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1.  Plasma FGF23 and Calcified Atherosclerotic Plaque in African Americans with Type 2 Diabetes Mellitus 
American journal of nephrology  2015;42(6):391-401.
Background
Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone implicated in disorders of serum phosphorus concentration and vitamin D. The role of FGF23 in vascular calcification remains controversial.
Methods
Relationships between FGF23 and coronary artery calcified atherosclerotic plaque (CAC), aorto-iliac calcified plaque (CP), carotid artery CP, volumetric bone mineral density (vBMD), albuminuria, and estimated glomerular filtration rate (eGFR) were determined in 545 African Americans with type 2 diabetes (T2D) and preserved kidney function in African American-Diabetes Heart Study participants. Generalized linear models were fitted to test associations between FGF23 and cardiovascular, bone, and renal phenotypes, and change in measurements over time, adjusting for age, sex, African ancestry proportion, BMI, diabetes duration, HbA1c, blood pressure, renin-angiotensin-system inhibitors, statins, calcium supplements, serum calcium, and serum phosphate.
Results
The sample was 56.7% female with mean/SD age 55.6/9.6 years, diabetes duration 10.3/8.2 years, eGFR 90.9/22.1 ml/min/1.73m2, urine albumin:creatinine ratio (UACR) 151/588 (median 13) mg/g, plasma FGF23 161/157 RU/mL, and CAC 637/1179 mg. In fully-adjusted models, FGF23 was negatively associated with eGFR (p<0.0001) and positively associated with UACR (p<0.0001) and CAC (p=0.0006), but not with carotid CP or aortic CP. Baseline FGF23 concentration did not associate with changes in vBMD or CAC after mean 5.1 year follow-up.
Conclusions
Plasma FGF23 concentrations were independently associated with subclinical coronary artery disease, albuminuria, and kidney function in the understudied African American population with T2D. Findings support relationships between FGF23 and vascular calcification, but not bone mineral density, in African Americans lacking advanced nephropathy.
doi:10.1159/000443241
PMCID: PMC4732898  PMID: 26693712
African American; albuminuria; calcified atherosclerotic plaque; FGF23; kidney disease; type 2 diabetes mellitus
2.  GENOME-WIDE INTERACTION WITH SELECTED TYPE 2 DIABETES LOCI REVEALS NOVEL LOCI FOR TYPE 2 DIABETES IN AFRICAN AMERICANS 
Type 2 diabetes (T2D) is the result of metabolic defects in insulin secretion and insulin sensitivity, yet most T2D loci identified to date influence insulin secretion. We hypothesized that T2D loci, particularly those affecting insulin sensitivity, can be identified through interaction with known T2D loci implicated in insulin secretion. To test this hypothesis, single nucleotide polymorphisms (SNPs) nominally associated with acute insulin response to glucose (AIRg), a dynamic measure of first-phase insulin secretion, and previously associated with T2D in genome-wide association studies (GWAS) were identified in African Americans from the Insulin Resistance Atherosclerosis Family Study (IRASFS; n=492 subjects). These SNPs were tested for interaction, individually and jointly as a genetic risk score (GRS), using GWAS data from five cohorts (ARIC, CARDIA, JHS, MESA, WFSM; n=2,725 cases, 4,167 controls) with T2D as the outcome. In single variant analyses, suggestively significant (Pinteraction < 5×10−6) interactions were observed at several loci including DGKB (rs978989), CDK18 (rs12126276), CXCL12 (rs7921850), HCN1 (rs6895191), FAM98A (rs1900780), and MGMT (rs568530). Notable beta-cell GRS interactions included two SNPs at the DGKB locus (rs6976381; rs6962498). These data support the hypothesis that additional genetic factors contributing to T2D risk can be identified by interactions with insulin secretion loci.
PMCID: PMC5146756  PMID: 27896979
3.  Genetic Predisposition to Weight Loss and Regain With Lifestyle Intervention: Analyses From the Diabetes Prevention Program and the Look AHEAD Randomized Controlled Trials 
Diabetes  2015;64(12):4312-4321.
Clinically relevant weight loss is achievable through lifestyle modification, but unintentional weight regain is common. We investigated whether recently discovered genetic variants affect weight loss and/or weight regain during behavioral intervention. Participants at high-risk of type 2 diabetes (Diabetes Prevention Program [DPP]; N = 917/907 intervention/comparison) or with type 2 diabetes (Look AHEAD [Action for Health in Diabetes]; N = 2,014/1,892 intervention/comparison) were from two parallel arm (lifestyle vs. comparison) randomized controlled trials. The associations of 91 established obesity-predisposing loci with weight loss across 4 years and with weight regain across years 2–4 after a minimum of 3% weight loss were tested. Each copy of the minor G allele of MTIF3 rs1885988 was consistently associated with greater weight loss following lifestyle intervention over 4 years across the DPP and Look AHEAD. No such effect was observed across comparison arms, leading to a nominally significant single nucleotide polymorphism×treatment interaction (P = 4.3 × 10−3). However, this effect was not significant at a study-wise significance level (Bonferroni threshold P < 5.8 × 10−4). Most obesity-predisposing gene variants were not associated with weight loss or regain within the DPP and Look AHEAD trials, directly or via interactions with lifestyle.
doi:10.2337/db15-0441
PMCID: PMC4657576  PMID: 26253612
4.  Whole genome sequence analysis of serum amino acid levels 
Genome Biology  2016;17:237.
Background
Blood levels of amino acids are important biomarkers of disease and are influenced by synthesis, protein degradation, and gene–environment interactions. Whole genome sequence analysis of amino acid levels may establish a paradigm for analyzing quantitative risk factors.
Results
In a discovery cohort of 1872 African Americans and a replication cohort of 1552 European Americans we sequenced exons and whole genomes and measured serum levels of 70 amino acids. Rare and low-frequency variants (minor allele frequency ≤5%) were analyzed by three types of aggregating motifs defined by gene exons, regulatory regions, or genome-wide sliding windows. Common variants (minor allele frequency >5%) were analyzed individually. Over all four analysis strategies, 14 gene–amino acid associations were identified and replicated. The 14 loci accounted for an average of 1.8% of the variance in amino acid levels, which ranged from 0.4 to 9.7%. Among the identified locus–amino acid pairs, four are novel and six have been reported to underlie known Mendelian conditions. These results suggest that there may be substantial genetic effects on amino acid levels in the general population that may underlie inborn errors of metabolism. We also identify a predicted promoter variant in AGA (the gene that encodes aspartylglucosaminidase) that is significantly associated with asparagine levels, with an effect that is independent of any observed coding variants.
Conclusions
These data provide insights into genetic influences on circulating amino acid levels by integrating -omic technologies in a multi-ethnic population. The results also help establish a paradigm for whole genome sequence analysis of quantitative traits.
Electronic supplementary material
The online version of this article (doi:10.1186/s13059-016-1106-x) contains supplementary material, which is available to authorized users.
doi:10.1186/s13059-016-1106-x
PMCID: PMC5123402  PMID: 27884205
Amino acids; Whole genome sequence; Metabolomics; Rare variants; Multi-ethnic
5.  Obesity, insulin resistance and incident small vessel disease on MRI: the Atherosclerosis Risk in Communities Study 
Background and purpose
The term “metabolic syndrome” (MetS) describes the clustering of risk factors found in many individuals with obesity. Due to their pathophysiology, we hypothesized that two features of MetS, central obesity and insulin resistance (IR), would be associated with cerebrovascular changes on MRI, and specifically with incident lacunar disease and not white matter hyperintensity progression (WMH).
Methods
Risk factors were defined at study baseline in 934 participants in the Atherosclerosis Risk in Communities (ARIC) study who completed two brain MRIs approximately ten years apart. WMH progression and incident lacunes between the two MRIs were determined. An IR score for each participant was created using principal component analysis of 11 risk factors, including (among others): insulin, HOMA-IR, body mass index (BMI) and waist circumference. MetS (presence/absence), using standard clinical definitions, and IR score at the first MRI, were independent variables, evaluated in multivariate logistic regression to determine odds of WMH progression (Q5 vs. Q1–4) and incident lacunes.
Results
MetS (adjusted OR 1.98; 95% confidence interval (CI) 1.28, 3.05) and IR score (adjusted OR per 1-standard deviation increase: 1.33, 95% CI 1.05, 1.68) were associated with incident lacunes but not with WMH progression. Insulin, HOMA-IR and BMI were not associated with incident lacunes or WMH progression in separate models.
Conclusions
The IR score and central obesity are associated with incident lacunar disease but not WMH progression in individuals. Central obesity and IR may be important risk factors to target to prevent lacunar disease.
doi:10.1161/STROKEAHA.115.010060
PMCID: PMC4624467  PMID: 26451022
metabolic syndrome; white matter hyperintensities; lacunes; obesity; insulin resistance; leukoaraiosis
6.  Genetic predictors of depressive symptoms in the Look AHEAD Trial 
Psychosomatic medicine  2015;77(9):982-992.
Objective
Numerous studies find elevated depressive symptoms among individuals with type 2 diabetes, yet the mechanisms remain unclear. We examined whether genetic loci previously associated with depressive symptoms predict depressive symptoms among overweight/obese individuals with type 2 diabetes or change in depressive symptoms during behavioral weight loss.
Methods
The Illumina CARe iSelect (IBC) chip and Cardiometabochip were characterized in 2,118 overweight or obese participants with type 2 diabetes from Look AHEAD (Action for Health in Diabetes), a randomized trial to determine the effects of intensive lifestyle intervention (ILI) and Diabetes Support and Education (DSE) on cardiovascular morbidity and mortality. Primary analyses focused on baseline Beck Depression Inventory (BDI) scores and depressive symptom change at one year.
Results
Of eight single nucleotide polymorphisms (SNPs) in six loci, three a priori SNPs in two loci (Chr5: rs60271; LBR: rs2230419, rs1011319) were associated with baseline BDI scores, but in the opposite direction of prior research. In joint analysis of 90,003 IBC and Cardiometabochip SNPs, rs1543654 in the region of KCNE1 predicted change in BDI scores at year 1 in DSE (beta= −1.05, SE=0.21, p=6.9 × 10−7) at the level of chip-wide significance, while also showing a nominal association with baseline BDI (beta=0.35, SE=0.16, p=0.026). Adjustment for antidepressant medication and/or limiting analyses to Non-Hispanic White individuals did not meaningfully alter results.
Conclusions
Previously reported genetic associations with depressive symptoms did not replicate in this cohort of overweight/obese individuals with type 2 diabetes. We identified KCNE1 as a potential novel locus associated with depressive symptoms.
doi:10.1097/PSY.0000000000000242
PMCID: PMC4643359  PMID: 26489030
genetics; depression; diabetes; weight loss; obesity
7.  Genetic Variants Associated With Quantitative Glucose Homeostasis Traits Translate to Type 2 Diabetes in Mexican Americans: The GUARDIAN (Genetics Underlying Diabetes in Hispanics) Consortium 
Diabetes  2014;64(5):1853-1866.
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.
doi:10.2337/db14-0732
PMCID: PMC4407862  PMID: 25524916
8.  Changes in Body Composition over Eight Years in a Randomized Trial of a Lifestyle Intervention: The Look AHEAD Study 
Obesity (Silver Spring, Md.)  2015;23(3):565-572.
Objective
To determine the effects of an intensive lifestyle intervention vs. a comparison group on body composition in obese or overweight persons with type 2 diabetes at baseline and at 1, 4, and 8 years.
Design and Methods
Body composition was measured by dual energy X-ray absorptiometry in a subset of 1019 Look Ahead study volunteers randomized to intervention or comparison groups. The intervention was designed to achieve and maintain ≥7% weight loss through increased physical activity and reduced caloric intake. The comparison group received social support and diabetes education.
Results
At 1 year, the intervention group lost fat (5.6 ± 0.2 kg) and lean mass (2.3 ± 0.1 kg) but regained fat (~100%), and lost lean mass between years 1 and 8. Between baseline and year-8, weight-loss was greater in intervention vs. comparison groups (4.0 ± 0.4 vs. 2.3 ± 0.4 kg); comparison group weight-loss was mostly lean mass (2.1 ± 0.17 kg). Fat mass in the intervention group was lower than that of the comparison group at all post-baseline time points.
Conclusions
Reduced FM may place the intervention group at a lower risk of obesity-linked sequelae, a hypothesis that can be tested by future studies of this cohort.
Trial Registration
ClinicalTrials.gov Identifier: NCT00017953
doi:10.1002/oby.21005
PMCID: PMC4707962  PMID: 25707379
Obesity; diabetes; body composition; weight loss
9.  Genome-Wide Interaction with Insulin Secretion Loci Reveals Novel Loci for Type 2 Diabetes in African Americans 
PLoS ONE  2016;11(7):e0159977.
Type 2 diabetes (T2D) is the result of metabolic defects in insulin secretion and insulin sensitivity, yet most T2D loci identified to date influence insulin secretion. We hypothesized that T2D loci, particularly those affecting insulin sensitivity, can be identified through interaction with insulin secretion loci. To test this hypothesis, single nucleotide polymorphisms (SNPs) associated with acute insulin response to glucose (AIRg), a dynamic measure of first-phase insulin secretion, were identified in African Americans from the Insulin Resistance Atherosclerosis Family Study (IRASFS; n = 492 subjects). These SNPs were tested for interaction, individually and jointly as a genetic risk score (GRS), using genome-wide association study (GWAS) data from five cohorts (ARIC, CARDIA, JHS, MESA, WFSM; n = 2,725 cases, 4,167 controls) with T2D as the outcome. In single variant analyses, suggestively significant (Pinteraction<5×10−6) interactions were observed at several loci including LYPLAL1 (rs10746381), CHN2 (rs7796525), and EXOC1 (rs4289500). Notable AIRg GRS interactions were observed with SAMD4A (rs11627203) and UTRN (rs17074194). These data support the hypothesis that additional genetic factors contributing to T2D risk can be identified by interactions with insulin secretion loci.
doi:10.1371/journal.pone.0159977
PMCID: PMC4957757  PMID: 27448167
10.  Diabetes in midlife and cognitive change over 20 years: the Atherosclerosis Risk in Communities Neurocognitive Study 
Annals of internal medicine  2014;161(11):785-793.
Background
Type 2 diabetes mellitus is associated with dementia risk, however evidence is limited for possible associations of diabetes and pre-diabetes with cognitive decline.
Objective
To determine if diabetes in mid-life is associated with 20-year cognitive decline, and to characterize long-term cognitive decline across clinical categories of hemoglobin A1c (HbA1c).
Design
Prospective cohort.
Setting
The community-based Atherosclerosis Risk in Communities (ARIC) Study.
Participants
13351 black and white adults aged 48-67 years at baseline (1990-1992).
Measurements
Diabetes was defined by self-report of physician diagnosis or medication use or HbA1c≥6.5%. Undiagnosed diabetes, pre-diabetes, and glucose control in persons with diagnosed diabetes were defined using clinical categories of HbA1c. Delayed Word Recall, Digit Symbol Substitution, and Word Fluency tests were used to assess cognitive performance, and were summarized using a global Z-score.
Results
Diabetes in midlife was associated with significantly greater cognitive decline over 20 years (adjusted global Z-score difference=-0.15, 95% CI:-0.22,-0.08), representing a 19% greater decline than those without diabetes. Cognitive decline was significantly greater among persons with pre-diabetes (HbA1c 5.7-6.4%) than those without diabetes and HbA1c<5.7%. Participants with poorly controlled diabetes (HbA1c≥7.0%) had a larger decline compared to persons whose diabetes was controlled (adjusted global Z-score difference=-0.16,p-value=0.071). Longer duration of diabetes was also associated with greater late-life cognitive decline (p-value-for-trend=<0.001). No significant differences in the rates of declines were seen in whites compared to blacks (p-value-for-interaction=0.4357).
Limitations
Single measurement of HbA1c at baseline, only one test to per cognitive domain, potential geographic confounding of race comparisons.
Conclusions
These findings suggest that diabetes prevention and glucose control in midlife may protect against late-life cognitive decline.
doi:10.7326/M14-0737
PMCID: PMC4432464  PMID: 25437406
11.  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.
doi:10.1093/aje/kwm091
PMCID: PMC4450101  PMID: 17493948
atherosclerosis; calcification; physiologic; diabetes mellitus; type 2; North Carolina; risk factors; siblings
12.  Association of an Intensive Lifestyle Intervention With Remission of Type 2 Diabetes 
JAMA  2012;308(23):2489-2496.
Context
The frequency of remission of type 2 diabetes achievable with lifestyle intervention is unclear.
Objective
To examine the association of a long-term intensive weight-loss intervention with the frequency of remission from type 2 diabetes to prediabetes or normoglycemia.
Design, Setting, and Participants
Ancillary observational analysis of a 4-year randomized controlled trial (baseline visit, August 2001–April 2004; last follow-up, April 2008) comparing an intensive lifestyle intervention (ILI) with a diabetes support and education control condition (DSE) among 4503 US adults with body mass index of 25 or higher and type 2 diabetes.
Interventions
Participants were randomly assigned to receive the ILI, which included weekly group and individual counseling in the first 6 months followed by 3 sessions per month for the second 6 months and twice-monthly contact and regular refresher group series and campaigns in years 2 to 4 (n=2241) or the DSE, which was an offer of 3 group sessions per year on diet, physical activity, and social support (n=2262).
Main Outcome Measures
Partial or complete remission of diabetes, defined as transition from meeting diabetes criteria to a prediabetes or nondiabetic level of glycemia (fasting plasma glucose <126 mg/dL and hemoglobin A1c <6.5% with no antihyperglycemic medication).
Results
Intensive lifestyle intervention participants lost significantly more weight than DSE participants at year 1 (net difference, −7.9%; 95% CI, −8.3% to −7.6%) and at year 4 (−3.9%; 95% CI, −4.4% to −3.5%) and had greater fitness increases at year 1 (net difference, 15.4%; 95% CI, 13.7%–17.0%) and at year 4 (6.4%; 95% CI, 4.7%–8.1%) (P<.001 for each). The ILI group was significantly more likely to experience any remission (partial or complete), with prevalences of 11.5% (95% CI, 10.1%–12.8%) during the first year and 7.3% (95% CI, 6.2%–8.4%) at year 4, compared with 2.0% for the DSE group at both time points (95% CIs, 1.4%–2.6% at year 1 and 1.5%–2.7% at year 4) (P<.001 for each). Among ILI participants, 9.2% (95% CI, 7.9%–10.4%), 6.4% (95% CI, 5.3%–7.4%), and 3.5% (95% CI, 2.7%–4.3%) had continuous, sustained remission for at least 2, at least 3, and 4 years, respectively, compared with less than 2% of DSE participants (1.7% [95% CI, 1.2%–2.3%] for at least 2 years; 1.3% [95% CI, 0.8%–1.7%] for at least 3 years; and 0.5% [95% CI, 0.2%–0.8%] for 4 years).
Conclusions
In these exploratory analyses of overweight adults, an intensive lifestyle intervention was associated with a greater likelihood of partial remission of type 2 diabetes compared with diabetes support and education. However, the absolute remission rates were modest.
Trial Registration
clinicaltrials.gov Identifier: NCT00017953
doi:10.1001/jama.2012.67929
PMCID: PMC4771522  PMID: 23288372
13.  Empirical Characteristics of Family-Based Linkage to a Complex Trait: the ADIPOQ Region and Adiponectin Levels 
Human genetics  2014;134(2):203-213.
We previously identified a low frequency (1.1%) coding variant (G45R; rs200573126) in the adiponectin gene (ADIPOQ) which was the basis for a multipoint microsatellite linkage signal (LOD=8.2) for plasma adiponectin levels in Hispanic families. We have empirically evaluated the ability of data from targeted common variants, exome chip genotyping, and genome-wide association study (GWAS) data to detect linkage and association to adiponectin protein levels at this locus. Simple two-point linkage and association analyses were performed in 88 Hispanic families (1150 individuals) using 10,958 SNPs on chromosome 3. Approaches were compared for their ability to map the functional variant, G45R, which was strongly linked (two-point LOD=20.98) and powerfully associated (p-value=8.1×10−50). Over 450 SNPs within a broad 61 Mb interval around rs200573126 showed nominal evidence of linkage (LOD>3) but only four other SNPs in this region were associated with p-values<1.0×10−4. When G45R was accounted for, the maximum LOD score across the interval dropped to 4.39 and the best p-value was 1.1×10−5. Linked and/or associated variants ranged in frequency (0.0018 to 0.50) and type (coding, non-coding) and had little detectable linkage disequilibrium with rs200573126 (r2<0.20). In addition, the two-point linkage approach empirically outperformed multipoint microsatellite and multipoint SNP analysis. In the absence of data for rs200573126, family-based linkage analysis using a moderately dense SNP dataset, including both common and low frequency variants, resulted in stronger evidence for an adiponectin locus than association data alone. Thus, linkage analysis can be a useful tool to facilitate identification of high impact genetic variants.
doi:10.1007/s00439-014-1511-8
PMCID: PMC4293344  PMID: 25447270
14.  A Comprehensive Analysis of Common and Rare Variants to Identify Adiposity Loci in Hispanic Americans: The IRAS Family Study (IRASFS) 
PLoS ONE  2015;10(11):e0134649.
Obesity is growing epidemic affecting 35% of adults in the United States. Previous genome-wide association studies (GWAS) have identified numerous loci associated with obesity. However, the majority of studies have been completed in Caucasians focusing on total body measures of adiposity. Here we report the results from genome-wide and exome chip association studies focusing on total body measures of adiposity including body mass index (BMI), percent body fat (PBF) and measures of fat deposition including waist circumference (WAIST), waist-hip ratio (WHR), subcutaneous adipose tissue (SAT), and visceral adipose tissue (VAT) in Hispanic Americans (nmax = 1263) from the Insulin Resistance Atherosclerosis Family Study (IRASFS). Five SNPs from two novel loci attained genome-wide significance (P<5.00x10-8) in IRASFS. A missense SNP in the isocitrate dehydrogenase 1 gene (IDH1) was associated with WAIST (rs34218846, MAF = 6.8%, PDOM = 1.62x10-8). This protein is postulated to play an important role in fat and cholesterol biosynthesis as demonstrated in cell and knock-out animal models. Four correlated intronic SNPs in the Zinc finger, GRF-type containing 1 gene (ZGRF1; SNP rs1471880, MAF = 48.1%, PDOM = 1.00x10-8) were strongly associated with WHR. The exact biological function of ZGRF1 and the connection with adiposity remains unclear. SNPs with p-values less than 5.00x10-6 from IRASFS were selected for replication. Meta-analysis was computed across seven independent Hispanic-American cohorts (nmax = 4156) and the strongest signal was rs1471880 (PDOM = 8.38x10-6) in ZGRF1 with WAIST. In conclusion, a genome-wide and exome chip association study was conducted that identified two novel loci (IDH1 and ZGRF1) associated with adiposity. While replication efforts were inconclusive, when taken together with the known biology, IDH1 and ZGRF1 warrant further evaluation.
doi:10.1371/journal.pone.0134649
PMCID: PMC4658008  PMID: 26599207
15.  Risk Factors for Atrial Fibrillation in Patients with Normal versus Dilated Left Atria (from the Atherosclerosis Risk in Communities [ARIC] Study) 
The American journal of cardiology  2014;114(9):1368-1372.
Epidemiological data are limited regarding risk factors of atrial fibrillation (AF) in patients with normal-sized left atria (LA). We evaluated whether traditional risk factors of AF differ between patients with normal-sized and dilated LA. This is a cross sectional study of community-dwelling participants of Atherosclerosis Risk in Communities Study. LA volume index (LAVI) was measured by 2-dimensional echocardiography. LAVI ≥29mm3/m2 defined dilated LA. Prevalent AF was defined by electrocardiogram and hospital discharge international classification of diseases - 9 codes. Multivariable adjusted logistic regression analysis was used to examine whether magnitude of association of risk factors with AF differ by LA cavity size. Interaction of risk factors by LA cavity size was evaluated to determine significance of these differential associations. Of 5496 participants (mean age 75±5 years, women 58%), 1230 (22%) had dilated LA. The prevalence of AF was 11% in individuals with normal-sized LA and 15% in individuals with dilated LA. Age >75 years [Odds Ratio (OR) 1.87; 95% confidence interval (CI) 1.49 – 2.35, interaction p=0.12] and heart failure (OR 5.43; 95% CI 3.77 – 7.87, interaction p=0.10) were stronger risk factors for AF in normal-sized LA than dilated-LA. Female sex (OR 1.67; 95% CI 1.01 – 2.77, interaction p=0.09), weight (OR 1.32; 95% CI 1.02 – 1.71, interaction p=0.19) and alcohol-use (OR 1.61; 95% CI 1.08 – 2.41, interaction p=0.004) were stronger risk factors for AF in individuals with dilated LA than normal-sized LA. In conclusion, risk factors of AF may differ by left ventricular cavity size.
doi:10.1016/j.amjcard.2014.07.073
PMCID: PMC4195803  PMID: 25245413
Atrial fibrillation; normal size left atrium; left atrium; risk factors; epidemiology
16.  Association ofPNPLA3 with non-alcoholic fatty liver disease in a minority cohort: the Insulin Resistance Atherosclerosis Family Study 
Background
Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent condition, particularly among Hispanic Americans. A genetic variant in PNPLA3 (rs738409) has been identified as a strong predictor of hepatic fat content.
Aims
To confirm the association of this variant with NAFLD in two minority cohorts, Hispanic Americans and African Americans, in whom liver density was quantified by computed tomography (CT).
Methods
This analysis was conducted in the Insulin Resistance Atherosclerosis (IRAS) Family Study. Participants were recruited from the general community and included 843 Hispanic American and 371 African American adults aged 18–81 years. A single variant in PNPLA3 (rs738409) was genotyped. Liver density was calculated in Hounsfield Units from abdominal CT scans.
Results
Single nucleotide polymorphism (SNP) rs738409 was strongly associated with reduced liver density (i.e. NAFLD) in Hispanic Americans (1.18 × 10−9) and in African Americans (P = 4.99 × 10−6). The association followed an additive genetic model with the G allele conferring risk. The allele was two times more common in Hispanic Americans than in African Americans (40 vs 19%), consistent with the greater prevalence of NAFLD in Hispanic Americans (24 vs 9%). The SNP explained 4.4 and 5.6% of the variance of the adjusted liver density outcome in Hispanic Americans and African Americans, respectively.
Conclusions
We confirmed the association of a PNPLA3 variant with NAFLD in Hispanic Americans and African Americans, suggesting that PNPLA3 contributes to the variation in NAFLD across multiple ethnicities. This study adds to the growing evidence that some of the ethnic variation in NAFLD is genetic.
doi:10.1111/j.1478-3231.2010.02444.x
PMCID: PMC3703938  PMID: 21281435
African Americans; computed tomography; genetic epidemiology; hepatic steatosis; Hispanic Americans; non-alcoholic fatty liver disease; PNPLA3
17.  The Metabolic Syndrome and Cognitive Decline in the Atherosclerosis Risk in Communities Study (ARIC) 
Background
Midlife Metabolic Syndrome (MetS) may impact cognitive health as a construct independently of hypertension, hyperlipidemia and other components.
Methods
10,866 participants aged 45 to 64 at baseline were assessed for MetS and completed cognitive testing at two later time points (3 and 9 years from baseline visit).
Results
MetS is associated with increased odds of low cognitive performance in the domains of executive function and word fluency, but not 6-year cognitive decline. Individual MetS components explained this association (hypertension, diabetes, low HDL, elevated triglycerides and increased waist circumference).
Conclusions
A focus on the individual risk factors as opposed to MetS during midlife is important to reduce the incidence of cognitive impairment in later life.
doi:10.1159/000362265
PMCID: PMC4201882  PMID: 25171458
metabolic syndrome; cognition; cognitive decline; obesity; hypertension and dementia
18.  Racial Differences in the Association of Insulin Resistance with Stroke Risk: The REasons for Geographic And Racial Differences in Stroke (REGARDS) Study 
Background and Purpose
Insulin resistance is associated with increased stroke risk, but the effect has not been adequately examined separately in white and black populations.
Methods
The association of baseline insulin resistance with risk of cerebral infarction (CI) and intracerebral hemorrhage (ICH) was assessed in 12,366 white and 6,782 black participants from the REGARDS cohort, recruited between 2003 and 2007 and followed an average of 5.7 years. Insulin resistance was measured with the homeostasis model assessment (HOMA-IR).
Results
There were 364 incident CI and 41 incident ICH events. The risk for CI increased with the log of insulin resistance in whites (HRln(IR) = 1.17; 95% CI: 1.00 – 1.38), but was largely attenuated by adjustment for stroke risk factors (HRln(IR) = 1.05; 95% CI: 0.88 – 1.26). There was no association in blacks (HRln(IR) = 1.01; 95% CI: 0.81 – 1.25). After adjustment for demographic factors and risk factors, there was a significant difference by race in the association of insulin resistance with risk of ICH (p = 0.07), with a decrease in the risk of ICH in whites (HRln(IR) = 0.61; 95% CI: 0.35 – 1.04) but a non-significant increase for blacks (HRln(IR) = 1.20; 95% CI: 0.60 – 2.39).
Conclusion
These data support the growing evidence that insulin resistance may play a more important role in stroke risk among white than black individuals, and suggest a potentially discordant relationship of insulin resistance on CI and ICH among whites.
doi:10.1161/STROKEAHA.114.005306
PMCID: PMC4430474  PMID: 24968932
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.
doi:10.1038/ki.2014.255
PMCID: PMC4281283  PMID: 25054777
African Americans; apolipoprotein L1 gene (APOL1); atherosclerosis; calcified atherosclerotic plaque; diabetes mellitus; kidney disease
20.  Effect of a Long-Term Behavioral Weight Loss Intervention on Nephropathy in Overweight or Obese Adults with Type 2 Diabetes: the Look AHEAD Randomized Clinical Trial 
Background
Long-term effects of behavioral weight loss interventions on diabetes complications are unknown. We assessed whether an intensive lifestyle intervention (ILI) affects the development of nephropathy in Look AHEAD, a multicenter randomized clinical trial in type 2 diabetes.
Methods
5145 overweight or obese persons aged 45–76 years with type 2 diabetes were randomized to ILI designed to achieve and maintain weight loss through reduced caloric consumption and increased physical activity or to a diabetes support and education (DSE) group. Randomization to ILI or DSE, in a 1:1 ratio, was implemented in a central web-based data management system, stratified by clinical center, and blocked with random block sizes. Outcomes assessors and laboratory staff were masked to treatment. The interventions ended early because of lack of effect on the primary outcome of cardiovascular disease events. Albuminuria and estimated glomerular filtration rate were prespecified “other” outcomes and were assessed from baseline through 9.6 years (median) of follow-up until the interventions ended. They were combined post-hoc to define the main outcome for this report: very-high-risk chronic kidney disease (CKD) based on the 2013 Kidney Disease Improving Global Outcomes classification. Data were analyzed by intention to treat. The trial is registered as Clinicaltrials.gov NCT00017953.
Findings
The incidence rate of very-high-risk CKD was 31% lower in ILI than DSE with hazard rates of 0.90 cases/100 person-years in DSE and 0.63 in ILI (difference=0.27 cases/100 person-years, hazard ratio and 95% confidence interval: HR=0.69, 0.55 to 0.87). This effect was partly attributable to reductions in weight, HbA1c, and blood pressure.
Interpretation
Weight loss should be considered as an adjunct to medical therapies to prevent or delay progression of CKD in overweight or obese persons with type 2 diabetes.
Primary Funding
National Institute of Diabetes and Digestive and Kidney Diseases.
doi:10.1016/S2213-8587(14)70156-1
PMCID: PMC4443484  PMID: 25127483
21.  CORRELATES OF CORONARY ARTERY CALCIFIED PLAQUE IN BLACKS AND WHITES WITH TYPE 2 DIABETES 
Annals of epidemiology  2011;21(1):34-41.
Purpose
To examine whether the relationship between cardiovascular disease risk factors and coronary artery calcification (CAC) is modified by race among those with diabetes.
Methods
Data were pooled data from three studies (Multi-Ethnic Study of Atherosclerosis, Family Heart Study, Diabetes Heart Study) for a total of 835 blacks and 1122 whites with diabetes. CAC was quantified by cardiac computed tomography and risk factors were obtained using standard methods. Regression models examined the relationship between risk factors and presence and quantity of CAC.
Results
The average age of the cohort was 60 years; 57% were women. Presence of CAC was lower in blacks compared to whites (odds ratio = 0.22 for men, 0.57 for women, p<0.01). HbA1c, duration of diabetes, LDL, smoking, and BMI were independently associated with presence of CAC; HDL, triglycerides and CRP were not. Race did not modify these associations. Adjustment for multiple risk factors did not explain the race disparity in CAC.
Conclusions
CAC was reduced in blacks compared to whites in persons with diabetes. This effect was most pronounced in men. The relationship between risk factors and CAC did not differ between races. Racial differences in CAC are likely due to unmeasured risk factors and/or genetic susceptibility.
doi:10.1016/j.annepidem.2010.10.007
PMCID: PMC3026318  PMID: 21130367
coronary artery disease; diabetes mellitus; epidemiology; African Americans; cohort studies
22.  Impact of Differential Attrition on the Association of Education With Cognitive Change Over 20 Years of Follow-up 
American Journal of Epidemiology  2014;179(8):956-966.
Studies of long-term cognitive change should account for the potential effects of education on the outcome, since some studies have demonstrated an association of education with dementia risk. Evaluating cognitive change is more ideal than evaluating cognitive performance at a single time point, because it should be less susceptible to confounding. In this analysis of 14,020 persons from a US cohort study, the Atherosclerosis Risk in Communities (ARIC) Study, we measured change in performance on 3 cognitive tests over a 20-year period, from ages 48–67 years (1990–1992) through ages 70–89 years (2011–2013). Generalized estimating equations were used to evaluate the association between education and cognitive change in unweighted adjusted models, in models incorporating inverse probability of attrition weighting, and in models using cognitive scores imputed from the Telephone Interview for Cognitive Status for participants not examined in person. Education did not have a strong relationship with change in cognitive test performance, although the rate of decline was somewhat slower among persons with lower levels of education. Methods used to account for selective dropout only marginally changed these observed associations. Future studies of risk factors for cognitive impairment should focus on cognitive change, when possible, to allow for reduction of confounding by social or cultural factors.
doi:10.1093/aje/kwu020
PMCID: PMC3966720  PMID: 24627572
aging; cognition; cognitive decline; cognitive reserve; education
23.  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.
doi:10.1038/ncomms6897
PMCID: PMC4311266  PMID: 25631608
24.  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 | Hua Zhao, Jing | 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-DerI | 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 | Goddard, William A | 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-Cowdin, 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 | Adrienne Cupples, L | 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 | Laakso, Markku | Borecki, Ingrid B | Chasman, Daniel I | Pedersen, Oluf | Psaty, Bruce M | Shyong Tai, E | van Duijn, Cornelia M | Wareham, Nicholas J | Waterworth, Dawn M | Boerwinkle, Eric | Linda Kao, W H | 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.
Both rare and common variants contribute to the aetiology of complex traits such as type 2 diabetes (T2D). Here, the authors examine the effect of coding variation on glycaemic traits and T2D, and identify low-frequency variation in GLP1R significantly associated with these traits.
doi:10.1038/ncomms6897
PMCID: PMC4311266  PMID: 25631608
25.  Relationships Between Calcified Atherosclerotic Plaque and Bone Mineral Density in African Americans With Type 2 Diabetes 
Inverse relationships have been reported between bone mineral density (BMD) and calcified atherosclerotic plaque (CP). This suggests these processes may be related. We examined relationships between BMD and CP in 753 African Americans with type 2 diabetes from 664 families, accounting for the effects of modifiable cardiovascular disease (CVD) risk factors. Association analyses were performed using generalized estimating equations (GEEs) to assess cross-sectional relationships between computed tomography–determined measures of thoracic and lumbar vertebral volumetric BMD (vBMD) and CP in the coronary and carotid arteries and infrarenal aorta. Significant inverse associations were seen between thoracic and lumbar vBMD and CP in all three vascular beds in unadjusted analyses. A fully adjusted model accounting for age, sex, body mass index, systolic blood pressure, low-density lipoprotein cholesterol, C-reactive protein, hemoglobin A1c, smoking, and hormone-replacement therapy revealed significant inverse associations between thoracic vBMD and CP in coronary and carotid arteries and aorta, whereas lumbar vBMD was associated with CP in coronary artery and aorta. Inverse associations exist between vertebral BMD and calcified atherosclerotic plaque in African-American men and women with type 2 diabetes. This relationship was independent of conventional CVD risk factors and supports the hypothesis that bone metabolism and atherosclerotic plaque mineralization are related processes.
doi:10.1002/jbmr.389
PMCID: PMC4341826  PMID: 21437982
AFRICAN AMERICANS; ATHEROSCLEROSIS; CALCIFIED PLAQUE; BONE MINERAL DENSITY; DIABETES MELLITUS; OSTEOPOROSIS

Results 1-25 (80)