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1.  Contributors to Mortality in High-Risk Diabetic Patients in the Diabetes Heart Study 
Diabetes Care  2014;37(10):2798-2803.
Not all individuals with type 2 diabetes and high coronary artery calcified plaque (CAC) experience the same risk for adverse outcomes. This study examined a subset of high-risk individuals based on CAC >1,000 mg (using a total mass score) and evaluated whether differences in a range of modifiable cardiovascular disease (CVD) risk factors provided further insights into risk for mortality.
We assessed contributors to all-cause mortality among 371 European American individuals with type 2 diabetes and CAC >1,000 from the Diabetes Heart Study (DHS) after 8.2 ± 3.0 years (mean ± SD) of follow-up. Differences in known CVD risk factors, including modifiable CVD risk factors, were compared between living (n = 218) and deceased (n = 153) participants. Cox proportional hazards regression models were used to quantify risk for all-cause mortality.
Deceased participants had a longer duration of type 2 diabetes (P = 0.02) and reduced use of cholesterol-lowering medications (P = 0.004). Adjusted analyses revealed that vascular calcified plaque scores were associated with increased risk for mortality (hazard ratio 1.31–1.63; 3.89 × 10−5 < P < 0.03). Higher HbA1c, lipids, and C-reactive protein and reduced kidney function also were associated with a 1.1- to 1.5-fold increased risk for mortality (3.45 × 10−6 < P < 0.03) after adjusting for confounding factors.
Even in this high-risk group, vascular calcification and known CVD risk factors provide useful information for ongoing assessment. The use of cholesterol-lowering medication seemed to be protective for mortality.
PMCID: PMC4392938  PMID: 24989706
2.  Epigenetic profiles of pre-diabetes transitioning to type 2 diabetes and nephropathy 
World Journal of Diabetes  2015;6(9):1113-1121.
AIM: To examine DNA methylation profiles in a longitudinal comparison of pre-diabetes mellitus (Pre-DM) subjects who transitioned to type 2 diabetes mellitus (T2DM).
METHODS: We performed DNA methylation study in bisulphite converted DNA from Pre-DM (n = 11) at baseline and at their transition to T2DM using Illumina Infinium HumanMethylation27 BeadChip, that enables the query of 27578 individual cytosines at CpG loci throughout the genome, which are focused on the promoter regions of 14495 genes.
RESULTS: There were 694 CpG sites hypomethylated and 174 CpG sites hypermethylated in progression from Pre-DM to T2DM, representing putative genes involved in glucose and fructose metabolism, inflammation, oxidative and mitochondrial stress, and fatty acid metabolism. These results suggest that this high throughput platform is able to identify hundreds of prospective CpG sites associated with diverse genes that may reflect differences in Pre-DM compared with T2DM. In addition, there were CpG hypomethylation changes associated with a number of genes that may be associated with development of complications of diabetes, such as nephropathy. These hypomethylation changes were observed in all of the subjects.
CONCLUSION: These data suggest that some epigenomic changes that may be involved in the progression of diabetes and/or the development of complications may be apparent at the Pre-DM state or during the transition to diabetes. Hypomethylation of a number of genes related to kidney function may be an early marker for developing diabetic nephropathy.
PMCID: PMC4530325  PMID: 26265998
Epigenetic changes; Pre-diabetes; Diabetes; Nephropathy
3.  Analysis of Coding Variants Identified from Exome Sequencing Resources for Association with Diabetic and Non-diabetic Nephropathy in African Americans 
Human genetics  2014;133(6):769-779.
Prior studies have identified common genetic variants influencing diabetic and non-diabetic nephropathy, diseases which disproportionately affect African Americans. Recently, exome sequencing techniques have facilitated identification of coding variants on a genome-wide basis in large samples. Exonic variants in known or suspected end-stage kidney disease (ESKD) or nephropathy genes can be tested for their ability to identify association either singly or in combination with known associated common variants. Coding variants in genes with prior evidence for association with ESKD or nephropathy were identified in the NHLBI-ESP GO database and genotyped in 5045 African Americans (3324 cases with type 2 diabetes associated nephropathy [T2D-ESKD] or non-T2D ESKD, and 1721 controls) and 1465 European Americans (568 T2D-ESKD cases and 897 controls). Logistic regression analyses were performed to assess association, with admixture and APOL1 risk status incorporated as covariates. Ten of 31 SNPs were associated in African Americans; four replicated in European Americans. In African Americans, SNPs in OR2L8, OR2AK2, C6orf167 (MMS22L), LIMK2, APOL3, APOL2, and APOL1 were nominally associated (P=1.8×10−4-0.044). Haplotype analysis of common and coding variants increased evidence of association at the OR2L13 and APOL1 loci (P=6.2×10−5 and 4.6×10−5, respectively). SNPs replicating in European Americans were in OR2AK2, LIMK2, and APOL2 (P=0.0010-0.037). Meta-analyses highlighted four SNPs associated in T2DESKD and all-cause ESKD. Results from this study suggest a role for coding variants in the development of diabetic, non-diabetic, and/or all-cause ESKD in African Americans and/or European Americans.
PMCID: PMC4024071  PMID: 24385048
African Americans; Association; European Americans; Exonic Variants; Type 2 Diabetes; Nephropathy
4.  Heart Rate–Corrected QT Interval Is an Independent Predictor of All-Cause and Cardiovascular Mortality in Individuals With Type 2 Diabetes: The Diabetes Heart Study 
Diabetes Care  2014;37(5):1454-1461.
Heart rate–corrected QT (QTc) interval is associated with mortality in the general population, but this association is less clear in individuals with type 2 diabetes. We assessed the association of QTc interval with all-cause and cardiovascular disease (CVD) mortality in the Diabetes Heart Study.
We studied 1,020 participants with type 2 diabetes (83% European Americans; 55% women; mean age 61.4 years) who were free of atrial fibrillation, major ventricular conduction defects, and antiarrhythmic therapy at baseline. QT duration was automatically calculated from a standard 12-lead electrocardiogram (ECG). Following American Heart Association/American College of Cardiology Foundation recommendations, a linear scale was used to correct the QT for heart rate. Using Cox regression, risk was estimated per 1-SD increase in QTc interval as well as prolonged QTc interval (>450 ms) vs. normal QTc interval for mortality.
At baseline, the mean (SD) QTc duration was 414.9 ms (18.1), and 3.0% of participants had prolonged QTc. After a median follow-up time of 8.5 years (maximum follow-up time 13.9 years), 204 participants were deceased. In adjusted multivariate models, a 1-SD increase in QTc interval was associated with an 18% higher risk for all-cause mortality (hazard ratio 1.18 [95% CI 1.03–1.36]) and 29% increased risk for CVD mortality (1.29 [1.05–1.59]). Similar results were obtained when QTc interval was used as a categorical variable (prolonged vs. normal) (all-cause mortality 1.73 [0.95–3.15]; CVD mortality 2.86 [1.35–6.08]).
Heart rate QTc interval is an independent predictor of all-cause and CVD mortality in this population with type 2 diabetes, suggesting that additional prognostic information may be available from this simple ECG measure.
PMCID: PMC4182905  PMID: 24574343
5.  Genetic Risk Score Associations With Cardiovascular Disease and Mortality in the Diabetes Heart Study 
Diabetes Care  2014;37(4):1157-1164.
Given the high rates of cardiovascular disease (CVD) and associated mortality in individuals with type 2 diabetes, identifying and understanding predictors of CVD events and mortality could help inform clinical management in this high-risk group. Recent large-scale genetic studies may provide additional tools in this regard.
Genetic risk scores (GRSs) were constructed in 1,175 self-identified European American (EA) individuals comprising the family-based Diabetes Heart Study based on 1) 13 single nucleotide polymorphisms (SNPs) and 2) 30 SNPs with previously documented associations with CVD in genome-wide association studies. Associations between each GRS and a self-reported history of CVD, coronary artery calcified plaque (CAC) determined by noncontrast computed tomography scan, all-cause mortality, and CVD mortality were examined using marginal models with generalized estimating equations and Cox proportional hazards models.
The weighted 13-SNP GRS was associated with prior CVD (odds ratio [OR] 1.51 [95% CI 1.22–1.86]; P = 0.0002), CAC (β-coefficient [β] 0.22 [0.02–0.43]; P = 0.04) and CVD mortality (hazard ratio [HR] 1.35 [1.10–1.81]; P = 0.04) when adjusting for the other known CVD risk factors: age, sex, type 2 diabetes affection status, BMI, current smoking status, hypertension, and dyslipidemia. The weighted 30-SNP GRS was also associated with prior CVD (OR 1.33 [1.08–1.65]; P = 0.008), CAC (β 0.29 [0.08–0.50]; P = 0.006), all-cause mortality (HR 1.28 [1.05–1.56]; P = 0.01), and CVD mortality (HR 1.46 [1.08–1.96]; P = 0.01).
These findings support the utility of two simple GRSs in examining genetic associations for adverse outcomes in EAs with type 2 diabetes.
PMCID: PMC4178326  PMID: 24574349
6.  Genetic variants in Selenoprotein P plasma 1 gene (SEPP1) are associated with fasting insulin and first phase insulin response in Hispanics 
Gene  2013;534(1):10.1016/j.gene.2013.10.035.
Insulin resistance is not fully explained on a molecular level, though several genes and proteins have been tied to this defect. Knockdowns of the SEPP1 gene, which encodes the Selenoprotein P (SeP) protein, have been shown to increase insulin sensitivity in mice. SeP is a liver-derived plasma protein and a major supplier of selenium, which is a proposed insulin mimetic and antidiabetic agent.
SEPP1 single nucleotide polymorphisms (SNPs) were selected for analysis with glucometabolic measures.
Participants and Measures
1424 Hispanics from families in the Insulin Resistance Atherosclerosis Family Study (IRASFS). Additionally, the multi-ethnic Insulin Resistance Atherosclerosis Study was used. A frequently sampled intravenous glucose tolerance test was used to obtain precise measures of acute insulin response (AIR) and the insulin sensitivity index (SI).
21 SEPP1 SNPs (tagging SNPs (n=12) from HapMap, 4 coding variants and 6 SNPs in the promoter region) were genotyped and analyzed for association.
Two highly correlated (r2=1) SNPs showed association with AIR (rs28919926; Cys368Arg; p=0.0028 and rs146125471; Ile293Met; p=0.0026) while rs16872779 (intronic) was associated with fasting insulin levels (p=0.0097). In the smaller IRAS Hispanic cohort, few of the associations seen in the IRASFS were replicated, but meta-analysis of IRASFS and all 3 IRAS cohorts (N= 2446) supported association of rs28919926 and rs146125471 with AIR (p=0.013 and 0.0047, respectively) as well as rs7579 with SI (p=0.047).
Overall, these results in a human sample are consistent with the literature suggesting a role for SEPP1 in insulin resistance.
PMCID: PMC3856675  PMID: 24161883
Acute Insulin Response (AIR); Selenium; Selenoproteins; Insulin Resistance; Fibrinogen; Hispanic Americans
7.  Genome-Wide Family-Based Linkage Analysis of Exome Chip Variants and Cardiometabolic Risk 
Genetic epidemiology  2014;38(4):345-352.
Linkage analysis of complex traits has had limited success in identifying trait-influencing loci. Recently, coding variants have been implicated as the basis for some biomedical associations. We tested whether coding variants are the basis for linkage peaks of complex traits in 42 African-American (n = 596) and 90 Hispanic (n = 1,414) families in the Insulin Resistance Atherosclerosis Family Study (IRASFS) using Illumina HumanExome Beadchips. A total of 92,157 variants in African Americans (34%) and 81,559 (31%) in Hispanics were polymorphic and tested using two-point linkage and association analyses with 37 cardiometabolic phenotypes. In African Americans 77 LOD scores greater than 3 were observed. The highest LOD score was 4.91 with the APOE SNP rs7412 (MAF = 0.13) with plasma apolipoprotein B (ApoB). This SNP was associated with ApoB (P-value = 4 × 10−19) and accounted for 16.2% of the variance in African Americans. In Hispanic families, 104 LOD scores were greater than 3. The strongest evidence of linkage (LOD = 4.29) was with rs5882 (MAF = 0.46) in CETP with HDL. CETP variants were strongly associated with HDL (0.00049 < P-value <4.6 × 10−12), accounting for up to 4.5% of the variance. These loci have previously been shown to have effects on the biomedical traits evaluated here. Thus, evidence of strong linkage in this genome wide survey of primarily coding variants was uncommon. Loci with strong evidence of linkage was characterized by large contributions to the variance, and, in these cases, are common variants. Less compelling evidence of linkage and association was observed with additional loci that may require larger family sets to confirm.
PMCID: PMC4281959  PMID: 24719370
Hispanic; African American; genetic variance
8.  Genetic Analysis of Adiponectin Variation and its Association with Type 2 Diabetes in African Americans 
Obesity (Silver Spring, Md.)  2013;21(12):10.1002/oby.20419.
Adiponectin is an adipocytokine that has been implicated in a variety of metabolic disorders, including T2D and cardiovascular disease. Studies evaluating genetic variants in ADIPOQ have been contradictory when testing association with T2D in different ethnic groups.
Design and Methods
In this study, 18 SNPs in ADIPOQ were tested for association with plasma adiponectin levels and diabetes status. SNPs were examined in two independent African-American cohorts (nmax=1116) from the Insulin Resistance Atherosclerosis Family Study (IRASFS) and the African American-Diabetes Heart Study (AA-DHS).
Five polymorphisms were nominally associated with plasma adiponectin levels in the meta-analysis (p=0.035–1.02x10−6) including a low frequency arginine to cysteine mutation (R55C) which reduced plasma adiponectin levels to <15% of the mean. Variants were then tested for association with T2D in a meta-analysis of these and the Wake Forest T2D Case-Control study (n=3233 T2D, 2645 non-T2D). Association with T2D was not observed (p≥0.08), suggesting limited influence of ADIPOQ variants on T2D risk.
Despite identification of variants associated with adiponectin levels, a detailed genetic analysis of ADIPOQ revealed no association with T2D risk. This puts into question the role of adiponectin in T2D pathogenesis: whether low adiponectin levels are truly causal for or rather a consequence.
PMCID: PMC3690163  PMID: 23512866
9.  Coronary Calcium Score Predicts Cardiovascular Mortality in Diabetes 
Diabetes Care  2013;36(4):972-977.
In type 2 diabetes mellitus (T2DM), it remains unclear whether coronary artery calcium (CAC) provides additional information about cardiovascular disease (CVD) mortality beyond the Framingham Risk Score (FRS) factors.
A total of 1,123 T2DM participants, ages 34–86 years, in the Diabetes Heart Study followed up for an average of 7.4 years were separated using baseline computed tomography scans of CAC (0–9, 10–99, 100–299, 300–999, and ≥1,000). Logistic regression was performed to examine the association between CAC and CVD mortality adjusting for FRS. Areas under the curve (AUC) with and without CAC were compared. Net reclassification improvement (NRI) compared FRS (model 1) versus FRS+CAC (model 2) using 7.4-year CVD mortality risk categories 0% to <7%, 7% to <20%, and ≥20%.
Overall, 8% of participants died of cardiovascular causes during follow-up. In multivariate analysis, the odds ratios (95% CI) for CVD mortality using CAC 0–9 as the reference group were, CAC 10–99: 2.93 (0.74–19.55); CAC 100–299: 3.17 (0.70–22.22); CAC 300–999: 4.41(1.15–29.00); and CAC ≥1,000: 11.23 (3.24–71.00). AUC (95% CI) without CAC was 0.70 (0.67–0.73), AUC with CAC was 0.75 (0.72–0.78), and NRI was 0.13 (0.07–0.19).
In T2DM, CAC predicts CVD mortality and meaningfully reclassifies participants, suggesting clinical utility as a risk stratification tool in a population already at increased CVD risk.
PMCID: PMC3609509  PMID: 23230101
Genetic epidemiology  2012;37(1):13-24.
Common genetic variation frequently accounts for only a modest amount of inter-individual variation in quantitative traits and complex disease susceptibility. Circulating adiponectin, an adipocytokine implicated in metabolic disease, is a model for assessing the contribution of genetic and clinical factors to quantitative trait variation. The adiponectin locus, ADIPOQ, is the primary source of genetically-mediated variation in plasma adiponectin levels. This study sought to define the genetic architecture of ADIPOQ in the comprehensively phenotyped Hispanic (n=1151) and African American (n=574) participants from the Insulin Resistance Atherosclerosis Family Study (IRASFS). Through resequencing and bioinformatic analysis, rare/low frequency (<5% MAF) and common variants (>5% MAF) in ADIPOQ were identified. Genetic variants and clinical variables were assessed for association with adiponectin levels and contribution to adiponectin variance in the Hispanic and African American cohorts. Clinical traits accounted for the greatest proportion of variance (POV) at 31% (p=1.16×10−47) and 47% (p=5.82×10−20), respectively. Rare/low frequency variants contributed more than common variants to variance in Hispanics: POV=18% (p= 6.40×10−15) and POV=5% (p=0.19), respectively. In African Americans, rare/low frequency and common variants both contributed approximately equally to variance: POV=6% (p=5.44×10−12) and POV=9% (P=1.44×10−10), respectively. Importantly, single low frequency alleles in each ethnic group were as important as, or more important than, common variants in explaining variation in adiponectin. Cumulatively, these clinical and ethnicity-specific genetic contributors explained half or more of the variance in Hispanic and African Americans and provide new insight into the sources of variation for this important adipocytokine.
PMCID: PMC3736586  PMID: 23032297
adiponectin; proportion of variation; rare variants; common variants; clinical traits
11.  Relevance of the ACTN4 gene in African Americans with non-diabetic ESRD 
American journal of nephrology  2012;36(3):252-260.
African Americans (AAs) are predisposed to non-diabetic (non-DM) end-stage renal disease (ESRD) and studies have shown a genetic component to this risk. Rare mutations in ACTN4 (α-actinin-4) an actin binding protein expressed in podocytes cause familial focal segmental glomerulosclerosis.
We assessed the contribution of coding variants in ACTN4 to non-DM ESRD risk in AAs. Nineteen exons, 2800 bases of the promoter and 392 bases of the 3’ untranslated region of ACTN4 were sequenced in 96 AA non-DM ESRD cases and 96 non-nephropathy controls (384 chromosomes). Sixty-seven single nucleotide polymorphisms (SNPs) including 51 novel SNPs were identified. The SNPs comprised 33 intronic, 21 promoter, 12 exonic, and 1 3’ variant. Sixty-two of the SNPs were genotyped in 296 AA non-DM ESRD cases and 358 non-nephropathy controls.
One SNP, rs10404257, was associated with non-DM ESRD (p<1.0E-4, odds ratio (OR)=0.76, confidence interval (CI)=0.59–0.98; additive model). Forty-seven SNPs had minor allele frequencies less than 5%. These SNPs were segregated into risk and protective SNPs and each category was collapsed into a single marker, designated by the presence or absence of any rare allele. The presence of any rare allele at a risk SNP was significantly associated with non-DM ESRD (p = 0.001, dominant model). The SNPs with the strongest evidence for association (n = 20) were genotyped in an independent set of 467 non-DM ESRD cases and 279 controls. Although, rs10404257 was not associated in this replication sample, when the samples were combined rs10404257 was modestly associated (p=0.032, OR=0.78, CI=0.63–0.98; dominant model). SNPs were tested for interaction with markers in the APOL1 gene, previously associated with non-DM ESRD in AAs and rs10404257 was modestly associated (p = 0.0261, additive model).
This detailed evaluation of ACTN4 variation revealed limited evidence of association with non-DM ESRD in AAs.
PMCID: PMC3510331  PMID: 22965004
ACTN4; non-diabetic ESRD; FSGS; kidney; hypertensive nephrosclerosis; African Americans
12.  The Challenging Search for Diabetic Nephropathy Genes 
Diabetes  2012;61(8):1923-1924.
PMCID: PMC3402322  PMID: 22826311
13.  Relationship between genetic variants in myocardial sodium and potassium channel genes and QT interval duration in diabetics: the Diabetes Heart Study 
Genetic variants in myocardial sodium and potassium channel genes are associated with prolonged QT interval and increased risk of sudden death. It is unclear whether these genetic variants remain relevant in subjects with underlying conditions such as diabetes that are associated with prolonged QT interval.
We tested single nucleotide polymorphisms (SNPs) in five candidate genes for association with QT interval in a family-based study of subjects with type 2 diabetes mellitus (T2DM). Thirty-six previously reported SNPs were genotyped in KCNQ1, HERG, SCN5A, KCNE1, and KCNE2 in 901 European Americans from 366 families. The heart rate-corrected (QTc) durations were determined using the Marquette 12SL program. Associations between the QTc interval and the genotypes were evaluated using SOLAR adjusting for age, gender, T2DM status, and body mass index.
Within KCNQ1 there was weak evidence for association between the minor allele of IVS12+14T>C and increased QTc (p=0.02). The minor allele of rs2236609 in KCNE1 trended toward significance with longer QTc (p=0.06), while the minor allele of rs1805123 in HERG trended toward significance with shorter QTc (p=0.07). However, no statistically significant associations were observed between the remaining SNPs and QTc variation.
We found weak evidence of association between three previously-reported SNPs and QTc interval duration. While it appears as though genetic variants in previously identified candidate genes may be associated with QT duration in subjects with diabetes, the clinical implications of these associations in diabetic subjects at high risk for sudden death remains to be determined.
PMCID: PMC3650725  PMID: 19149796
QT interval; diabetes; association study; genetics; ion channels
14.  Polymorphisms in MYH9 are associated with diabetic nephropathy in European Americans 
Nephrology Dialysis Transplantation  2011;27(4):1505-1511.
Polymorphisms in the non-muscle myosin IIA gene (MYH9) are associated with focal segmental glomerulosclerosis (FSGS) and non-diabetic end-stage renal disease (ESRD) in African Americans and FSGS in European Americans. We tested for association of single nucleotide polymorphisms (SNPs) in MYH9 with T2DM–ESRD in European Americans; additionally, three APOL1 gene variants were evaluated.
Fifteen MYH9 SNPs and two APOL1 SNPs plus a 6-bp deletion were genotyped in 1963 European Americans, 536 cases with T2DM–ESRD and 1427 non-nephropathy controls (467 with T2DM and 960 without diabetes).
Comparing T2DM–ESRD cases with the 467 T2DM non-nephropathy controls, single variant associations trending toward significance were detected with SNPs rs4821480, rs2032487 and rs4281481 comprising part of the major MYH9 E1 risk haplotype [P-values 0.053–0.055 recessive, odds ratio (OR) 6.08–6.14]. Comparing T2DM–ESRD cases to all 1427 non-nephropathy controls, we confirmed evidence of association in these three SNPs as well as in the fourth E1 SNP (rs3752462) (P-values 0.017–0.035, OR 1.41–3.72). APOL1 G1/G2 nephropathy risk variants were rare in individuals of European American heritage, present in 0.28% of chromosomes in T2DM–ESRD cases and 0.32% of controls.
MYH9 SNPs rs4821480, rs2032487, rs4281481 and rs3752462 are associated with T2DM–ESRD susceptibility in European Americans. The APOL1 risk variants are not present at appreciable frequency in this cohort with T2DM–ESRD. Therefore, polymorphisms in MYH9 appear to influence nephropathy risk in this sample.
PMCID: PMC3315672  PMID: 21968013
APOL1; diabetic nephropathy; end-stage renal disease; MYH9; type 2 diabetes mellitus
15.  Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility 
Wessel, Jennifer | Chu, Audrey Y. | Willems, Sara M. | Wang, Shuai | Yaghootkar, Hanieh | Brody, Jennifer A. | Dauriz, Marco | Hivert, Marie-France | Raghavan, Sridharan | Lipovich, Leonard | Hidalgo, Bertha | Fox, Keolu | Huffman, Jennifer E. | An, Ping | Lu, Yingchang | Rasmussen-Torvik, Laura J. | Grarup, Niels | Ehm, Margaret G. | Li, Li | Baldridge, Abigail S. | Stančáková, Alena | Abrol, Ravinder | Besse, Céline | Boland, Anne | Bork-Jensen, Jette | Fornage, Myriam | Freitag, Daniel F. | Garcia, Melissa E. | Guo, Xiuqing | Hara, Kazuo | Isaacs, Aaron | Jakobsdottir, Johanna | Lange, Leslie A. | Layton, Jill C. | Li, Man | Zhao, Jing Hua | Meidtner, Karina | Morrison, Alanna C. | Nalls, Mike A. | Peters, Marjolein J. | Sabater-Lleal, Maria | Schurmann, Claudia | Silveira, Angela | Smith, Albert V. | Southam, Lorraine | Stoiber, Marcus H. | Strawbridge, Rona J. | Taylor, Kent D. | Varga, Tibor V. | Allin, Kristine H. | Amin, Najaf | Aponte, Jennifer L. | Aung, Tin | Barbieri, Caterina | Bihlmeyer, Nathan A. | Boehnke, Michael | Bombieri, Cristina | Bowden, Donald W. | Burns, Sean M. | Chen, Yuning | Chen, Yii-Der I. | Cheng, Ching-Yu | Correa, Adolfo | Czajkowski, Jacek | Dehghan, Abbas | Ehret, Georg B. | Eiriksdottir, Gudny | Escher, Stefan A. | Farmaki, Aliki-Eleni | Frånberg, Mattias | Gambaro, Giovanni | Giulianini, Franco | III, William A. Goddard | Goel, Anuj | Gottesman, Omri | Grove, Megan L. | Gustafsson, Stefan | Hai, Yang | Hallmans, Göran | Heo, Jiyoung | Hoffmann, Per | Ikram, Mohammad K. | Jensen, Richard A. | Jørgensen, Marit E. | Jørgensen, Torben | Karaleftheri, Maria | Khor, Chiea C. | Kirkpatrick, Andrea | Kraja, Aldi T. | Kuusisto, Johanna | Lange, Ethan M. | Lee, I.T. | Lee, Wen-Jane | Leong, Aaron | Liao, Jiemin | Liu, Chunyu | Liu, Yongmei | Lindgren, Cecilia M. | Linneberg, Allan | Malerba, Giovanni | Mamakou, Vasiliki | Marouli, Eirini | Maruthur, Nisa M. | Matchan, Angela | McKean, Roberta | McLeod, Olga | Metcalf, Ginger A. | Mohlke, Karen L. | Muzny, Donna M. | Ntalla, Ioanna | Palmer, Nicholette D. | Pasko, Dorota | Peter, Andreas | Rayner, Nigel W. | Renström, Frida | Rice, Ken | Sala, Cinzia F. | Sennblad, Bengt | Serafetinidis, Ioannis | Smith, Jennifer A. | Soranzo, Nicole | Speliotes, Elizabeth K. | Stahl, Eli A. | Stirrups, Kathleen | Tentolouris, Nikos | Thanopoulou, Anastasia | Torres, Mina | Traglia, Michela | Tsafantakis, Emmanouil | Javad, Sundas | Yanek, Lisa R. | Zengini, Eleni | Becker, Diane M. | Bis, Joshua C. | Brown, James B. | Cupples, L. Adrienne | Hansen, Torben | Ingelsson, Erik | Karter, Andrew J. | Lorenzo, Carlos | Mathias, Rasika A. | Norris, Jill M. | Peloso, Gina M. | Sheu, Wayne H.-H. | Toniolo, Daniela | Vaidya, Dhananjay | Varma, Rohit | Wagenknecht, Lynne E. | Boeing, Heiner | Bottinger, Erwin P. | Dedoussis, George | Deloukas, Panos | Ferrannini, Ele | Franco, Oscar H. | Franks, Paul W. | Gibbs, Richard A. | Gudnason, Vilmundur | Hamsten, Anders | Harris, Tamara B. | Hattersley, Andrew T. | Hayward, Caroline | Hofman, Albert | Jansson, Jan-Håkan | Langenberg, Claudia | Launer, Lenore J. | Levy, Daniel | Oostra, Ben A. | O'Donnell, Christopher J. | O'Rahilly, Stephen | Padmanabhan, Sandosh | Pankow, James S. | Polasek, Ozren | Province, Michael A. | Rich, Stephen S. | Ridker, Paul M | Rudan, Igor | Schulze, Matthias B. | Smith, Blair H. | Uitterlinden, André G. | Walker, Mark | Watkins, Hugh | Wong, Tien Y. | Zeggini, Eleftheria | Scotland, Generation | Laakso, Markku | Borecki, Ingrid B. | Chasman, Daniel I. | Pedersen, Oluf | Psaty, Bruce M. | Tai, E. Shyong | van Duijn, Cornelia M. | Wareham, Nicholas J. | Waterworth, Dawn M. | Boerwinkle, Eric | Kao, WH Linda | Florez, Jose C. | Loos, Ruth J.F. | Wilson, James G. | Frayling, Timothy M. | Siscovick, David S. | Dupuis, Josée | Rotter, Jerome I. | Meigs, James B. | Scott, Robert A. | Goodarzi, Mark O.
Nature communications  2015;6:5897.
Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF=1.4%) with lower FG (β=-0.09±0.01 mmol L−1, p=3.4×10−12), T2D risk (OR[95%CI]=0.86[0.76-0.96], p=0.010), early insulin secretion (β=-0.07±0.035 pmolinsulin mmolglucose−1, p=0.048), but higher 2-h glucose (β=0.16±0.05 mmol L−1, p=4.3×10−4). We identify a gene-based association with FG at G6PC2 (pSKAT=6.8×10−6) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF=20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (β=0.02±0.004 mmol L−1, p=1.3×10−8). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.
PMCID: PMC4311266  PMID: 25631608
16.  Genetic Risk Assessment of Type 2 Diabetes–Associated Polymorphisms in African Americans 
Diabetes Care  2012;35(2):287-292.
Multiple single nucleotide polymorphisms (SNPs) associated with type 2 diabetes (T2D) susceptibility have been identified in predominantly European-derived populations. These SNPs have not been extensively investigated for individual and cumulative effects on T2D risk in African Americans.
Seventeen index T2D risk variants were genotyped in 2,652 African American case subjects with T2D and 1,393 nondiabetic control subjects. Individual SNPs and cumulative risk allele loads were assessed for association with risk for T2D. Cumulative risk was assessed by counting risk alleles and evaluating the difference in cumulative risk scores between case subjects and control subjects. A second analysis weighted risk scores (ln [OR]) based on previously reported European-derived effect sizes.
Frequencies of risk alleles ranged from 8.6 to 99.9%. Eleven SNPs had ORs >1, and 5 from ADAMTS9, WFS1, CDKAL1, JAZF1, and TCF7L2 trended or had nominally significant evidence of T2D association (P < 0.05). Individuals carried between 13 and 29 risk alleles. Association was observed between T2D and increase in risk allele load (unweighted OR 1.04 [95% CI 1.01–1.08], P = 0.010; weighted 1.06 [1.03–1.10], P = 8.10 × 10−5). When TCF7L2 SNP rs7903146 was included as a covariate, the risk score was no longer associated with T2D in either model (unweighted 1.02 [0.98–1.05], P = 0.33; weighted 1.02 [0.98–1.06], P = 0.40).
The trend of increase in risk for T2D with increasing risk allele load is similar to observations in European-derived populations; however, these analyses indicate that T2D genetic risk is primarily mediated through the effect of TCF7L2 in African Americans.
PMCID: PMC3263882  PMID: 22275441
17.  Examination of Rare Variants in HNF4 α in European Americans with Type 2 Diabetes 
Journal of diabetes & metabolism  2011;2(145):1000145.
The hepatocyte nuclear factor 4-α (HNF4α) gene codes for a transcription factor which is responsible for regulating gene transcription in pancreatic beta cells, in addition to its primary role in hepatic gene regulation. Mutations in this gene can lead to maturity-onset diabetes of the young (MODY), an uncommon, autosomal dominant, non-insulin dependent form of diabetes. Mutations in HNF4α have been found in few individuals, and infrequently have they segregated completely with MODY in families. In addition, due to similarity of phenotypes, it is unclear what proportion of type 2 diabetes (T2DM) in the general population is due to MODY or HNF4α mutations specifically. In this study, 27 documented rare and common variants were genotyped in a European American population of 1270 T2DM cases and 1017 controls from review of databases and literature implicating HNF4α variants in MODY and T2DM. Seventeen variants were found to be monomorphic. Two cases and one control subject had one copy of a 6-bp P2 promoter deletion. The intron 1 variant (rs6103716; MAF = 0.31) was not significantly associated with disease status (p>0.8) and the missense variant Thr130Ile (rs1800961; MAF = 0.027) was also not significantly different between cases and controls (p>0.2), but showed a trend consistent with association with T2DM. Four variants were found to be rare as heterozygotes in small numbers of subjects. Since many variants were infrequent, a pooled chi-squared analysis of rare variants was used to assess the overall burden of variants between cases and controls. This analysis revealed no significant difference (P=0.22). We conclude there is little evidence to suggest that HNF4α variants contribute significantly to risk of T2DM in the general population, but a modest contribution cannot be excluded. In addition, the observation of some mutations in controls suggests they are not highly penetrant MODY-causing variants.
PMCID: PMC3515062  PMID: 23227446
Type 2 Diabetes; HNF4A; Rare variants
18.  Complement factor H gene associations with end-stage kidney disease in African Americans 
Nephrology Dialysis Transplantation  2014;29(7):1409-1414.
Mutations in the complement factor H gene (CFH) region associate with renal-limited mesangial proliferative forms of glomerulonephritis including IgA nephropathy (IgAN), dense deposit disease (DDD) and C3 glomerulonephritis (C3GN). Lack of kidney biopsies could lead to under diagnosis of CFH-associated end-stage kidney disease (ESKD) in African Americans (AAs), with incorrect attribution to other causes. A prior genome-wide association study in AAs with non-diabetic ESKD implicated an intronic CFH single nucleotide polymorphism (SNP).
Thirteen CFH SNPs (8 exonic, 2 synonymous, 2 3′UTR, and the previously associated intronic variant rs379489) were tested for association with common forms of non-diabetic and type 2 diabetes-associated (T2D) ESKD in 3770 AAs (1705 with non-diabetic ESKD, 1305 with T2D-ESKD, 760 controls). Most cases lacked kidney biopsies; those with known IgAN, DDD or C3GN were excluded.
Adjusting for age, gender, ancestry and apolipoprotein L1 gene risk variants, single SNP analyses detected 6 CFH SNPs (5 exonic and the intronic variant) as significantly associated with non-diabetic ESKD (P = 0.002–0.01), three of these SNPs were also associated with T2D-ESKD. Weighted CFH locus-wide Sequence Kernel Association Testing (SKAT) in non-diabetic ESKD (P = 0.00053) and T2D-ESKD (P = 0.047) confirmed significant evidence of association.
CFH was associated with commonly reported etiologies of ESKD in the AA population. These results suggest that a subset of cases with ESKD clinically ascribed to the effects of hypertension or glomerulosclerosis actually have CFH-related forms of mesangial proliferative glomerulonephritis. Genetic testing may prove useful to identify the causes of renal-limited kidney disease in patients with ESKD who lack renal biopsies.
PMCID: PMC4081633  PMID: 24586071
African Americans; CFH; end-stage kidney disease; genetics; kidney disease
19.  APOL1 associations with nephropathy, atherosclerosis, and all-cause mortality in African Americans with type 2 diabetes 
Kidney international  2014;87(1):176-181.
Albuminuria and reduced eGFR associate with two apolipoprotein L1 gene (APOL1) variants in non-diabetic African Americans. Whether APOL1 associates with subclinical atherosclerosis and survival remains unclear. To determine this, 717 African American-Diabetes Heart Study participants underwent computed tomography to determine coronary artery, carotid artery, and aorta calcified atherosclerotic plaque mass scores in addition to the urine albumin:creatinine ratio (UACR), eGFR, and C-reactive protein. Associations between mass scores and APOL1 were assessed adjusting for age, gender, African ancestry, BMI, HbA1c, smoking, hypertension, use of statins and ACE inhibitors, albuminuria, and eGFR. Participants were 58.9% female with mean age 56.5 years, eGFR 89.5 ml/min/1.73m2, UACR 169.6 mg/g, coronary artery, carotid artery and aorta calcified plaque mass scores of 610, 171 and 5378, respectively. In fully adjusted models, APOL1 risk variants were significantly associated with lower levels of carotid artery calcified plaque (β −0.42, SE 0.18, dominant model), and marginally lower coronary artery plaque (β −0.36, SE 0.21; dominant model), but not with aorta calcified plaque, C-reactive protein, UACR, or eGFR. After a mean follow-up of 5.0 years, 89 participants died. APOL1 nephropathy risk variants were significantly associated with improved survival (hazard ratio 0.67 for 1 copy; 0.44 for 2 copies). Thus, APOL1 nephropathy variants associate with lower levels of subclinical atherosclerosis and reduced risk of death in African Americans with type 2 diabetes mellitus.
PMCID: PMC4281283  PMID: 25054777
African Americans; apolipoprotein L1 gene (APOL1); atherosclerosis; calcified atherosclerotic plaque; diabetes mellitus; kidney disease
20.  Predictors of all-cause and cardiovascular disease mortality in type 2 diabetes: Diabetes Heart Study 
Many studies evaluated the best predictors for cardiovascular disease (CVD) events in individuals with type 2 diabetes (T2D), but few studies examined the factors most strongly associated with mortality in T2D. The Diabetes Heart Study (DHS), an intensively phenotyped family-based cohort enriched for T2D, provided an opportunity to address this question.
Associations with mortality were examined in 1022 European Americans affected by T2D from 476 DHS families. All-cause mortality was 31.2 % over an average 9.6 years of follow-up. Cox proportional hazards models with sandwich-based variance estimation were used to evaluate associations between all-cause and CVD mortality and 24 demographic and clinical factors, including coronary artery calcified plaque (CAC), carotid artery intima-media thickness, medications, body mass index, waist hip ratio, lipids, blood pressure, kidney function, QT interval, educational attainment, and glycemic control. Nominally significant factors (p < 0.25) from univariate analyses were included in model selection (backward elimination, forward selection, and stepwise selection). Age and sex were included in all models.
The all-cause mortality model selected from the full DHS sample included age, sex, CAC, urine albumin: creatinine ratio (UACR), insulin use, current smoking, and educational attainment. The CVD mortality model selected from the full sample included age, sex, CAC, UACR, triglycerides, and history of CVD events. Beyond age, the most significant associations for both mortality models were CAC (2.03 × 10−4 ≤ p ≤ 0.001) and UACR (1.99 × 10−8 ≤ p ≤ 2.23 × 10−8). To confirm the validity of the main predictors identified with model selection using the full sample, a two-fold cross-validation approach was used, and similar results were observed.
This analysis highlights important demographic and clinical factors, notably CAC and albuminuria, which predict mortality in the general population of patients with T2D.
Electronic supplementary material
The online version of this article (doi:10.1186/s13098-015-0055-y) contains supplementary material, which is available to authorized users.
PMCID: PMC4490739  PMID: 26146522
Type 2 diabetes; Mortality; Coronary artery calcified plaque; Urine albumin:creatinine ratio
21.  β-Cell Failure in Type 2 Diabetes: Postulated Mechanisms and Prospects for Prevention and Treatment 
Diabetes Care  2014;37(6):1751-1758.
This article examines the foundation of β-cell failure in type 2 diabetes (T2D) and suggests areas for future research on the underlying mechanisms that may lead to improved prevention and treatment.
A group of experts participated in a conference on 14–16 October 2013 cosponsored by the Endocrine Society and the American Diabetes Association. A writing group prepared this summary and recommendations.
The writing group based this article on conference presentations, discussion, and debate. Topics covered include genetic predisposition, foundations of β-cell failure, natural history of β-cell failure, and impact of therapeutic interventions.
β-Cell failure is central to the development and progression of T2D. It antedates and predicts diabetes onset and progression, is in part genetically determined, and often can be identified with accuracy even though current tests are cumbersome and not well standardized. Multiple pathways underlie decreased β-cell function and mass, some of which may be shared and may also be a consequence of processes that initially caused dysfunction. Goals for future research include to 1) impact the natural history of β-cell failure; 2) identify and characterize genetic loci for T2D; 3) target β-cell signaling, metabolic, and genetic pathways to improve function/mass; 4) develop alternative sources of β-cells for cell-based therapy; 5) focus on metabolic environment to provide indirect benefit to β-cells; 6) improve understanding of the physiology of responses to bypass surgery; and 7) identify circulating factors and neuronal circuits underlying the axis of communication between the brain and β-cells.
PMCID: PMC4179518  PMID: 24812433
22.  A Comparison of Risk Factors for Calcified Atherosclerotic Plaque in the Coronary, Carotid, and Abdominal Aortic Arteries 
American journal of epidemiology  2007;166(3):340-347.
The extent of shared risk factors for calcified atherosclerotic plaque (CAP) of the coronary, carotid, and abdominal aortic arteries is unknown. CAP was measured by computed tomography in 1,125 individuals in families affected with diabetes. Statistical methods adjusted for the lack of independence between observations. CAP scores were standardized, and tests of interaction were conducted to compare risk factor relations across vascular beds. The average age of the cohort was 61 years, and 84% had diabetes. The correlation in CAP scores across vascular beds ranged from 0.59 to 0.72. Age, albumin/creatinine ratio, hemoglobin A1c, diabetes, hypertension, and lipid-lowering therapy were correlated with quantity of CAP in all vascular beds (all p < 0.05); no differences in the strength of these relations were noted. In contrast, other significant correlates differed in the strength of their relations with CAP. The risk factor pack-years of smoking was most strongly correlated with CAP in the abdominal aorta (p < 0.005). Male gender, previous myocardial infarction, and coronary revascularization were most strongly correlated with CAP in the coronary arteries (p < 0.0001). In summary, CAPs of the coronary, carotid, and abdominal aortic arteries generally share common risk factors, even though several of these factors have a greater impact on CAP in one vascular bed than another.
PMCID: PMC4450101  PMID: 17493948
atherosclerosis; calcification; physiologic; diabetes mellitus; type 2; North Carolina; risk factors; siblings
Kidney international  2010;79(5):563-572.
A genome-wide association study was performed using the Affymetrix 6.0 chip to identify genes associated with diabetic nephropathy in African Americans. Association analysis was performed adjusting for admixture in 965 type 2 diabetic African American patients with end-stage renal disease (ESRD) and in 1029 African Americans without type 2 diabetes or kidney disease as controls. The top 724 single nucleotide polymorphisms (SNPs) with evidence of association to diabetic nephropathy were then genotyped in a replication sample of an additional 709 type 2 diabetes-ESRD patients and 690 controls. SNPs with evidence of association in both the original and replication studies were tested in additional African American cohorts consisting of 1246 patients with type 2 diabetes without kidney disease and 1216 with non-diabetic ESRD to differentiate candidate loci for type 2 diabetes-ESRD, type 2 diabetes, and/or all-cause ESRD. Twenty-five SNPs were significantly associated with type 2 diabetes-ESRD in the genome-wide association and initial replication. Although genome-wide significance with type 2 diabetes was not found for any of these 25 SNPs, several genes, including RPS12, LIMK2, and SFI1 are strong candidates for diabetic nephropathy. A combined analysis of all 2890 patients with ESRD showed significant association SNPs in LIMK2 and SFI1 suggesting that they also contribute to all-cause ESRD. Thus, our results suggest that multiple loci underlie susceptibility to kidney disease in African Americans with type 2 diabetes and some may also contribute to all-cause ESRD.
PMCID: PMC3056271  PMID: 21150874
24.  Resequencing and Analysis of Variation in the TCF7L2 Gene in African Americans Suggests That SNP rs7903146 Is the Causal Diabetes Susceptibility Variant 
Diabetes  2011;60(2):662-668.
Variation in the transcription factor 7-like 2 (TCF7L2) locus is associated with type 2 diabetes across multiple ethnicities. The aim of this study was to elucidate which variant in TCF7L2 confers diabetes susceptibility in African Americans.
Through the evaluation of tagging single nucleotide polymorphisms (SNPs), type 2 diabetes susceptibility was limited to a 4.3-kb interval, which contains the YRI (African) linkage disequilibrium (LD) block containing rs7903146. To better define the relationship between type 2 diabetes risk and genetic variation we resequenced this 4.3-kb region in 96 African American DNAs. Thirty-three novel and 13 known SNPs were identified: 20 with minor allele frequencies (MAF) >0.05 and 12 with MAF >0.10. These polymorphisms and the previously identified DG10S478 microsatellite were evaluated in African American type 2 diabetic cases (n = 1,033) and controls (n = 1,106).
Variants identified from direct sequencing and databases were genotyped or imputed. Fifteen SNPs showed association with type 2 diabetes (P < 0.05) with rs7903146 being the most significant (P = 6.32 × 10−6). Results of imputation, haplotype, and conditional analysis of SNPs were consistent with rs7903146 being the trait-defining SNP. Analysis of the DG10S478 microsatellite, which is outside the 4.3-kb LD block, revealed consistent association of risk allele 8 with type 2 diabetes (odds ratio [OR] = 1.33; P = 0.022) as reported in European populations; however, allele 16 (MAF = 0.016 cases and 0.032 controls) was strongly associated with reduced risk (OR = 0.39; P = 5.02 × 10−5) in contrast with previous studies.
In African Americans, these observations suggest that rs7903146 is the trait-defining polymorphism associated with type 2 diabetes risk. Collectively, these results support ethnic differences in type 2 diabetes associations.
PMCID: PMC3028368  PMID: 20980453
25.  Heritability and genetic association analysis of cognition in the Diabetes Heart Study 
Neurobiology of aging  2014;35(8):1958.e3-1958.e12.
Cognitive performance is an important component of healthy aging. Type 2 diabetes (T2D) is associated with negative outcomes for the brain and cognition, although causal mechanisms have not been definitely determined. Genetic risk factors warrant further consideration in this context. This study examined the heritability of cognitive function as assessed by (1) the Digit Symbol Substitution Task; (2) the Modified Mini-Mental State Examination; (3) the Stroop Task; (4) the Rey Auditory-Verbal Learning Task; and (5) the Controlled Oral Word Association Task for Phonemic and Semantic Fluency, in the family-based, T2D-enriched, Diabetes Heart Study sample (n = 550 participants from 257 families). The genetic basis of these cognitive measures was further evaluated by association analysis with candidate single-nucleotide polymorphisms (SNPs) and genome-wide SNP data. Measures of cognitive function were significantly heritable (ĥ2 = 0.28–0.62) following adjustment for age, gender, and education. A total of 31 SNPs (from 26 genes/regions) selected to form an a priori set of candidate SNPs showed limited evidence of association with cognitive function when applying conservative metrics of significance. Genome-wide assessment of both noncoding and coding variants revealed suggestive evidence of association for several coding variants including rs139509083 in CNST (p = 4.9 × 10−9), rs199968569 in PLAA (p = 4.9 × 10−9) and rs138487371 in PCDH8 (p = 3.7 × 10−8). The identification of a heritable component to cognitive performance in T2D suggests a role for genetic contributors to cognitive performance even in the presence of metabolic disease and other associated comorbidities and is supported by the identification of genetic association signals in functionally plausible candidates.
PMCID: PMC4418030  PMID: 24684796
Cognitive function; Heritability; Genetics; Type 2 diabetes

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