A Loss-of-Function Splice Acceptor Variant in <i>IGF2</i> Is Protective for Type 2 Diabetes

Mercader, Josep M.; Liao, Rachel G.; Bell, Avery Davis; Dymek, Zachary; Estrada, Karol; Tukiainen, Taru; Huerta-Chagoya, Alicia; Moreno-Macías, Hortensia; Jablonski, Kathleen A.; Hanson, Robert L.; Walford, Geoffrey; Morán, Ignasi; Chen, Ling; Agarwala, Vineeta; Ordóñez-Sánchez, María Luisa; Rodríguez‐Guillén, Rosario; Rodrı́guez-Torres, Maribel; Segura-Kato, Yayoi; Garcia‐Ortíz, Humberto; Centeno-Cruz, Federico; Barajas‐Olmos, Francisco; Caulkins, Lizz; Puppala, Sobha; Fontanillas, Pierre; Williams, Amy L.; Bonàs-Guarch, Sílvia; Hartl, Christopher; Ripke, Stephan; Tooley, Katherine; Lane, Jacqueline M.; Zerrweck, Carlos; Martínez‐Hernández, Angélica; Córdova, Emilio J.; Mendoza-Caamal, Elvia; Contreras-Cubas, Cecilia; González-Villalpando, María Elena; Cruz-Bautista, Ivette; Muñóz-Hernández, Liliana; Gómez‐Velasco, Donají; Alvirde, Ulises; Henderson, Brian E.; Wilkens, Lynne R.; Marchand, Loı̈c Le; Arellano-Campos, Olimpia; Riba, Laura; Harden, Maegan; Gabriel, Stacey; Abboud, Hanna E.; Cortés, Maria L.; Revilla-Monsalve, Cristina; Islas-Andrade, Sergio; Soberón, Xavier; Curran, Joanne E.; Jenkinson, Christopher P.; DeFronzo, Ralph A.; Lehman, Donna M.; Hanis, Craig L.; Bell, Graeme I.; Boehnke, Michael; Blangero, John; Duggirala, Ravindranath; Saxena, Richa; MacArthur, Daniel G.; Ferrer, Jorge; McCarroll, Steven A.; Torrents, David; Knowler, William C.; Baier, Leslie J.; Burtt, Noél P.; González‐Villalpando, Clicerio; Haiman, Christopher A.; Aguilar-Salinas, Carlos A.; Tusié-Luna, Teresa; Flannick, Jason; Jacobs, Suzanne B.R.; Orozco, Lorena; Altshuler, David; Florez, José C.

doi:10.2337/db17-0187

Cited by 54 publications

(54 citation statements)

References 57 publications

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“…These findings indicated that interact with IGF2, which played an important role in multiple diseases. [48][49][50] Besides, rs326049 showed significant association with CCDC127 expression, a significantly upregulated gene in lung tumor tissues. Furthermore, co-expression genes with RP11-43F13.3 mainly enriched in DNA replication, homologous recombination, spliceosome pathways.…”

Section: Discussionmentioning

confidence: 94%

“…In addition, the expression of RP11‐43F13.3 was significantly decreased in tumor tissues compared with adjacent normal tissues, indicating that RP11‐43F13.3 might play as a tumor inhibitor. According to lncRNome database, the RP11‐43F13.3 was an antisense and could interact with IGF2 , which played an important role in multiple diseases . Besides, rs326049 showed significant association with CCDC127 expression, a significantly upregulated gene in lung tumor tissues.…”

Section: Discussionmentioning

confidence: 99%

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Fine mapping in TERT‐CLPTM1L region identified three independent lung cancer susceptibility signals: A large‐scale multi‐ethnic population study

Fan

et al. 2018

Molecular Carcinogenesis

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Genome-wide association studies (GWAS) and fine mapping studies have identified multiple lung cancer susceptibility variants in TERT-CLPTM1L region. However, it is still unclear about the relationship between these risk variants and the independent lung cancer risk signals in this region. Therefore, we evaluated the independent susceptibility signals for lung cancer and explored the potential functional variants in this region. Sequential conditional analysis was used to detect the independent susceptibility loci based on four lung cancer GWAS datasets with 12 843 lung cases and 12 639 controls. Comprehensively functional annotations were performed for each independent signal. Three independent susceptibility signals were identified in multi-ethnic population. For the first signal, rs2736100 showed the most significant association with lung cancer risk (C > A, OR = 0.82, 95%CI: 0.79-0.85, P = 1.98 × 10 ). Rs36019446 was the top-ranked site (A > G, OR = 0.88, 95%CI: 0.84-0.92, P = 1.74 × 10 ) in the second signal. For the third signal, rs326048 was the leading SNP (A > G, OR = 0.91, 95%CI: 0.87-0.95, P = 1.38 × 10 ). The following subgroup analysis found the same three loci among Asian population. Further, we compared the difference between various subgroup populations. Functional annotations revealed that rs2736100, rs27996 (r = 0.85 with rs36019446) and rs326049 (r = 0.73 with rs326048) could be potential functional variants in these three risk signals, respectively. In conclusion, although multiple variants have been found associated with lung cancer risk in TERT-CLPTM1L region, our findings indicated that there are three independent lung cancer susceptibility signals in this region.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Fine mapping in TERT‐CLPTM1L region identified three independent lung cancer susceptibility signals: A large‐scale multi‐ethnic population study

Fan

et al. 2018

Molecular Carcinogenesis

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“…50 Recently, a genetic variant in the IGF2 gene associated with about 20% reduced risk for T2D by comparing individuals with and without T2D of Hispanic descent. 51 A loss of function splice acceptor variant in IGF2 is protective for T2D. The absence of this variant was associated with increased incidence of T2D and increased plasma glycated HbA 1c and could be considered as a new therapeutic strategy.…”

Section: Resultsmentioning

confidence: 99%

“…Recently, a genetic variant in the IGF2 gene associated with about 20% reduced risk for T2D by comparing individuals with and without T2D of Hispanic descent . A loss of function splice acceptor variant in IGF2 is protective for T2D.…”

Section: Pathophysiology Of T2dmentioning

confidence: 99%

Understanding the growing epidemic of type 2 diabetes in the Hispanic population living in the United States

Aguayo-Mazzucato

Diaque

Hernandez

et al. 2018

Diabetes Metabolism Res

155

130

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Summary The prevalence and incidence of type 2 diabetes (T2D) among the Hispanic population in the United States are higher than the national average. This is partly due to sociocultural factors, such as lower income and decreased access to education and health care, as well as a genetic susceptibility to obesity and higher insulin resistance. This review focuses on understanding the Hispanic population living in the United States from a multidisciplinary approach and underlines the importance of cultural, social, and biological factors in determining the increased risk of T2D in this population. An overview of the acute and chronic complications of T2D upon this population is included, which is of paramount importance to understand the toll that diabetes has upon this population, the health system, and society as a whole. Specific interventions directed to the Hispanic populations are needed to prevent and alleviate some of the burdens of T2D. Different prevention strategies based on medications, lifestyle modifications, and educational programmes are discussed herein. Diabetes self‐management education (DSME) is a critical element of care of all people with diabetes and is considered necessary to improve patient outcomes. To be more effective, programmes should take into consideration cultural factors that influence the development and progression of diabetes. These interventions aim to enhance long‐term effects by reducing the incidence, morbidity, and mortality of T2D in the Hispanic population of the United States.

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“…Samples collected among isolated populations have facilitated the discovery of a range of relatively common variants with large effect sizes for metabolic phenotypes (Table ). These discoveries include type 2 diabetes susceptibility variants in ABCC8 identified in Pima Indians , and in TBC1D4 identified in Greenlanders , as well as in SLC16A11 and HNF1A identified in the admixed Mexican population , where also a protective type 2 diabetes variant has been identified in IGF2 . Moreover, variants associated with lower lipid levels in APOC3 and DSCAML1 have been identified in an isolated Greek population , variants associated with levels of fatty acids in ACSL6 and CPT1A have been identified in Greenlanders , as well as variants associated with obesity in CREBRF and ADCY3 in Samoans and Greenlanders, respectively , and increased fasting insulin in AKT2 identified in Finns .…”

Section: Genetic Association Studies Of Metabolic Traits In Isolatedmentioning

confidence: 97%

Genetics of metabolic traits in Greenlanders: lessons from an isolated population

Andersen

Hansen

2018

J Intern Med

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In this review, we describe the extraordinary population of Greenland, which differs from large outbred populations of Europe and Asia, both in terms of population history and living conditions. Many years in isolation, small population size and an extreme environment have shaped the genetic composition of the Greenlandic population. The unique genetic background combined with the transition from a traditional Inuit lifestyle and diet, to a more Westernized lifestyle, has led to an increase in the prevalence of metabolic conditions like obesity, where the prevalence from 1993 to 2010 has increased from 16.4% to 19.4% among men, and from 13.0% to 25.4% among women, type 2 diabetes and cardiovascular diseases. The genetic susceptibility to metabolic conditions has been explored in Greenlanders, as well as other isolated populations, taking advantage of population-genetic properties of these populations. During the last 10 years, these studies have provided examples of loci showing evidence of positive selection, due to adaption to Arctic climate and Inuit diet, including TBC1D4 and FADS/CPT1A, and have facilitated the discovery of several loci associated with metabolic phenotypes. Most recently, the c.2433-1G>A loss-of-function variant in ADCY3 associated with obesity and type 2 diabetes was described. This locus has provided novel biological insights, as it has been shown that reduced ADCY3 function causes obesity through disrupted function in primary cilia. Future studies of isolated populations will likely provide further genetic as well as biological insights.

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A Loss-of-Function Splice Acceptor Variant in IGF2 Is Protective for Type 2 Diabetes

Cited by 54 publications

References 57 publications

Fine mapping in TERT‐CLPTM1L region identified three independent lung cancer susceptibility signals: A large‐scale multi‐ethnic population study

Fine mapping in TERT‐CLPTM1L region identified three independent lung cancer susceptibility signals: A large‐scale multi‐ethnic population study

Understanding the growing epidemic of type 2 diabetes in the Hispanic population living in the United States

Genetics of metabolic traits in Greenlanders: lessons from an isolated population

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