Dataset Information

Novel epigenetic determinants of type 2 diabetes in Mexican-American families.

ABSTRACT: Although DNA methylation is now recognized as an important mediator of complex diseases, the extent to which the genetic basis of such diseases is accounted for by DNA methylation is unknown. In the setting of large, extended families representing a minority, high-risk population of the USA, we aimed to characterize the role of epigenome-wide DNA methylation in type 2 diabetes (T2D). Using Illumina HumanMethylation450 BeadChip arrays, we tested for association of DNA methylation at 446 356 sites with age, sex and phenotypic traits related to T2D in 850 pedigreed Mexican-American individuals. Robust statistical analyses showed that (i) 15% of the methylome is significantly heritable, with a median heritability of 0.14; (ii) DNA methylation at 14% of CpG sites is associated with nearby sequence variants; (iii) 22% and 3% of the autosomal CpG sites are associated with age and sex, respectively; (iv) 53 CpG sites were significantly associated with liability to T2D, fasting blood glucose and insulin resistance; (v) DNA methylation levels at five CpG sites, mapping to three well-characterized genes (TXNIP, ABCG1 and SAMD12) independently explained 7.8% of the heritability of T2D (vi) methylation at these five sites was unlikely to be influenced by neighboring DNA sequence variation. Our study has identified novel epigenetic indicators of T2D risk in Mexican Americans who have increased risk for this disease. These results provide new insights into potential treatment targets of T2D.

SUBMITTER: Kulkarni H

PROVIDER: S-EPMC4550817 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Novel epigenetic determinants of type 2 diabetes in Mexican-American families.

Kulkarni Hemant H Kos Mark Z MZ Neary Jennifer J Dyer Thomas D TD Kent Jack W JW Göring Harald H H HH Cole Shelley A SA Comuzzie Anthony G AG Almasy Laura L Mahaney Michael C MC Curran Joanne E JE Blangero John J Carless Melanie A MA

Human molecular genetics 20150622 18

Although DNA methylation is now recognized as an important mediator of complex diseases, the extent to which the genetic basis of such diseases is accounted for by DNA methylation is unknown. In the setting of large, extended families representing a minority, high-risk population of the USA, we aimed to characterize the role of epigenome-wide DNA methylation in type 2 diabetes (T2D). Using Illumina HumanMethylation450 BeadChip arrays, we tested for association of DNA methylation at 446 356 sites ...[more]

PMID: 26101197

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Project description:ObjectiveWhile the role of type 2 diabetes (T2D) in inducing endothelial dysfunction is fairly well-established the etiological role of endothelial dysfunction in the onset of T2D is still a matter of debate. In the light of conflicting evidence in this regard, we conducted a prospective study to determine the association of circulating levels of soluble intercellular adhesion molecule 1 (sICAM-1) and soluble vessel cell adhesion molecule 1 (sVCAM-1) with incident T2D.MethodsData from this study came from 1,269 Mexican Americans of whom 821 initially T2D-free individuals were longitudinally followed up in the San Antonio Family Heart Study. These individuals were followed for 9752.95 person-years for development of T2D. Prospective association of sICAM-1 and sVCAM-1 with incident T2D was studied using Kaplan-Meier survival plots and mixed effects Cox proportional hazards modeling to account for relatedness among study participants. Incremental value of adhesion molecule biomarkers was studied using integrated discrimination improvement (IDI) and net reclassification improvement (NRI) indexes.ResultsDecreasing median values for serum concentrations of sICAM-1 and sVCAM-1 were observed in the following groups in this order: individuals with T2D at baseline, individuals who developed T2D during follow-up, individuals with prediabetes at baseline and normal glucose tolerant (NGT) individuals who remained T2D-free during follow-up. Top quartiles for sICAM-1 and sVCAM-1 were strongly and significantly associated with homeostatic model of assessment--insulin resistance (HOMA-IR). Mixed effects Cox proportional hazards modeling revealed that after correcting for important clinical confounders, high sICAM-1 and sVCAM-1 concentrations were associated with 2.52 and 1.99 times faster progression to T2D as compared to low concentrations, respectively. Individuals with high concentrations for both sICAM-1 and sVCAM-1 progressed to T2D 3.42 times faster than those with low values for both sICAM-1 and sVCAM-1. The results were similar in women in reproductive age group and the remainder of the cohort. Inclusion of sICAM-1 and sVCAM-1 in predictive models significantly improved reclassification and discrimination. The majority of these results were seen even when the analyses were restricted to NGT individuals.ConclusionSerum concentrations of sICAM-1 and sVCAM-1 independently and additively predict future T2D and represent important candidate biomarkers of T2D.

Project description:Background: Diabetes is a major health burden in Mexican American populations, especially among those in the Lower Rio Grande Valley (LRGV) in the border region of Texas. Understanding the roles that social determinants of health (SDOH) play in diabetes management programs, both at the individual and community level, may inform future intervention strategies. Methods: This study performed a secondary data analysis on 1,568 individuals who participated in Salud y Vida (SyV), a local diabetes and chronic disease management program, between October 2013 and September 2018 recruited from a local clinic. The primary outcome was the reduction of hemoglobin A1C (HbA1C) at the last follow-up visit compared to the baseline. In addition to age, gender, insurance status, education level and marital status, we also investigated 15 community (census tract) SDOH using the American Community Survey. Because of the high correlation in the community SDOH, we developed the community-level indices representing different domains. Using Bayesian multilevel spatial models that account for the geographic dependency, we were able to simultaneously investigate the individual- and community-level SDOH that may impact HbA1C reduction. Results: After accounting for the diabetes self-management education classes taken by the participants and their length of stay in the program, we found that older age at baseline, being married (compared to being widowed or divorced) and English speaking (compared to Spanish) were significantly associated with greater HbA1C reduction. Moreover, we found that the community level SDOH were also highly associated with HbA1C reduction. With every percentile rank decrease in the socioeconomic advantage index, we estimated an additional 0.018% reduction in HbA1C [95% CI (-0.028, -0.007)]. Besides the socioeconomic advantage index, urban core opportunity and immigrant's cohesion and accessibility indices were also statistically associated with HbA1C reduction. Conclusion: To our knowledge, our study is the first to utilize Bayesian multilevel spatial models and simultaneously investigate both individual- and community-level SDOH in the context of diabetes management. Our findings suggest that community SDOH play an important role in diabetes control and management, and the need to consider community and neighborhood context in future interventions programs to maximize their overall effectiveness.

Dataset Information

Novel epigenetic determinants of type 2 diabetes in Mexican-American families.

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Novel epigenetic determinants of type 2 diabetes in Mexican-American families.

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