TY - JOUR
T1 - Complex patterns of direct and indirect association between the transcription Factor-7 like 2 gene, body mass index and type 2 diabetes diagnosis in adulthood in the Hispanic Community Health Study/Study of Latinos
AU - Fernández-Rhodes, Lindsay
AU - Howard, Annie Green
AU - Graff, Mariaelisa
AU - Isasi, Carmen R.
AU - Highland, Heather M.
AU - Young, Kristin L.
AU - Parra, Esteban
AU - Below, Jennifer E.
AU - Qi, Qibin
AU - Kaplan, Robert C.
AU - Justice, Anne E.
AU - Papanicolaou, George
AU - Laurie, Cathy C.
AU - Grant, Struan F.A.
AU - Haiman, Christopher
AU - Loos, Ruth J.F.
AU - North, Kari E.
N1 - Funding Information:
This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (Grant 5R01DK101855). LFR was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (T32-HD007168) and the Carolina Population Center (P2C-HD050924). Additionally, the Hispanic Community Health Study/Study of Latinos was carried out as a collaborative study supported by contracts from the National Heart, Lung, and Blood Institute to the University of North Carolina (Grant N01-HC65233), University of Miami (Grant N01-HC65234), Albert Einstein College of Medicine (Grant N01-HC65235), Northwestern University (Grant N01-HC65236), and San Diego State University (Grant N01-HC65237). The following Institutes/Centers/Offices contributed to the HCHS/SOL through a transfer of funds to the NHLBI: National Center on Minority Health and Health Disparities, the National Institute of Deafness and Other Communications Disorders, the National Institute of Dental and Craniofacial Research, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Neurological Disorders and Stroke, and the Office of Dietary Supplements.
Publisher Copyright:
© 2018 The Author(s).
PY - 2018/10/2
Y1 - 2018/10/2
N2 - Background: Genome-wide association studies have implicated the transcription factor 7-like 2 (TCF7L2) gene in type 2 diabetes risk, and more recently, in decreased body mass index. Given the contrary direction of genetic effects on these two traits, it has been suggested that the observed association with body mass index may reflect either selection bias or a complex underlying biology at TCF7L2. Methods: Using 9031 Hispanic/Latino adults (21-76 years) with complete weight history and genetic data from the community-based Hispanic Community Health Study/Study of Latinos (HCHS/SOL, Baseline 2008-2011), we estimated the multivariable association between the additive number of type 2 diabetes increasing-alleles at TCF7L2 (rs7903146-T) and body mass index. We then used structural equation models to simultaneously model the genetic association on changes in body mass index across the life course and estimate the odds of type 2 diabetes per TCF7L2 risk allele. Results: We observed both significant increases in type 2 diabetes prevalence at examination (independent of body mass index) and decreases in mean body mass index and waist circumference across genotypes at rs7903146. We observed a significant multivariable association between the additive number of type 2 diabetes-risk alleles and lower body mass index at examination. In our structured modeling, we observed non-significant inverse direct associations between rs7903146-T and body mass index at ages 21 and 45 years, and a significant positive association between rs7903146-T and type 2 diabetes onset in both middle and late adulthood. Conclusions: Herein, we replicated the protective effect of rs7930146-T on body mass index at multiple time points in the life course, and observed that these effects were not explained by past type 2 diabetes status in our structured modeling. The robust replication of the negative effects of TCF7L2 on body mass index in multiple samples, including in our diverse Hispanic/Latino community-based sample, supports a growing body of literature on the complex biologic mechanism underlying the functional consequences of TCF7L2 on obesity and type 2 diabetes across the life course.
AB - Background: Genome-wide association studies have implicated the transcription factor 7-like 2 (TCF7L2) gene in type 2 diabetes risk, and more recently, in decreased body mass index. Given the contrary direction of genetic effects on these two traits, it has been suggested that the observed association with body mass index may reflect either selection bias or a complex underlying biology at TCF7L2. Methods: Using 9031 Hispanic/Latino adults (21-76 years) with complete weight history and genetic data from the community-based Hispanic Community Health Study/Study of Latinos (HCHS/SOL, Baseline 2008-2011), we estimated the multivariable association between the additive number of type 2 diabetes increasing-alleles at TCF7L2 (rs7903146-T) and body mass index. We then used structural equation models to simultaneously model the genetic association on changes in body mass index across the life course and estimate the odds of type 2 diabetes per TCF7L2 risk allele. Results: We observed both significant increases in type 2 diabetes prevalence at examination (independent of body mass index) and decreases in mean body mass index and waist circumference across genotypes at rs7903146. We observed a significant multivariable association between the additive number of type 2 diabetes-risk alleles and lower body mass index at examination. In our structured modeling, we observed non-significant inverse direct associations between rs7903146-T and body mass index at ages 21 and 45 years, and a significant positive association between rs7903146-T and type 2 diabetes onset in both middle and late adulthood. Conclusions: Herein, we replicated the protective effect of rs7930146-T on body mass index at multiple time points in the life course, and observed that these effects were not explained by past type 2 diabetes status in our structured modeling. The robust replication of the negative effects of TCF7L2 on body mass index in multiple samples, including in our diverse Hispanic/Latino community-based sample, supports a growing body of literature on the complex biologic mechanism underlying the functional consequences of TCF7L2 on obesity and type 2 diabetes across the life course.
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U2 - 10.1186/s40608-018-0200-x
DO - 10.1186/s40608-018-0200-x
M3 - Article
C2 - 30305909
AN - SCOPUS:85054366367
SN - 2052-9538
VL - 5
JO - BMC Obesity
JF - BMC Obesity
IS - 1
M1 - 26
ER -