Genetic associations of leptin-related polymorphisms with systemic lupus erythematosus

Zhao, Jian; Wu, Hui; Langefeld, Carl D.; Kaufman, Kenneth M.; Kelly, Jennifer A.; Bae, Sang Cheol; Alarcón‐Riquelme, Marta E.; Alarcón, Graciela S.; Anaya, Juan Manuel; Criswell, Lindsey A.; Freedman, Barry I.; Kamen, Diane L.; Gilkeson, Gary S.; Jacob, Chaim O.; James, Judith A.; Merrill, Joan T.; Gaffney, Patrick M.; Sivils, Kathy Moser; Niewold, Timothy B.; Petri, Michelle; Song, Seung Hwan; Jeong, Hye Jin; Ramsey‐Goldman, Rosalind; Reveille, John D.; Scofield, R. Hal; Stevens, Anne M.; Boackle, Susan A.; Vilá, Luis M.; Chang, Deh Ming; Song, Yeong Wook; Vyse, Timothy J.; Harley, John B.; Brown, Elizabeth E.; Edberg, Jeffrey C.; Kimberly, Robert P.; Hahn, Bevra H.; Grossman, Jennifer M.; Tsao, Betty P.; Cava, Antonio La; Frostegård, Johan; Truedsson, Lennart; Enrique, Rafael; Sabio, José Mario; González‐Escribano, María Francisca; Martín, Javier; Ortego‐Centeno, Norberto; Callejas‐Rubio, José Luis; Sánchez-Román, Julio; D’Alfonso, Sandra; Migliarese, Sergio; Sebastiani, Gian Domenico; Galeazzi, Mauro; Witte, Torsten; Lauwerys, Bernard; Endreffy, E.; Kovács, László; Vasconcelos, Carlos; Silva, Ana Martins; Scherbarth, Hugo R.; Marino, Pilar C.; E, Motta; Gamron, Susana; Drenkard, Cristina; Menso, Emilia; Allievi, Alberto; Tate, Guillermo; Presas, José; Palatnik, Simon A.; Abdala, Marcelo; Bearzotti, Mariela; Alvarellos, Alejandro; Caeiro, Francisco; Bertoli, Ana M.; Paira, Sergio; Roverano, Susana; Graf, César; Bertero, Estela; Caprarulo, Cesar; Buchanan, Griselda; Guillerón, Carolina; Grimaudo, Sebastián; Manni, Jorge A.; Catoggio, Luís J.; Soriano, Enrique R.; Santos, Carlos David; Prigione, Cristina; Ramos, Fernando; Navarro, Sandra; Berbotto, Guillermo; Jorfen, Marisa; Romero, Elisa J.; García, Mercedes; Marcos, Juan Carlos; Marcos, Ana Isabel Sánchez; Perandones, Carlos E.; Eimon, Alicia; Parque, Sanatorio; Battagliotti, Cristina; Acevedo, Eduardo; Cucho, M; Torre, Ignacio García de la; Ríos, Mario Cardiel; Moctezuma, Francisco; Ceceña, Marco Maradiaga

doi:10.1016/j.clim.2015.09.007

Cited by 9 publications

(12 citation statements)

References 29 publications

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“…Together, the data from the present study suggest a propathogenetic role of leptin that is not in conflict with our recent investigations on associations between selected leptin gene polymorphisms and human SLE (24). Weak associations with certain SNPs did not remain significant after correction for multiple testing, although associations with selected ethnicities and/or subgroups of SLE patients were identified (24).…”

Section: Discussioncontrasting

confidence: 58%

“…Weak associations with certain SNPs did not remain significant after correction for multiple testing, although associations with selected ethnicities and/or subgroups of SLE patients were identified (24). Those findings bring to mind the lack of genetic associations observed for SLE and gene polymorphisms of BLyS (25,26), a proinflammatory cytokine that, like leptin, is elevated in SLE, promotes SLE in mice and in humans (27), and is targeted for therapy in certain SLE patients (28).…”

Section: Discussionmentioning

confidence: 91%

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Leptin promotes systemic lupus erythematosus by increasing autoantibody production and inhibiting immune regulation

Lourenço

Liu

Matarese

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Leptin is an adipocytokine that plays a key role in the modulation of immune responses and the development and maintenance of inflammation. Circulating levels of leptin are elevated in systemic lupus erythematosus (SLE) patients, but it is not clear whether this association can reflect a direct influence of leptin on the propathogenic events that lead to SLE. To investigate this possibility, we compared the extent of susceptibility to SLE and lupus manifestations between leptin-deficient (ob/ob) and H2-matched leptinsufficient (wild-type, WT) mice that had been treated with the lupus-inducing agent pristane. Leptin deficiency protected ob/ob mice from the development of autoantibodies and renal disease and increased the frequency of immunoregulatory T cells (Tregs) compared with leptin-sufficient WT mice. The role of leptin in the development of SLE was confirmed in the New Zealand Black (NZB) × New Zealand White (NZW)F 1 (NZB/W) mouse model of spontaneous SLE, where elevated leptin levels correlated with disease manifestations and the administration of leptin accelerated development of autoantibodies and renal disease. Conversely, leptin antagonism delayed disease progression and increased survival of severely nephritic NZB/W mice. At the cellular level, leptin promoted effector T-cell responses and facilitated the presentation of self-antigens to T cells, whereas it inhibited the activity of regulatory CD4 T cells. The understanding of the role of leptin in modulating autoimmune responses in SLE can open possibilities of leptin-targeted therapeutic intervention in the disease.systemic lupus erythematosus | leptin | autoimmunity | immune regulation | animal models

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Section: Discussioncontrasting

confidence: 58%

Section: Discussionmentioning

confidence: 91%

Leptin promotes systemic lupus erythematosus by increasing autoantibody production and inhibiting immune regulation

Lourenço

Liu

Matarese

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

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“…This aspect, together with the observation that leptin concentration is abnormally elevated in autoimmune mice and in patients affected by autoimmune disease [6] , led to wonder whether certain gene polymorphisms in SLE patients could contribute to the pathogenesis of the disease [3,7] . Additionally, past studies indicated an abnormal increase in serum/plasma leptin levels in SLE patients (independent of disease activity) [8][9][10][11][12] .…”

Section: Why Leptin and Slementioning

confidence: 99%

“…More recently, a large study genotyped a collection of DNA samples from 8,269 cases and 7,437 controls belonging to four different ancestral groups to test the possibility that leptin pathway-related gene polymorphism could contribute to risk of SLE [3] . The study was rendered possible by the fact that conspicuous numbers of samples were contributed by the Large Lupus Association Study 2 (LLAS2), whose participating institutions are located worldwide (United States, Asia and Europe).…”

Section: Leptin-related Polymorphisms and Slementioning

confidence: 99%

“…As such, genetic polymorphisms can influence the expression and/or activity of certain genes that are relevant to the SLE disease process, thereby affecting predisposition and, ultimately, disease outcomes and response to therapy. Although many genes have been tested by genetic association studies for possible contribution to an increased risk of SLE [1][2] , gene association studies investigating leptin-related polymorphisms in the disease have been sparse and inconclusive, until recently [3] .…”

Section: Introductionmentioning

confidence: 99%

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Leptin-related polymorphisms and SLE

Cava

2016

Inflamm Cell Signal

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Leptin is a hormone/cytokine that is mainly produced by adipocytes and has a range of actions that span from the control of metabolic balance to the modulation of adaptive and innate immune responses. Many investigations have indicated that the pro-inflammatory activities of leptin can contribute significantly to the promotion and maintenance of autoimmune responses. It is not known whether the abnormal elevation of leptin in patients with systemic lupus erythematous (SLE) -an autoimmune disease characterized by multi-organ involvement and the presence of autoantibodies -can reflect the chronic inflammatory status of the disease or can contribute to the pathogenesis of the disease. To partly address this question, a recent investigation analyzed several leptin-related gene polymorphisms in SLE in large numbers of individuals from different ancestral groups. The study identified weak associations with certain SNPs that did not remain significant after correction for multiple testing. This review discusses the implications of those findings for the pathogenesis of SLE and for the possibility of leptin-based modalities of therapeutic intervention in the disease.

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Role of serum leptin levels and leptin receptor gene polymorphisms in systemic lupus erythematosus

et al. 2020

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Genetic associations of leptin-related polymorphisms with systemic lupus erythematosus

Cited by 9 publications

References 29 publications

Leptin promotes systemic lupus erythematosus by increasing autoantibody production and inhibiting immune regulation

Leptin promotes systemic lupus erythematosus by increasing autoantibody production and inhibiting immune regulation

Leptin-related polymorphisms and SLE

Role of serum leptin levels and leptin receptor gene polymorphisms in systemic lupus erythematosus

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