2016;98(1):16584. Additionally, we also observed non-significant multivariable associations between rs7903146-T and lower BMIs at 21, and 45years of age, and non-significant increases in BMI at 65years of age.
2006;55(10):29038.
PubMed
Genetics of type 2 diabetes in U.S. Hispanic/Latino individuals: results from the Hispanic community health study/study of Latinos (HCHS/SOL).
All HCHS/SOL participants provided their written informed consent, following Institutional Review Board approval from all participating academic centers, such as the approval received from the University of North Carolina at Chapel Hill Biomedical Institutional Review Board by the HCHS/SOL Coordinating Center located at the Collaborative Studies Coordinating Center at the University of North Carolina at Chapel Hill. 
We observed protective associations on BMI at 21 and 45years of age, which were not explained by accounting for indirect pathways through T2D or earlier BMI in our structured modeling. 2007;117(8):215563. This indicates that the possible impact of pre-diagnosis metabolic dysfunction, T2D-related lifestyle counseling, or medical intervention also does not fully explain the apparent negative association between the TCF7L2 T2D risk allele and BMI [15].
2007;56(7):19437.
CRI, HMH, KLY, ES, JEB, QQ, AEJ, SFG, CH, RJFL, and KEN have contributed to the content of the final manuscript.
Venous blood samples were collected and for all fully consenting participants (i.e.
Without medical or medication histories, we were unable to validate if these were T2D, or Latent Autoimmune Diabetes in Adults cases who would be expected to be leaner on average [50].
2015;518:197206.
lb.
or kg) and measured (to a tenth of a kg) and height was measured (to whole cm) on participants who were able to stand on both feet.
Seventh ed. Nat Genet.
Am J Hum Genet. Hum Mol Genet.
Nat Genet. Between 2008 and 2011, up to 15 participants per site were invited to repeat the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) examination, including the weight history questionnaire, one to three months after their initial baseline examination without additional reimbursement of their time (N=56).
Gustafson B, Hedjazifar S, Gogg S, Hammarstedt A, Smith U. Insulin resistance and impaired adipogenesis. Nat Genet.
2017;28(6):84753. TCF7L2 and diabetes: a tale of two tissues, and of two species. Specifically, we found that each Tallele associated with lower BMI at examination (2176years), based on either measured or self-reported weight (Table4).
As shown in Fig.1, of the entire HCHS/SOL baseline cohort of 16,415 participants, 16,322 individuals had self-reported and measured weight values that passed quality control (additional information provided as part of Additional file 1: Figure S2 and Table S1).
All multivariable and structural equation models were estimated using Mplus 7.11 software [43], using full-information maximum likelihood methods to account for missing outcome data.
This work contributes to a mounting body of literature reporting consistent protective effects of T2D risk alleles at TCF7L2 and BMI, which points to a complex mechanistic structure underlying the functional consequences of TCF7L2 on both T2D and BMI.
Flowchart of Quality Control and Exclusions Applied to the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) Cohort of 16,415 Individuals (1876years), which Resulted in a Final Analytic Sample of 9031 Hispanic/Latino Adults (2176years), Which Are Detailed Further in the Additional file 1: Table S1 and Figure S2*. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ, et al. 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.
This current analysis is additionally strengthened by its focus on adults of varied Hispanic/Latino backgrounds [45]. In fact, individuals with impaired glucose tolerance and undiagnosed diabetes at examination had the greatest protective effect on BMI of T2D-risk alleles at TCF7L2. J Clin Invest. h24T0PwqH)BDKP5/9?%3/pqsO ( AQ.I HH,*QutQ0Psrq*203cK!o'r{(srru =
Age at baseline examination (age at time of recall), sex, education level, admixture proportions and genetic analysis group, and were included in all pathways to BMI and T2D.
2015;23(1):1039.
This work leverages detailed weight history data to provide further evidence for a complex mechanism underlying TCF7L2 action across the life course that may explain its associations with both T2D and BMI [3, 10,11,12], or the apparent statistical interaction between TCF7L2 genotype and adiposity on T2D related traits seen in previous cross-sectional studies of US Hispanic/Latinos [31]. Weaker effects per allele on BMI were estimated among participants who reported having diabetes at examination as compared to those without diabetes, regardless of the use of measured or self-reported BMI at examination (0.30 to 0.17 versus 0.45 to 0.48kg/m2 per allele). Participants were asked to fast overnight (>8h) and their glucose was measured in the entire sample, and 2-h post-oral glucose tolerance tests was measured among those who reported never having received a diabetes diagnosis. Google Scholar.
Nonetheless we take confidence in the observation that the association of TCF7L2 T2D-risk alleles and BMI was stronger among those without previous T2D diagnosis. Cell Metab. Epidemiology of obesity and diabetes and their cardiovascular complications.
PLoS Genet. Loos RJ, Franks PW, Francis RW, Barroso I, Gribble FM, Savage DB, Ong KK, O'Rahilly S, Wareham NJ.
Based on previous trans-ethnic fine-mapping studies with T2D [37] and BMI [15], we selected rs7903146 as our presumed functional variant of interest at TCF7L2 as it was in strong linkage disequilibrium with several other variants in the area (Additional file 1: Figure S1).
Herein, we replicated the protective effect of rs7930146-T on body mass index at multiple timepoints in the life course, and observed that these effects were not explained by past type 2 diabetes status in our structured modeling. Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci. Individuals with missing covariate information, such as missing genetic analysis group (N=122) or information on their highest education level achieved (categorized as less than or at least a high school diploma or equivalency) (N=14), were excluded. Fernndez-Rhodes, L., Howard, A.G., Graff, M. et al.
Article 2012;308(17):177584. Nature. Acosta JL, Hernandez-Mondragon AC, Correa-Acosta LC, Cazanas-Padilla SN, Chavez-Florencio B, Ramirez-Vega EY, Monge-Cazares T, Aguilar-Salinas CA, Tusie-Luna T, Del Bosque-Plata L. Rare intronic variants of TCF7L2 arising by selective sweeps in an indigenous population from Mexico.
As an exploratory analysis, we also examined the multivariable associations with the measured BMI stratified by previous diabetes diagnosis, as well as glucose tolerance and diabetic medication at examination. Qi Q, Stilp AM, Sofer T, Moon JY, Hidalgo B, Szpiro AA, Wang T, Ng MCY, Guo X, ME-aotDiAA C, et al.
Google Scholar. Of the 12,209 individuals providing their full informed consent for genotyping and data sharing, 12,117 passed genetic quality control, as described above. 1), from which we excluded 87 individuals who reported diabetes diagnosis prior to 22years of age, to restrict our analysis to those for which a diabetes diagnosis was more likely to be T2D, and 1054 individuals that did not have both a measured current height or at least one self-reported weight at 21, 45 or 65years and who were therefore unable to contribute to our structural equation modeling.
Adiposity-related heterogeneity in patterns of type 2 diabetes susceptibility observed in genome-wide association data. BMC Obes 5, 26 (2018). Genome Res. 1998;19(4):37983. Among Hispanic/Latinos 1519year old, less than two thirds of diabetes cases may be Type 1, but the type distribution of cases steadily trends towards more T2D cases into early adulthood [49]a period captured in HCHS/SOL. Clin Genet.
The authors thank the staff and participants of HCHS/SOL for their important contributions. We also observed consistently protective, albeit non-significant, associations on BMI at 21 and 45years.
or kg).
2013;17(2):1579.
Table S1 Staged data cleaning and outlier identification on total sample of 40,525 self-reported weights from 16,355 adult participants (1876years) in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL).
Yet, clearly future functional or longitudinal analyses in population-based samples are required to substantiate our studys findings. Google Scholar.
Diabetes. Even though a previous study, which did not genotype rs7903146 directly, has posited that their best marker SNP at TCF7L2 (rs12255372, r2=0.7 in AMR with rs7903146) may capture a secondary BMI signal in Hispanic/Latinos [12], subsequent trans-ethnic fine-mapping studies of BMI and T2D including diverse Hispanic/Latino samples [8, 46] and large Hispanic/Latino studies have not supported the presence of multiple signals [47].
2014;506(7486):97101. These results collectively suggest that there may be a persistent independent protective effect of TCF7L2 T2D risk alleles on BMI across most of adulthood. Hispanic/Latino adults in the United States (US) are disproportionally affected by obesity and it consequences such as type 2 diabetes (T2D) [1] and this disparity is widening as compared to non-Hispanic Whites [2]. 2007;71(4):35966. Diabetes.
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. Article Nonetheless this study cohort self-reported their current weight with good accuracy and reliability at baseline [34], and we robustly replicated our unstructured TCF7L2 associations with BMI at examination (2176years) using both measured and self-reported current weights.
Evaluation of the metabochip genotyping array in African Americans and implications for fine mapping of GWAS-identified loci: the PAGE study. Provided by the Springer Nature SharedIt content-sharing initiative. 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).
Similarly, our structural equation modeling was notably limited by its reliance on self-reported weighthistories, and height measured at the baseline examination to approximate the BMIs at 21, 45 and 65years of age. 2015;26(4):193200.
PubMed
https://doi.org/10.1186/s40608-018-0200-x, DOI: https://doi.org/10.1186/s40608-018-0200-x. The authors declare that they have no competing interests.
Sample design and cohort selection in the Hispanic community health study/study of Latinos. strain behaviors african cebp T2D between 22 and 45years and 45-year-old weight) was assumed to be directly associated with the BMI at that time. JAMA.
Grant SF, Thorleifsson G, Reynisdottir I, Benediktsson R, Manolescu A, Sainz J, Helgason A, Stefansson H, Emilsson V, Helgadottir A, et al.
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We did not find any significant direct associations between the rs7903146-T and BMI at any age; however, the direction of estimated effect was inverse on BMI at 21 and 45years (Fig.2).
The union of these two quality controlled data sets included 12,073 individuals (Fig.
Maller JB, McVean G, Byrnes J, Vukcevic D, Palin K, Su Z, Howson JM, Auton A, Myers S, Morris A, et al. In our structured modeling, we observed non-significant inverse direct associations between rs7903146-T and body mass index at ages 21 and 45years, and a significant positive association between rs7903146-T and type 2 diabetes onset in both middle and late adulthood.
0
PubMed
2008;57(5):14337.
Waist circumference was measured in cm at the umbilicus using a tape measure, and body fat percentage estimated by a Tanita Body Composition Analyzer. We observed a significant multivariable association between the additive number of type 2 diabetes-risk alleles and lower body mass index at examination.
2010;33(Suppl 1):S629.
Alexander DH, Novembre J, Lange K. Fast model-based estimation of ancestry in unrelated individuals. 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.
The T2D-increasing allele at TCF7L2 has also been associated with lower body mass index (BMI) [3, 10,11,12], resulting in a subsequent call for future research [13] given the strong epidemiologic correlation between increasing BMI and risk of T2D [14].
Diabetes.
Lindsay Fernndez-Rhodes.
We excluded all weights from women who reported currently being pregnant at baseline or individuals with limb amputations that otherwise did not limit their ability to stand (Additional file 1: Figure S2 and Table S1).
In our dataset, missingness for age-specific BMIs was primarily determined by ones age (BMI at 45 and 65years of age would be missing for a 35-year-old participant).
This gives us confidence that rs7903146, the lead variant for the single T2D signal observed in HCHS/SOL [48],is the best available SNP marker to simultaneously investigate allelic effects on BMI and T2D diagnosis within a structural equation modeling framework.
Terms and Conditions,
The consistent negative association between T2D risk alleles and BMI in early and mid-adulthood seen in this and previous work [3, 10, 11] may point to another explanation. Helgason A, Palsson S, Thorleifsson G, Grant SF, Emilsson V, Gunnarsdottir S, Adeyemo A, Chen Y, Chen G, Reynisdottir I, et al.
Table S4. Of the entire set of 16,355 individuals with at least one self-reported weight in adulthood (40,525 observations) and based on our staged quality control protocol, we recoded a total of 54 observations, and excluded an additional 541 observations (Additional file 1: Table S1). 2007;2(4):23843. Lin DY, Tao R, Kalsbeek WD, Zeng D, Gonzalez F 2nd, Fernandez-Rhodes L, Graff M, Koch GG, North KE, Heiss G. Genetic association analysis under complex survey sampling: the Hispanic community health study/study of Latinos. 2015;24(6):164654. Parameter Estimates for Select Indeirect Pathway Model Results. 2007;39(2):21825. Springer Nature.
Further information can be found at investigators website at https://sites.cscc.unc.edu/hchs/publications-pub.
Kaminska D, Kuulasmaa T, Venesmaa S, Kakela P, Vaittinen M, Pulkkinen L, Paakkonen M, Gylling H, Laakso M, Pihlajamaki J. Adipose tissue TCF7L2 splicing is regulated by weight loss and associates with glucose and fatty acid metabolism.
In contrast, among the subset of individuals 65years or older, the non-significant association between T2D-risk variants and BMI at 65years of age was positive. Diabetes.
Bhupathiraju SN, Hu FB.
We did observe a similar, but non-significant association of T2D diagnosis between 46 and 65years on BMI at 65years. Florez JC, Jablonski KA, Bayley N, Pollin TI, de Bakker PI, Shuldiner AR, Knowler WC, Nathan DM, Altshuler D. Diabetes prevention program research G: TCF7L2 polymorphisms and progression to diabetes in the diabetes prevention program.
Only two participants, 65years of age, recalled their 65-year old weight twice, which precluded reliability calculations for 65-year old weights.
2007, 50(1):14.
Mondal AK, Das SK, Baldini G, Chu WS, Sharma NK, Hackney OG, Zhao J, Grant SF, Elbein SC. All authors read and approved the final manuscript. BMC Genet. Gaulton KJ, Ferreira T, Lee Y, Raimondo A, Magi R, Reschen ME, Mahajan A, Locke A, Rayner NW, Robertson N, et al.
However, herein, we extended this protocol to also include recalled weights at 21, 45, or 65years of age.
In addition we applied a data quality control protocol, as described previously for self-reported current weight collected as part of the anthropometric examination [34] to 1) minimize potential instances of unit confusion in the self-report (lb versus kg) or 2) exclude self-reported weights during pregnancy reported during the baseline examination, self-reported or measured weights made by individuals with past limb amputation or when scaled by measured baseline height that correspond to extreme underweight (<16kg/m2) or obesity (>70kg/m2).
Refining the impact of TCF7L2 gene variants on type 2 diabetes and adaptive evolution.
The mean differences of the 21 and 45-year old self-reported weight were0.9kg (2.7, 1.0) and1.3kg (3.8, 1.1) resulting in good reliabilities and low coefficients of variation (21-year recall: ICC=0.89, CV=7.7% n=52; 45-year recall: 0.86, 6.7%, n=29). We used data from the HCHS/SOL study, a multi-center, longitudinal, household-basedcohort study of 16,415 Hispanic/Latino adults, aged 1876years in 20082011, who were sampled using a two-stage probability design from four US urban communities (The Bronx, NY; Chicago, IL; Miami, FL; San Diego, CA), as described previously in detail [32, 33].
Palmer ND, Lehtinen AB, Langefeld CD, Campbell JK, Haffner SM, Norris JM, Bergman RN, Goodarzi MO, Rotter JI, Bowden DW. Daviglus ML, Talavera GA, Aviles-Santa ML, Allison M, Cai J, Criqui MH, Gellman M, Giachello AL, Gouskova N, Kaplan RC, et al.
This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (Grant 5R01DK101855). 2015;47(12):141525. Xia Q, Deliard S, Yuan CX, Johnson ME, Grant SF. J Cardiometab Syndr. 2014;28(9):155870.
Diabetes. If an individual was younger than 45 or 65years at the baseline examination, then the classification of T2D diagnosis of the incomplete age period was set to missing (e.g.
2014;37(2):4028. Gaulton KJ, Nammo T, Pasquali L, Simon JM, Giresi PG, Fogarty MP, Panhuis TM, Mieczkowski P, Secchi A, Bosco D, et al.
Average BMIs increased across age of recalled weight (24kg/m2 at 21years to 29kg/m2 at 65years).
2).
A map of open chromatin in human pancreatic islets. Parameter Estimates from Pathway Model Results.
Next, we modeled the association between the additive number of rs7903146-T alleles with multiple BMI measures using multivariable models (e.g.
In contrast to a previous cross-sectional study of 1235 Hispanic/Latinos, which estimated a larger effects of T2D-risk alleles at TCF7L2 on BMI by adjusting for concurrent T2D status (0.3 to 1.1kg/m2 for rs12255372-T) [12], our large and diverse study of US Hispanic/Latinos estimated more modest effects of T2D-risk alleles on BMI (0.4kg/m2 for rs7903146-T; unadjusted for T2D status) and leveraged information on weight and T2D histories collected during the HCHS/SOL baseline examination to further decompose the complex relationships between priorBMI and T2D (Effect of each T2D-risk allele on BMI ranged from 0.2 to 0.2kg/m2 at 21 and 65years of age, respectively).
In a structural equation model, we noted that each T allele at rs7903146 was directly associated with a 1.32 (95% CI: 1.05, 1.67) higher odds of T2D diagnosis between the ages of 22 and 45years, and a 1.67 (95% CI: 1.15, 2.42) higher odds of T2D diagnosis between 22 and 65years of age.
Article Five percent of those who were at least 45years old (unweighted n=5605) received a T2D diagnosis by age 45 (Table 1). Bailey KA, Savic D, Zielinski M, Park SY, Wang LJ, Witkowski P, Brady M, Hara M, Bell GI, Nobrega MA.
Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. Nat Genet.
Bayesian refinement of association signals for 14 loci in 3 common diseases. 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.
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2017;66(5):141925. 0.35<<0.98) [42], and exclude the individual in each pair with the least weight measurements (N=1765). By using this website, you agree to our 2008;93(1):3049.
This was further supported by our non-significant TCF7L2 associations on BMI at the examination among T2D individuals concurrently taking medications (Additional file 1: Table S2).
HCHS/SOL personnel (requiring a minimum of 5 practice subjects with 0.5kg weight and 0.5cm height agreement between a trainee and expert) measured height (cm) and weight (kg) during the anthropometric examination of the full HCHS/SOL cohort using a fixed (wall mounted) stadiometer (inspected daily) and a digital scale (scales zero balanced daily and calibrated weekly) on all participants that were able to stand on both feet while wearing a scrub suit or examination gown and no shoes [34]. LFR and AGH then drafted the manuscript jointly. Descriptive statistics were estimated using SAS 9.3 (Research Triangle Park, NC). Mean BMI and waist circumference at examination showed similar quantitative decreases by 0.50.6kg/m2 and 1.1cm as the number of T2D-risk allele increased (P values<0.1).
2010;42(3):2559. Forthcoming HCHS/SOL, or other prospective cohort follow up data will allow future investigators to explore the contemporaneous and interacting relationships between TCF7L2, BMI and T2D status across the adult life course.
The number of T2D-risk alleles at rs7903146associated with an increase in T2D prevalence by 7% (P value=0.0002) and decreased obesity prevalence by 35%, based on either the use of measured or self-reported weights (P value <0.04, Table2). 2006;355(3):24150.
In Hispanic/Latinos each risk-allele has been associated with a 40% increased odds of T2D [7, 9]. Furthermore, we found no evidence of indirect associations between rs7903146 and either BMI or T2D at any time point (Additional file 1: Table S3).
Genotype and tissue-specific effects on alternative splicing of the transcription factor 7-like 2 gene in humans.
Direct pathways between rs7903146 to BMIs and T2D measurements were also included. Locke AE, Kahali B, Berndt SI, Justice AE, Pers TH, Day FR, Powell C, Vedantam S, Buchkovich M, Consortium G. Genetic studies of body mass index yield new insights for obesity biology.
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Timpson NJ, Lindgren CM, Weedon MN, Randall J, Ouwehand WH, Strachan DP, Rayner NW, Walker M, Hitman GA, Doney AS, et al. Hum Mol Genet.
A total of 9031 individuals remained in the final analytic dataset used for all analyses, and we described their characteristics using descriptive statistics such as means, 95% confidence intervals (CIs), and frequencies. Yaghootkar H, Bancks MP, Jones SE, McDaid A, Beaumont R, Donnelly L, Wood AR, Campbell A, Tyrrell J, Hocking LJ, et al. Sequence variants in SLC16A11 are a common risk factor for type 2 diabetes in Mexico.
Correspondence to
Using 9031 Hispanic/Latino adults (2176years) with complete weight history and genetic data from the community-based Hispanic Community Health Study/Study of Latinos (HCHS/SOL, Baseline 20082011), we estimated the multivariable association between the additive number of type 2 diabetes increasing-alleles at TCF7L2 (rs7903146-T) and body mass index.