Type 2 diabetes mellitus is associated with dementia risk, however evidence is limited for possible associations of diabetes and pre-diabetes with cognitive decline.
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).
The community-based Atherosclerosis Risk in Communities (ARIC) Study.
13351 black and white adults aged 48-67 years at baseline (1990-1992).
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.
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).
Single measurement of HbA1c at baseline, only one test to per cognitive domain, potential geographic confounding of race comparisons.
These findings suggest that diabetes prevention and glucose control in midlife may protect against late-life cognitive decline.
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.
atherosclerosis; calcification; physiologic; diabetes mellitus; type 2; North Carolina; risk factors; siblings
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.
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).
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.
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.
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.
African Americans; computed tomography; genetic epidemiology; hepatic steatosis; Hispanic Americans; non-alcoholic fatty liver disease; PNPLA3
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.
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).
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).
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.
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.
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.
African Americans; apolipoprotein L1 gene (APOL1); atherosclerosis; calcified atherosclerotic plaque; diabetes mellitus; kidney disease
To examine whether the relationship between cardiovascular disease risk factors and coronary artery calcification (CAC) is modified by race among those with diabetes.
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.
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.
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.
coronary artery disease; diabetes mellitus; epidemiology; African Americans; cohort studies
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.
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.
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.
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.
National Institute of Diabetes and Digestive and Kidney Diseases.
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.
aging; cognition; cognitive decline; cognitive reserve; education
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.
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.
AFRICAN AMERICANS; ATHEROSCLEROSIS; CALCIFIED PLAQUE; BONE MINERAL DENSITY; DIABETES MELLITUS; OSTEOPOROSIS
Metabolomic studies of increased fat oxidation showed increase in circulating acylcarnitines C2, C8, C10, and C12 and decrease in C3, C4, and C5. We hypothesize that urinary F2-isoprostanes reflect intensity of fatty acid oxidation and are associated with circulating C2, C8, C10, and C12 directly and with C3, C4, and C5 inversely. Four urinary F2-isoprostane isomers and serum acylcarnitines are quantified using LC-MS/MS within the Insulin Resistance Atherosclerosis Study nondiabetic cohort (n = 682). Cross-sectional associations between fasting urinary F2-isoprostanes (summarized as a composite index) and the selected acylcarnitines are examined using generalized linear models. F2-isoprostane index is associated with C2 and C12 directly and with C5 inversely: the adjusted beta coefficients are 0.109, 0.072, and −0.094, respectively (P < 0.05). For these acylcarnitines and for F2-isoprostanes, the adjusted odds ratios (ORs) of incident diabetes are calculated from logistic regression models: the ORs (95% CI) are 0.77 (0.60–0.97), 0.79 (0.62–1.01), 1.18 (0.92–1.53), and 0.51 (0.35–0.76) for C2, C12, C5, and F2-isoprostanes, respectively. The direction of the associations between urinary F2-isoprostanes and three acylcarnitines (C2, C5, and C12) supports our hypothesis. The inverse associations of C2 and C12 and with incident diabetes are consistent with the suggested protective role of efficient fat oxidation.
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.
Hispanic; African American; genetic variance
The present study identified genetic predictors of weight change during behavioral weight loss treatment.
Participants were 3,899 overweight/obese individuals with type 2 diabetes from Look AHEAD, a randomized controlled trial to determine the effects of intensive lifestyle intervention (ILI), including weight loss and physical activity, relative to diabetes support and education, on cardiovascular outcomes. Analyses focused on associations of single nucleotide polymorphisms (SNPs) on the Illumina CARe iSelect (IBC) chip (minor allele frequency >5%; n = 31,959) with weight change at year 1 and year 4, and weight regain at year 4, among individuals who lost ≥ 3% at year 1.
Two novel regions of significant chip-wide association with year-1 weight loss in ILI were identified (p < 2.96E-06). ABCB11 rs484066 was associated with 1.16 kg higher weight per minor allele at year 1, whereas TNFRSF11A, or RANK, rs17069904 was associated with 1.70 kg lower weight per allele at year 1.
This study, the largest to date on genetic predictors of weight loss and regain, indicates that SNPs within ABCB11, related to bile salt transfer, and TNFRSF11A, implicated in adipose tissue physiology, predict the magnitude of weight loss during behavioral intervention. These results provide new insights into potential biological mechanisms and may ultimately inform weight loss treatment.
Type 2 diabetes; Obesity; Weight loss; Diet; Genetics
We describe the GUARDIAN (Genetics UndeRlying DIAbetes in HispaNics) consortium, along with heritability estimates and genetic and environmental correlations of insulin sensitivity and metabolic clearance rate of insulin (MCRI).
Design and Methods
GUARDIAN is comprised of seven cohorts, consisting of 4336 Mexican-American individuals in 1346 pedigrees. Insulin sensitivity (SI), MCRI, and acute insulin response (AIRg) were measured by frequently sampled intravenous glucose tolerance test in four cohorts. Insulin sensitivity (M, M/I) and MCRI were measured by hyperinsulinemic-euglycemic clamp in three cohorts. Heritability and genetic and environmental correlations were estimated within the family cohorts (totaling 3925 individuals) using variance components.
Across studies, age and gender-adjusted heritability of insulin sensitivity (SI, M, M/I) ranged from 0.23–0.48 and of MCRI from 0.35–0.73. The ranges for the genetic correlations were 0.91 to 0.93 between SI and MCRI; and −0.57 to −0.59 for AIRg and MCRI (all P<0.0001). The ranges for the environmental correlations were 0.54 to 0.74 for SI and MCRI (all P<0.0001); and −0.16 to −0.36 for AIRg and MCRI (P <0.0001−0.06).
These data support a strong familial basis for insulin sensitivity and MCRI in Mexican Americans. The strong genetic correlations between MCRI and SI suggest common genetic determinants.
insulin sensitivity; insulin clearance; heritability; genetic correlation; environmental correlation
Nonalcoholic Fatty Liver Disease (NAFLD) is an obesity-related condition affecting over 50% of individuals in some populations and is expected to become the number one cause of liver disease worldwide by 2020. Common, robustly associated genetic variants in/near five genes were identified for hepatic steatosis, a quantifiable component of NAFLD, in European-ancestry individuals. Here we tested whether these variants were associated with hepatic steatosis in African and/or Hispanic Americans and fine-mapped the observed association signals. We measured hepatic steatosis using computed tomography in five African-American (n=3124) and one Hispanic-American (n=849) cohorts. All analyses controlled for variation in age, age2, gender, alcoholic drinks, and population substructure. Heritability of hepatic steatosis was estimated in three cohorts. Variants in/near PNPLA3, NCAN, LYPLAL1, GCKR, and PPP1R3B were tested for association with hepatic steatosis using a regression framework in each cohort and meta-analyzed. Fine-mapping across African-American cohorts was conducted using meta-analysis. African- and Hispanic-American cohorts were 33.9/37.5% male, with average age of 58.6/42.6 years and body mass index of 31.8/28.9kg/m2, respectively. Hepatic steatosis was 0.20–0.34 heritable in African-and Hispanic-American families (p<0.02 in each cohort). Variants in or near PNPLA3, NCAN, GCKR, PPP1R3B in African Americans and PNPLA3 and PPP1R3B in Hispanic Americans were significantly associated with hepatic steatosis; however, allele frequency and effect size varied across ancestries. Fine-mapping in African Americans highlighted missense variants at PNPLA3 and GCKR and redefined the association region at LYPLAL1.
We show for the first time that multiple genetic variants are associated with hepatic steatosis across ancestries and explain a substantial proportion of the genetic predisposition in African and Hispanic Americans. Missense variants in PNPLA3 and GCKR are likely functional across multiple ancestries.
liver steatosis; single nucleotide polymorphisms; obesity; meta-analysis; genetic variance
Obesity has been associated with increased F2-isoprostane (F2-IsoP) levels cross-sectionally. However, the prospective association may be inverse, based on our earlier finding that elevated urinary F2-IsoP levels predict lower risk of diabetes. This earlier finding led us to hypothesize that urinary F2-IsoPs reflect the intensity of oxidative metabolism and as such predict lower risk of both diabetes and weight gain. We examined cross-sectional relationships with obesity and prospective relationships with weight gain using the data from 299 participants of the Insulin Resistance Atherosclerosis Study (IRAS), all of whom were free of diabetes at baseline. Four urinary F2- IsoPs were assayed in stored baseline urine samples using liquid chromatography with tandem mass spectrometry: iPF(2α)-III, 2,3-dinor-iPF(2α)-III, iPF(2α)-VI, and 8,12-iso-iPF(2α)-VI (F2-IsoP 1–4, respectively). Baseline F2-IsoPs were positively associated with baseline measures of obesity; the strongest associations were found with two F2-IsoPs: odds ratios (95% confidence intervals) for overall and abdominal obesity were 1.74 (1.26–2.40) and 1.63 (1.18–2.24) for F2-IsoP2 and 1.47 (1.12–1.94) and 1.64 (1.22–2.20) for F2-IsoP4. F2-IsoP2 showed the strongest and significant inverse association with weight gain during the 5-year follow-up period: increase in F2-IsoP2 equal to 1 s.d. was associated with 0.90 kg lower weight gain (P = 0.02) and the odds ratios for relative (≥5%) and absolute (≥5 kg) weight gain were 0.67 (0.47–0.96) and 0.57 (0.37–0.87), respectively. The other three F2-IsoPs were consistently inversely associated with weight gain, although not significantly, suggesting that different F2-IsoPs vary in their ability to detect the association with weight gain.
High-density lipoprotein cholesterol (HDL-C) and triglycerides are cardiovascular risk factors susceptible to lifestyle behavior modification and genetics. We hypothesized that genetic variants identified by genome-wide association studies (GWASs) as associated with HDL-C or triglyceride levels will modify 1-year treatment response to an intensive lifestyle intervention (ILI), relative to a usual care of diabetes support and education (DSE).
Methods and Results
We evaluated 82 SNPs, representing 31 loci demonstrated by GWAS to be associated with HDL-C and/or triglycerides, in 3,561 participants who consented for genetic studies and met eligibility criteria. Variants associated with higher baseline HDL-C levels, cholesterol ester transfer protein (CETP) rs3764261 and hepatic lipase (LIPC) rs8034802, were found to be associated with HDL-C increases with ILI (p=0.0038 and 0.013, respectively) and had nominally significant treatment interactions (p=0.047 and 0.046, respectively). The fatty acid desaturase-2 (FADS-2) rs1535 variant, associated with low baseline HDL-C (p=0.017), was associated with HDL-C increases with ILI (0.0037) and had a nominal treatment interaction (p= 0.035). ApoB (rs693) and LIPC (rs8034802) SNPs showed nominally significant associations with HDL-C and triglyceride changes with ILI and a treatment interaction (p<0.05). A PGS1 SNP (rs4082919) showed the most significant triglyceride treatment interaction in the full cohort (p=0.0009).
This is the first study to identify genetic variants modifying lipid responses to a randomized lifestyle behavior intervention in overweight/obese diabetic individuals. The effect of genetic factors on lipid changes may differ from the effects on baseline lipids and are modifiable by behavioral intervention.
genomics; physiological; cholesterylester transfer protein genetics; triglycerides; behavior modification; lipoprotein
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
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
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.
Genome-wide association studies have provided new insights into the genetic factors that contribute to the development of obesity. We hypothesized that these genetic markers would also predict magnitude of weight loss and weight regain after initial weight loss.
Established obesity risk alleles available on the Illumina CARe iSelect (IBC) chip were characterized in 3,899 overweight or obese participants with type 2 diabetes from the 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 examined the interaction between 13 obesity-risk polymorphisms in 8 genes and randomized treatment arm in predicting weight change at year 1, and weight regain at year 4 among individuals who lost 3% or more of their baseline weight by year 1.
No SNPs were significantly associated with magnitude of weight loss or interacted with treatment arm at year 1. However, FTO rs3751812 predicted weight regain within DSE (1.56 kg per risk allele, p = 0.005), but not ILI (p = 0.761), resulting in SNP×treatment arm interaction (p = 0.009). In a partial replication of prior research, the obesity risk (G) allele at BDNF rs6265 was associated with greater weight regain across treatment arms (0.773 kg per risk allele), although results were of borderline statistical significance (p=0.051).
Variations in the FTO and BDNF loci may contribute risk of weight regain after weight loss.
type 2 diabetes; obesity; weight loss, diet, genetics
Increased carotid intima‐media thickness (IMT) is associated with subclinical left ventricular myocardial dysfunction, suggesting a possible role of carotid IMT in heart failure (HF) risk determination.
Methods and Results
Mean far wall carotid IMT, measured by B‐mode ultrasound, was available for 13 590 Atherosclerosis Risk in Communities study participants aged 45 to 64 years and free of HF at baseline. HF was defined using ICD‐9 428 and ICD‐10 I‐50 codes from hospitalization records and death certificates. The association between carotid IMT and incident HF was assessed using Cox proportional hazards analysis with models adjusted for demographic variables, major CVD risk factors, and interim CHD. There were 2008 incident HF cases over a median follow‐up of 20.6 years (8.1 cases per 1000 person‐years). Mean IMT was higher in those with HF than in those without (0.81 mm±0.23 versus 0.71 mm±0.17, P<0.001). Unadjusted rate of HF for the fourth compared with the first quartile of IMT was 15.4 versus 3.9 per 1000 person‐years; P<0.001. In multivariable analysis, after adjustment, each standard deviation increase in IMT was associated with incident HF (HR 1.20 [95% CI: 1.16 to 1.25]). After adjustment, the top quartile of IMT was associated with HF (HR 1.60 [95% CI: 1.37 to 1.87]). Results were similar across race and gender groups.
Increasing carotid IMT is associated with incident HF in middle‐aged whites and blacks, beyond risks explained by major CVD risk factors and CHD. This suggests that carotid IMT may be associated with HF through mechanisms different from myocardial ischemia or infarction.
carotid intima‐media thickness; heart failure; subclinical atherosclerosis
The census classification of Hispanic origin is used in epidemiological studies to group individuals, even though there is geographical, cultural, and genetic diversity within Hispanic Americans of purportedly similar backgrounds. We observed differences in our measures of adiposity between our two Mexican American populations, and examined whether these differences were attributed to social, behavioral, physiologic or genetic differences between the two populations.
Research Design and Methods
In the IRAS Family Study, we examined 478 Hispanics from San Antonio, Texas and 447 Hispanics from the San Luis Valley, Colorado. Associations with body mass index (BMI), visceral adipose tissue area (VAT), and subcutaneous adipose tissue area (SAT) using social, behavioral, physiologic and genetic variables were examined.
Hispanics of Mexican origin in our clinic population in San Antonio had significantly higher mean BMI (31.09 vs 28.35 kg/m2), VAT (126.3 vs 105.5 cm2), and SAT (391.6 vs 336.9 cm2), than Hispanics of Mexican origin in the San Luis Valley. The amount of variation in adiposity explained by clinic population was 4.5% for BMI, 2.8% for VAT, and 2.7% for SAT. After adjustment, clinic population was no longer associated with VAT and SAT, but remained associated with BMI, although the amount of variation explained by population was substantially less (1.0% for BMI).
Adiposity differences within this population of Mexican origin can be largely explained by social, behavioral, physiologic and genetic differences. (Ethn Dis. 2012;22(1):65–71)
Hispanics; Adiposity; Admixture; Environmental Differences; Social Factors; Behavior; Genetics
Cross-sectional evidence indicates that abdominal adiposity, hypertension, dyslipidemia and glycemia are associated with reduced metabolic clearance of insulin (MCRI). Little is known about the progression of MCRI and whether components of metabolic syndrome are associated with the change in MCRI. In this study, we examined the association between components of metabolic syndrome and the 5-year change of MCRI.
Methods and Materials
At baseline and 5-year follow-up, we measured fasting plasma triglycerides (TG), high density lipoprotein (HDL)-cholesterol, blood pressure (BP), waist circumference (WC) and fasting blood glucose (FBG) in 784 non-diabetic participants in the Insulin Resistance Atherosclerosis Study. MCRI, insulin sensitivity (SI) and acute insulin response (AIR) were determined from frequently sampled intravenous glucose tolerance tests.
We observed a 29% decline of MCRI at follow-up. TG, systolic BP and WC at baseline were inversely associated with a decline of MCRI regression models adjusted for age, sex, ethnicity, smoking, alcohol consumption, energy expenditure, family history of diabetes, BMI, SI and AIR (β= −0.057 [95% CI −0.11, −0.0084] for TG, β= −0.0019 [95% CI −0.0035, −0.00023] for systolic BP, β= −0.0084 [95% CI −0.013, −0.0039] for WC; all p<0.05). Higher HDL-cholesterol at baseline was associated with an increase in MCRI (multivariable-adjusted β= 0.0029 [95% CI 0.0010, 0.0048], p=0.002). FBG at baseline was not associated with MCRI at follow-up (multivariable-adjusted β= 0.0014 [95% CI −0.0026, 0.0029]).
MCRI declined progressively over 5 years in a non-diabetic cohort. Components of metabolic syndrome at baseline were associated with a significant change in MCRI.
Some obese individuals appear to be protected from developing type 2 diabetes mellitus and cardiovascular disease (CVD). This has led to characterizing body size phenotypes based on cardiometabolic risk factors specifically as obese or overweight, and as metabolically healthy (MH) or metabolically abnormal (MA) based upon blood pressure, lipids, glucose homeostasis and inflammatory parameters. The aim of this study was to measure the prevalence of and describe fat distribution across these phenotypes in a minority population.
Design and Methods
Hispanic participants (N=1054) in the IRAS Family Study were categorized into different body size phenotypes. Computed tomography (CT) abdominal scans were evaluated for measures of non-alcoholic fatty liver disease (NAFLD) and abdominal fat distribution. Statistical models adjusting for familial relationships were estimated.
Seventy percent (70%) of the Hispanic cohort was overweight (32%) or obese (38%). Forty-one percent (n=138) of overweight participants and 19% (n=74) of obese participants met criteria for MH. Adjusted analyses showed the MH phenotype was associated with lower visceral adipose tissue (VAT) and higher liver density (indicating lower fat content) in obese participants (p=0.0005 and p=0.0002, respectively), and lower VAT but not liver density in overweight participants (p=0.008 and p=0.162, respectively) compared to their MA counterparts. Odds of NAFLD were reduced in MH obese (OR=0.34, p=0.0007) compared to MA obese. VAT did not differ between MH obese or overweight and normal weight groups.
These findings suggest that lower levels of visceral and liver fat, despite overall increased total body fat, may be a defining feature of MH obesity in Hispanic Americans.