Dataset Information

Genetic Variants Associated With Quantitative Glucose Homeostasis Traits Translate to Type 2 Diabetes in Mexican Americans: The GUARDIAN (Genetics Underlying Diabetes in Hispanics) Consortium.

ABSTRACT: Insulin sensitivity, insulin secretion, insulin clearance, and glucose effectiveness exhibit strong genetic components, although few studies have examined their genetic architecture or influence on type 2 diabetes (T2D) risk. We hypothesized that loci affecting variation in these quantitative traits influence T2D. We completed a multicohort genome-wide association study to search for loci influencing T2D-related quantitative traits in 4,176 Mexican Americans. Quantitative traits were measured by the frequently sampled intravenous glucose tolerance test (four cohorts) or euglycemic clamp (three cohorts), and random-effects models were used to test the association between loci and quantitative traits, adjusting for age, sex, and admixture proportions (Discovery). Analysis revealed a significant (P < 5.00 × 10(-8)) association at 11q14.3 (MTNR1B) with acute insulin response. Loci with P < 0.0001 among the quantitative traits were examined for translation to T2D risk in 6,463 T2D case and 9,232 control subjects of Mexican ancestry (Translation). Nonparametric meta-analysis of the Discovery and Translation cohorts identified significant associations at 6p24 (SLC35B3/TFAP2A) with glucose effectiveness/T2D, 11p15 (KCNQ1) with disposition index/T2D, and 6p22 (CDKAL1) and 11q14 (MTNR1B) with acute insulin response/T2D. These results suggest that T2D and insulin secretion and sensitivity have both shared and distinct genetic factors, potentially delineating genomic components of these quantitative traits that drive the risk for T2D.

SUBMITTER: Palmer ND

PROVIDER: S-EPMC4407862 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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Genetic Variants Associated With Quantitative Glucose Homeostasis Traits Translate to Type 2 Diabetes in Mexican Americans: The GUARDIAN (Genetics Underlying Diabetes in Hispanics) Consortium.

Palmer Nicholette D ND Goodarzi Mark O MO Langefeld Carl D CD Wang Nan N Guo Xiuqing X Taylor Kent D KD Fingerlin Tasha E TE Norris Jill M JM Buchanan Thomas A TA Xiang Anny H AH Haritunians Talin T Ziegler Julie T JT Williams Adrienne H AH Stefanovski Darko D Cui Jinrui J Mackay Adrienne W AW Henkin Leora F LF Bergman Richard N RN Gao Xiaoyi X Gauderman James J Varma Rohit R Hanis Craig L CL Cox Nancy J NJ Highland Heather M HM Below Jennifer E JE Williams Amy L AL Burtt Noel P NP Aguilar-Salinas Carlos A CA Huerta-Chagoya Alicia A Gonzalez-Villalpando Clicerio C Orozco Lorena L Haiman Christopher A CA Tsai Michael Y MY Johnson W Craig WC Yao Jie J Rasmussen-Torvik Laura L Pankow James J Snively Beverly B Jackson Rebecca D RD Liu Simin S Nadler Jerry L JL Kandeel Fouad F Chen Yii-Der I YD Bowden Donald W DW Rich Stephen S SS Raffel Leslie J LJ Rotter Jerome I JI Watanabe Richard M RM Wagenknecht Lynne E LE

Diabetes 20141218 5

Insulin sensitivity, insulin secretion, insulin clearance, and glucose effectiveness exhibit strong genetic components, although few studies have examined their genetic architecture or influence on type 2 diabetes (T2D) risk. We hypothesized that loci affecting variation in these quantitative traits influence T2D. We completed a multicohort genome-wide association study to search for loci influencing T2D-related quantitative traits in 4,176 Mexican Americans. Quantitative traits were measured by ...[more]

PMID: 25524916

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Project description:Although human leukocyte antigen (HLA) DQ and DR loci appear to confer the strongest genetic risk for type 1 diabetes, more detailed information is required for other loci within the HLA region to understand causality and stratify additional risk factors. The Type 1 Diabetes Genetics Consortium (T1DGC) study design included high-resolution genotyping of HLA-A, B, C, DRB1, DQ, and DP loci in all affected sibling pair and trio families, and cases and controls, recruited from four networks worldwide, for analysis with clinical phenotypes and immunological markers.In this article, we present the operational strategy of training, classification, reporting, and quality control of HLA genotyping in four laboratories on three continents over nearly 5 years.Methods to standardize HLA genotyping at eight loci included: central training and initial certification testing; the use of uniform reagents, protocols, instrumentation, and software versions; an automated data transfer; and the use of standardized nomenclature and allele databases. We implemented a rigorous and consistent quality control process, reinforced by repeated workshops, yearly meetings, and telephone conferences.A total of 15,246 samples have been HLA genotyped at eight loci to four-digit resolution; an additional 6797 samples have been HLA genotyped at two loci. The genotyping repeat rate decreased significantly over time, with an estimated unresolved Mendelian inconsistency rate of 0.21%. Annual quality control exercises tested 2192 genotypes (4384 alleles) and achieved 99.82% intra-laboratory and 99.68% inter-laboratory concordances.The chosen genotyping platform was unable to distinguish many allele combinations, which would require further multiple stepwise testing to resolve. For these combinations, a standard allele assignment was agreed upon, allowing further analysis if required.High-resolution HLA genotyping can be performed in multiple laboratories using standard equipment, reagents, protocols, software, and communication to produce consistent and reproducible data with minimal systematic error. Many of the strategies used in this study are generally applicable to other large multi-center studies.

Project description:Mexican-Americans carry a high burden of type 2 diabetes and are disproportionately affected by diabetes related mortality and morbidity. Poor adherence to medication is an important barrier to achieving metabolic control and contributes to adverse health outcomes and health disparities. Little is known about barriers and facilitators to medication adherence among Mexican-Americans with diabetes. This is a qualitative study of semi-structured interviews with a sample of 27 adults (25 Mexican-Americans and 2 Latinos of other origin) with self-reported type 2 diabetes who were recruited as part of a church-based, randomized controlled trial for diabetes self-management education in a low-income, immigrant neighborhood of Chicago. Face-to-face, in-depth interviews were conducted (one in English and 26 in Spanish), audio-recorded, transcribed verbatim, and professionally translated. Systematic qualitative methods were used to analyze interviews. All 27 participants were Latino, and 25 were of Mexican descent. Participants' mean age was 57 years, 81% were female, 69% had an annual income less than $20,000 and 48% had no health insurance. Mean A1C level was 8.6% and mean systolic blood pressure was 125 mmHg. The majority of participants (85%) reported using oral diabetes medication and 35% reported taking insulin. 76% reported being affiliated with one of the two partnering catholic churches based in the South Lawndale neighborhood of Chicago, also known as Little Village. Concerns regarding effectiveness and negative impact of diabetes medication were prevalent and expressed by 13 (48%) of 27 participants. Dissatisfaction with ineffective provider communication and not being able to pay for medication were other important barriers to adherence and were expressed by 7% and 11% of participants, respectively. Family support, for example, family members assisting in organizing medications in boxes and reminding participants to take them, was reported by 15% of participants and emerged as an important facilitator to medication adherence. There is a gap in research on factors influencing adherence to diabetes medication among Mexican-Americans. Our study suggests that concerns regarding negative impact of diabetes medication and concerns regarding effectiveness are prevalent barriers to adherence. These barriers can be addressed through educational efforts targeting patients and clinicians by specifically including content on beliefs that lead to poor adherence in diabetes self-management interventions for patients and continuing medical education for providers and by developing interventions that engage family members as a support system for medication adherence.

Dataset Information

Genetic Variants Associated With Quantitative Glucose Homeostasis Traits Translate to Type 2 Diabetes in Mexican Americans: The GUARDIAN (Genetics Underlying Diabetes in Hispanics) Consortium.

Publications

Genetic Variants Associated With Quantitative Glucose Homeostasis Traits Translate to Type 2 Diabetes in Mexican Americans: The GUARDIAN (Genetics Underlying Diabetes in Hispanics) Consortium.

Similar Datasets

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