samra A Front Endocrinol (Lausanne). 2024; 15:1384103.

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Mendelian randomization analyses suggest a causal role for circulating GIP and IL-1RA levels in homeostatic model assessment-derived measures of β-cell function and insulin sensitivity in Africans without type 2 diabetes.

Meeks K, Bentley A, Assimes T, Franceschini N, Adeyemo A, Rotimi C Genome Med. 2023; 15(1):108.

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Inter-organ crosstalk during development and progression of type 2 diabetes mellitus.

Xourafa G, Korbmacher M, Roden M Nat Rev Endocrinol. 2023; 20(1):27-49.

PMID: 37845351 DOI: 10.1038/s41574-023-00898-1.

References

Pruitt K, Tatusova T, Maglott D . NCBI reference sequences (RefSeq): a curated non-redundant sequence database of genomes, transcripts and proteins. Nucleic Acids Res. 2006; 35(Database issue):D61-5. PMC: 1716718. DOI: 10.1093/nar/gkl842. View

Horikoshi M, Mgi R, van de Bunt M, Surakka I, Sarin A, Mahajan A . Discovery and Fine-Mapping of Glycaemic and Obesity-Related Trait Loci Using High-Density Imputation. PLoS Genet. 2015; 11(7):e1005230. PMC: 4488845. DOI: 10.1371/journal.pgen.1005230. View

Bulik-Sullivan B, Finucane H, Anttila V, Gusev A, Day F, Loh P . An atlas of genetic correlations across human diseases and traits. Nat Genet. 2015; 47(11):1236-41. PMC: 4797329. DOI: 10.1038/ng.3406. View

Zhang J, McKenna L, Bogue C, Kaestner K . The diabetes gene Hhex maintains δ-cell differentiation and islet function. Genes Dev. 2014; 28(8):829-34. PMC: 4003275. DOI: 10.1101/gad.235499.113. View

Giambartolomei C, Vukcevic D, Schadt E, Franke L, Hingorani A, Wallace C . Bayesian test for colocalisation between pairs of genetic association studies using summary statistics. PLoS Genet. 2014; 10(5):e1004383. PMC: 4022491. DOI: 10.1371/journal.pgen.1004383. View

Thorand B, Zierer A, Baumert J, Meisinger C, Herder C, Koenig W . Associations between leptin and the leptin / adiponectin ratio and incident Type 2 diabetes in middle-aged men and women: results from the MONICA / KORA Augsburg study 1984-2002. Diabet Med. 2010; 27(9):1004-11. DOI: 10.1111/j.1464-5491.2010.03043.x. View

Wallace T, Levy J, Matthews D . Use and abuse of HOMA modeling. Diabetes Care. 2004; 27(6):1487-95. DOI: 10.2337/diacare.27.6.1487. View

. Human genomics. The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans. Science. 2015; 348(6235):648-60. PMC: 4547484. DOI: 10.1126/science.1262110. View

Xiang L, Li J, Wang Q, Tang R, Qi J . Leptin Gene Transfer Improves Symptoms of Type 2 Diabetic Mice by Regulating Leptin Signaling Pathway and Insulin Resistance of Peripheral Tissues. Hum Gene Ther. 2017; 29(1):68-76. DOI: 10.1089/hum.2016.174. View

10.

Benn M, Nordestgaard B . From genome-wide association studies to Mendelian randomization: novel opportunities for understanding cardiovascular disease causality, pathogenesis, prevention, and treatment. Cardiovasc Res. 2018; 114(9):1192-1208. DOI: 10.1093/cvr/cvy045. View

11.

Yang M, Peng S, Li W, Wan Z, Fan L, Du Y . Relationships between plasma leptin levels, leptin G2548A, leptin receptor Gln223Arg polymorphisms and gestational diabetes mellitus in Chinese population. Sci Rep. 2016; 6:23948. PMC: 4817025. DOI: 10.1038/srep23948. View

12.

OBrien R . Moving on from GWAS: functional studies on the G6PC2 gene implicated in the regulation of fasting blood glucose. Curr Diab Rep. 2013; 13(6):768-77. PMC: 4041587. DOI: 10.1007/s11892-013-0422-8. View

13.

Chandar A, Devanna S, Lu C, Singh S, Greer K, Chak A . Association of Serum Levels of Adipokines and Insulin With Risk of Barrett's Esophagus: A Systematic Review and Meta-Analysis. Clin Gastroenterol Hepatol. 2015; 13(13):2241-55.e1-4. PMC: 4827623. DOI: 10.1016/j.cgh.2015.06.041. View

14.

Gusev A, Ko A, Shi H, Bhatia G, Chung W, Penninx B . Integrative approaches for large-scale transcriptome-wide association studies. Nat Genet. 2016; 48(3):245-52. PMC: 4767558. DOI: 10.1038/ng.3506. View

15.

Pearson E . Type 2 diabetes: a multifaceted disease. Diabetologia. 2019; 62(7):1107-1112. PMC: 6560016. DOI: 10.1007/s00125-019-4909-y. View

16.

Kilpelainen T, Martin Carli J, Skowronski A, Sun Q, Kriebel J, Feitosa M . Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels. Nat Commun. 2016; 7:10494. PMC: 4740377. DOI: 10.1038/ncomms10494. View

17.

Gormley P, Anttila V, Winsvold B, Palta P, Esko T, Pers T . Meta-analysis of 375,000 individuals identifies 38 susceptibility loci for migraine. Nat Genet. 2016; 48(8):856-66. PMC: 5331903. DOI: 10.1038/ng.3598. View

18.

Uhlen M, Fagerberg L, Hallstrom B, Lindskog C, Oksvold P, Mardinoglu A . Proteomics. Tissue-based map of the human proteome. Science. 2015; 347(6220):1260419. DOI: 10.1126/science.1260419. View

19.

de Oliveira E, Moura E, Santos-Silva A, Pinheiro C, Lima N, Nogueira-Neto J . Neonatal nicotine exposure causes insulin and leptin resistance and inhibits hypothalamic leptin signaling in adult rat offspring. J Endocrinol. 2010; 206(1):55-63. DOI: 10.1677/JOE-10-0104. View

20.

Su S, Zhang C, Zhang F, Li H, Yang X, Tang X . The association between leptin receptor gene polymorphisms and type 2 diabetes mellitus: A systematic review and meta-analysis. Diabetes Res Clin Pract. 2016; 121:49-58. DOI: 10.1016/j.diabres.2016.08.008. View