To extend understanding of the genetic architecture and molecular basis of type 2 diabetes (T2D), we conducted a meta-analysis of genetic variants on the Metabochip involving 34,840 cases and 114,981 controls, overwhelmingly of European descent. We identified ten previously unreported T2D susceptibility loci, including two demonstrating sex-differentiated association. Genome-wide analyses of these data are consistent with a long tail of further common variant loci explaining much of the variation in susceptibility to T2D. Exploration of the enlarged set of susceptibility loci implicates several processes, including CREBBP-related transcription, adipocytokine signalling and cell cycle regulation, in diabetes pathogenesis.

Background

Stratification of individuals at risk for chronic kidney disease may allow optimization of preventive measures to reduce disease incidence and complications. We sought to develop a risk score that estimates an individual’s absolute risk of incident chronic kidney disease.

Methods

Framingham Heart Study participants free of baseline chronic kidney disease, who attended a baseline examination in 1995–1998 and follow-up in 2005–2008, were included in the analysis (n=2,490). Chronic kidney disease was defined as an estimated glomerular filtration rate <60 ml/min/1.73m2 using the Modification of Diet in Renal Disease (MDRD) equation. Participants were assessed for the development of chronic kidney disease at 10 years follow-up. Stepwise logistic regression was used to identify chronic kidney disease risk factors, and these were used to construct a risk score predicting 10-year chronic kidney disease risk. Performance characteristics were assessed using calibration and discrimination measures. The final model was externally validated in the bi-ethnic Atherosclerosis Risk in Communities (ARIC) Study (n=1,777).

Results

There were 1,171 men and 1,319 women at baseline, and the mean age was 57.1 years. At follow-up, 9.2% (n=229) had developed chronic kidney disease. Age, diabetes, hypertension, baseline estimated glomerular filtration rate and albuminuria were independently associated with incident chronic kidney disease (p<0.05), and these covariates were incorporated into a risk function (c-statistic 0.813). In external validation in the ARIC study, the c-statistic was 0.79 in whites (n=1,353) and 0.75 in blacks (n=424).

Conclusion

Risk stratification for chronic kidney disease is achievable using a risk score derived from clinical factors that are readily accessible in primary care. The utility of this score in identifying individuals in the community at high risk of chronic kidney disease warrants further investigation.

To extend understanding of the genetic architecture and molecular basis of type 2 diabetes (T2D), we conducted a meta-analysis of genetic variants on the Metabochip involving 34,840 cases and 114,981 controls, overwhelmingly of European descent. We identified ten previously unreported T2D susceptibility loci, including two demonstrating sex-differentiated association. Genome-wide analyses of these data are consistent with a long tail of further common variant loci explaining much of the variation in susceptibility to T2D. Exploration of the enlarged set of susceptibility loci implicates several processes, including CREBBP-related transcription, adipocytokine signalling and cell cycle regulation, in diabetes pathogenesis.

Background.

Several genome scans have explored the linkage of chronic kidney disease phenotypes to chromosomic regions with disparate results. Genome scan meta-analysis (GSMA) is a quantitative method to synthesize linkage results from independent studies and assess their concordance.

Methods.

We searched PubMed to identify genome linkage analyses of renal function traits in humans, such as estimated glomerular filtration rate (GFR), albuminuria, serum creatinine concentration and creatinine clearance. We contacted authors for numerical data and extracted information from individual studies. We applied the GSMA nonparametric approach to combine results across 14 linkage studies for GFR, 11 linkage studies for albumin creatinine ratio, 11 linkage studies for serum creatinine and 4 linkage studies for creatinine clearance.

Results.

No chromosomal region reached genome-wide statistical significance in the main analysis which included all scans under each phenotype; however, regions on Chromosomes 7, 10 and 16 reached suggestive significance for linkage to two or more phenotypes. Subgroup analyses by disease status or ethnicity did not yield additional information.

Conclusions.

While heterogeneity across populations, methodologies and study designs likely explain this lack of agreement, it is possible that linkage scan methodologies lack the resolution for investigating complex traits. Combining family-based linkage studies with genome-wide association studies may be a powerful approach to detect private mutations contributing to complex renal phenotypes.

Background

Limited data exist regarding the use of a genetic risk score for predicting risk of incident cardiovascular disease (CVD) in US based samples.

Methods and Results

Using findings from recent GWAS, we constructed genetic risk scores (GRS) comprised of 13 genetic variants associated with myocardial infarction (MI) or other manifestations of CHD and 102 genetic variants associated with CHD or its major risk factors. We also updated the 13 SNP GRS with 16 SNPs recently discovered by GWAS. We estimated the association, discrimination and risk reclassification of each GRS for incident cardiovascular events and for prevalent coronary artery calcium (CAC).

In analyses adjusted for age, sex, CVD risk factors and parental history of CVD, the 13 SNP GRS was significantly associated with incident hard CHD (HR 1.07, 95% CI 1.00-1.15, p=0.04), CVD (hazard ratio [HR] per-allele 1.05, 95% confidence interval [CI] 1.01-1.09; p=0.03), and high CAC (defined as >75th age and sex-specific percentile; odds ratio [OR] per-allele 1.18, 95% CI 1.11-1.26, p=3.4 × 10-7). The GRS did not improve discrimination for incident CHD or CVD but led to modest improvements in risk reclassification. However, significant improvements in discrimination and risk reclassification were observed for the prediction of high CAC. The addition of 16 newly discovered SNPs to the 13 SNP GRS did not significantly modify these results.

Conclusions

A GRS comprised of 13 SNPs associated with coronary disease is an independent predictor of cardiovascular events and of high CAC, modestly improves risk reclassification for incident CHD and significant improves discrimination for high CAC. The addition of recently discovered SNPs did not significantly improve the performance of this GRS.

Background

Acute kidney injury (AKI) is a risk factor for long-term adverse outcomes including acute myocardial infarction (MI) and death. However, the relationship between severity of AKI and in-hospital outcomes in the setting of acute MI has not been well-documented.

Methods and Results

The study population (n=59,970) was drawn from the ACTION Registry®-GWTG(tm), a nation-wide sample of MI patients admitted to 383 hospitals in the United States between July 2008 and September, 2009. AKI was defined using absolute changes in serum creatinine (SCr; peak SCr – admission SCr), and categorized as no AKI (SCr change<0.3 mg/dl), mild AKI (SCr change 0.3-<0.5 mg/dl), moderate AKI (SCr change 0.5-<1.0 mg/dl), and severe AKI (SCr change ≥1.0 mg/dl). Overall, 16.1% had AKI, including 6.5% with mild AKI, 5.6% with moderate AKI, and 4.0% with severe AKI. In-hospital mortality rates for those with mild, moderate and severe AKI were 6.6%, 14.2%, and 31.8% compared to 2.1% without AKI. The odds ratio for in-hospital death were 2.4 (95% CI 2.0-2.7), 4.5 (95% CI 3.9-5.1), and 12.6 (95% CI 11.1-14.3) for mild, moderate, and severe AKI compared to those without AKI. Although patients with AKI were less likely to undergo early invasive care or to receive antiplatelet therapies, rates of major bleeding ranged from 8.4% (no AKI) to 32.7% (severe AKI).

Conclusions

AKI is common and associated with mortality and bleeding, underscoring the importance of efforts to identify risk factors and prevent AKI in AMI care.

Diabetes mellitus and obesity are increasing in prevalence and are associated with an elevated risk of atrial fibrillation (AF). Given the aging of the US population, AF is projected to concomitantly increase in prevalence in the upcoming decades. Both diabetes and obesity are associated with insulin resistance. Whether insulin resistance is an intermediate step for the development of AF is uncertain. We hypothesized that insulin resistance is associated with an increased risk of incident AF. We examined the association of insulin resistance with incident AF using multivariable Cox proportional hazards regression adjusting for established AF risk factors (age, sex, systolic blood pressure, hypertension treatment, PR interval, significant heart murmur, heart failure and body mass index). Of the 3,023 eligible participants (55% women; mean age 59 years) representing 4,583 persons-examinations (Framingham Offspring 5th and 7th examination cycles), 279 individuals developed AF (9.3%) up to 10 years of follow-up. With multivariable modeling, insulin resistance was not significantly associated with incident AF (hazard ratio comparing the top with the other three quartiles of homeostatic model assessment index (HOMA) 1.18, 95% confidence interval 0.84 to 1.65, p = 0.34). In a community-based cohort with up to 10 years follow-up, no significant association was observed between insulin resistance and incident AF.

Background

Recent genome-wide association studies have identified multiple genetic loci that increase the risk of chronic kidney disease (CKD) in the general population. We hypothesized that knowledge of these loci might permit improved CKD risk prediction beyond that provided by traditional phenotypic risk factors.

Study design

Observational cohort study

Setting and participants

Participants who attended the 15th (1977–1979) and 24th (1995–1998) examination cycles of the Original cohort or the 6th (1995–1998) and 8th cycles (2005–2008) of the Offspring cohort of the Framingham Heart Study (n=2,489).

Predictors

Single-nucleotide polymorphisms (SNPs) at 16 stage 3 CKD loci were genotyped and used to construct a genetic risk score. Standard clinical predictors of incident stage 3 CKD were also used.

Outcomes and Measurements

Incident stage 3 CKD was defined as eGFR <60 mL/min/1.73m2 at follow-up. Participants with baseline stage 3 CKD were excluded. Logistic regression was used to generate C statistics, which measured the power of the genetic risk score to discriminate risk of incident CKD stage 3 with and without traditional risk factors.

Results

There were 270 new stage 3 CKD cases during an average of 10.8 years follow-up. The mean (±SD) genetic risk score was 17.5±2.8 among those who developed stage 3 CKD and 17.3±2.6 among those who did not (P-value for genotype score difference=0.2). The odds ratio for stage 3 CKD was 1.06 (95% CI, 1.01–1.11; p=0.03) per additional risk allele, adjusting for age and sex. In the age and sex-adjusted model, the C statistic was 0.748 without the genotype score and 0.751 with the score (P-value for difference=0.3). The risk score was not statistically significant in a multivariable model adjusted for standard stage 3 CKD risk factors (p=0.07).

Limitations

Participants all of European ancestry; genotype score may not be valid in different ancestral groups.

Conclusions

A genetic score generated from 16 known CKD risk alleles did not predict new cases of stage 3 CKD in the community beyond knowledge of common, clinical risk factors alone.

Background

Main pulmonary artery diameter (mPA) and ratio of mPA to ascending aorta diameter (ratio PA) derived from chest CT are commonly reported in clinical practice. We determined the age and sex-specific distribution and normal reference values for mPA and ratio PA by CT in an asymptomatic community-based population.

Methods and Results

In 3171 men and women (mean age 51 ± 10 years, 51% men) from the Framingham Heart Study, a non-contrast ECG gated eight-slice cardiac multi-detector CT was performed. We measured the mPA and transverse axial diameter of the ascending aorta at the level of the bifurcation of the right pulmonary artery and calculated the ratio PA. We defined the healthy referent cohort (n=706) as those without obesity, hypertension, current and past smokers, chronic obstructive pulmonary disease, history of pulmonary embolism, diabetics, cardiovascular disease, and heart valvular surgery. The mean mPA diameter in the overall cohort was 25.1 ± 2.8mm and mean ratio PA was 0.77 ± 0.09. The sex-specific 90th percentile cutoff value for mPA diameter was 28.9 mm in men and 26.9 mm in women and was associated with increase risk for self-reported dyspnea (adjusted odds ratio 1.31, p=0.02). The 90th percentile cutoff value for ratio PA of the healthy referent group was 0.91, similar between gender, but decreased with increasing age (range 0.82 to 0.94), though not associated with dyspnea.

Conclusions

For simplicity, we established 29 mm in men and 27 mm in women as sex-specific normative reference values for mPA and 0.9 for ratio PA.

Background

Coronary artery calcification (CAC) detected by computed tomography is a non-invasive measure of coronary atherosclerosis, that underlies most cases of myocardial infarction (MI). We aimed to identify common genetic variants associated with CAC and further investigate their associations with MI.

Methods and Results

Computed tomography was used to assess quantity of CAC. A meta-analysis of genome-wide association studies for CAC was carried out in 9,961 men and women from five independent community-based cohorts, with replication in three additional independent cohorts (n=6,032). We examined the top single nucleotide polymorphisms (SNPs) associated with CAC quantity for association with MI in multiple large genome-wide association studies of MI. Genome-wide significant associations with CAC for SNPs on chromosome 9p21 near CDKN2A and CDKN2B (top SNP: rs1333049, P=7.58×10−19) and 6p24 (top SNP: rs9349379, within the PHACTR1 gene, P=2.65×10−11) replicated for CAC and for MI. Additionally, there is evidence for concordance of SNP associations with both CAC and with MI at a number of other loci, including 3q22 (MRAS gene), 13q34 (COL4A1/COL4A2 genes), and 1p13 (SORT1 gene).

Conclusions

SNPs in the 9p21 and PHACTR1 gene loci were strongly associated with CAC and MI, and there are suggestive associations with both CAC and MI of SNPs in additional loci. Multiple genetic loci are associated with development of both underlying coronary atherosclerosis and clinical events.

Imputation has been widely used in genome-wide association studies (GWAS) to infer genotypes of un-genotyped variants based on the linkage disequilibrium in external reference panels such as the HapMap and 1000 Genomes. However, imputation has only rarely been performed based on family relationships to infer genotypes of un-genotyped individuals. Using 8998 Framingham Heart Study (FHS) participants genotyped with Affymetrix 550K SNPs, we imputed genotypes of same set of SNPs for additional 3121 participants, most of whom were never genotyped due to lack of DNA sample. Prior to imputation, 122 pedigrees were too large to be handled by the imputation software Merlin. Therefore, we developed a novel pedigree splitting algorithm that can maximize the number of genotyped relatives for imputing each un-genotyped individual, while keeping new sub-pedigrees under a pre-specified size. In GWAS of four phenotypes available in FHS (Alzheimer disease, circulating levels of fibrinogen, high-density lipoprotein cholesterol, and uric acid), we compared results using genotyped individuals only with results using both genotyped and imputed individuals. We studied the impact of applying different imputation quality filtering thresholds on the association results and did not found a universal threshold that always resulted in a more significant p-value for previously identified loci. However most of these loci had a lower p-value when we only included imputed genotypes with with ≥60% SNP- and ≥50% person-specific imputation certainty. In summary, we developed a novel algorithm for splitting large pedigrees for imputation and found a plausible imputation quality filtering threshold based on FHS. Further examination may be required to generalize this threshold to other studies.

Background

Thoracic periaortic adipose tissue (TAT) is associated with atherosclerosis and cardiovascular disease (CVD) risk factors and may play a role in obesity‐mediated vascular disease. We sought to determine the prevalence, distribution, and risk factor correlates of high TAT.

Methods and Results

Participants from the Framingham Heart Study (n=3246, 48% women, mean age 51.1 years) underwent multidetector computed tomography; high TAT and visceral adipose tissue (VAT) were defined on the basis of sex‐specific 90th percentiles in a healthy referent sample. The prevalence of high TAT was 38.1% in women and 35.7% in men. Among individuals without high VAT, 10.1% had high TAT. After adjustment for age and VAT, both women and men with high TAT in the absence of high VAT were older and had a higher prevalence of CVD (P<0.0001) compared with those without high TAT. In addition, men in this group were more likely to be smokers (P=0.02), whereas women were more likely to have low high‐density lipoprotein cholesterol (P=0.005).

Conclusions

Individuals in our community‐based sample with high TAT in the absence of high VAT were characterized by an adverse cardiometabolic profile. This adipose tissue phenotype may identify a subset of individuals with distinct metabolic characteristics.

Background

Periaortic fat, because of its contiguity with the aorta, may promote vascular remodeling and aortic dilatation. However, the relations between perioartic fat depots and aortic dimensions have not been previously described.

Methods and Results

A total of 3001 individuals (mean age 50±10 years, 49% women) from the Framingham Offspring and Third Generation cohorts underwent computed tomography for quantification of periaortic fat and aortic dimensions. We estimated the association between quantitative periaortic and visceral adipose tissue volumes (per standard deviation [SD] increment of volume) with aortic dimensions in both the thorax and abdomen. Thoracic periaortic fat was associated with higher thoracic aortic dimensions (β coefficient per SD of fat volume 0.67 mm, 95% confidence interval 0.58 to 0.76 mm; P<0.001). The association persisted after adjustment for age, sex, and cardiovascular risk factors including body mass index and visceral adipose tissue volume. Results for the association of periaortic fat and abdominal aortic dimensions were similar. Further adjustment for adipokines (resistin and adiponectin) had no significant impact on these associations.

Conclusions

Periaortic fat volume was associated with aortic dimensions in both the thorax and abdomen, supporting the notion that local fat depots may contribute to aortic remodeling. Further work to understand the mechanisms underlying this association is warranted.

Genome-wide association studies (GWAS) have been frequently conducted on general or isolated populations with related individuals. However, there is a lack of consensus on which strategy is most appropriate for analyzing dichotomous phenotypes in general pedigrees. Using simulation studies, we compared several strategies including generalized estimating equations (GEE) strategies with various working correlation structures, generalized linear mixed model (GLMM) and a variance component strategy (denoted LMEBIN) that treats dichotomous outcomes as continuous with special attentions to their performance with rare variants, rare diseases and small sample sizes. In our simulations, when the sample size is not small, for type I error, only GEE and LMEBIN maintain nominal type I error in most cases with exceptions for GEE with very rare disease and genetic variants. GEE and LMEBIN have similar statistical power and slightly outperform GLMM when the prevalence is low. In terms of computational efficiency, GEE with sandwich variance estimator outperforms GLMM and LMEBIN. We apply the strategies to GWAS of gout in the Framingham Heart Study. Based on our results, we would recommend using GEE ind-san in the GWAS for common variants and GEE ind-fij or LMEBIN for rare variants for GWAS of dichotomous outcomes with general pedigrees.

Objective

Pericoronary adipose tissue (PCAT) may create a pro-inflammatory state, contributing to the development of coronary artery disease (CAD). We sought to evaluate the feasibility of avolumetric PCAT quantification method using a novel threshold based computed tomography approach. In addition we determined the relation between PCAT volumes and CAD.

Methods

In 51 patients (49.5±5.1 years, 64.8% male) who underwent 64-slice MDCT, we measured threshold-based PCAT volumes using distance and anatomic-based methods. Using the most reproducible method, we performed the proximal 40-mm distance measurement in three groups as stratified by coronary plaque and high-sensitivity C-reactive protein (hs-CRP) levels: Group 1 (presence of coronary plaque, hs-CRP >2.0 mg/L); an intermediate group (Group 2, no plaque, hs-CRP >2.0 mg/L); and Group 3 (no plaque, hs-CRP<1.0 mg/L). We compared PCAT volumes to the presence of coronary plaque on a patient (n=51) and vessel (n=153) basis. On a subsegment basis (n=1224), we compared PCAT volume to the presence of plaque as well as plaque morphology.

Results

Distance-based PCAT volume measurements yielded excellent reproducibility with intra-observer intraclass correlation (ICC) of 0.997 and inter-observer ICC of 0.951. On a both a per-patient and per-vessel analysis, adjusted PCAT volume was greater in patients with plaque (Group 1) than without plaque (Group 2 and 3, p<0.001). No difference in PCAT volume was seen between high and low hs-CRP groups without plaque (p=0.51). Adjusted PCAT volumes were higher in subsegments with plaque as compared without (p<0.001). Additionally, adjusted PCAT volume was greatest in subsegments with mixed plaque followed by non-calcified plaque, calcified plaque, and the lowest volume in segments with no plaque (p<0.001).

Conclusion

In this proof-of-concept study, threshold based PCAT volume assessment is feasible and highly reproducible. PCAT volume is increased in patients and vessels with coronary plaques. Surrounding vessel subsegments with coronary plaque, particularly mixed plaques, have greatest PCAT volume and highlight the effect of local PCAT in the development of coronary atherosclerosis.

Ectopic fat depots may mediate local and systemic disease. Animal models of diet-induced obesity demonstrate increased fat accumulation in the renal sinus. The association of renal sinus fat with hypertension, chronic kidney disease (CKD), and other metabolic disorders has not been studied in a large, community-based sample. Participants from the Framingham Heart Study (n=2923, mean age 54 years, 51% women) underwent quantification of renal sinus fat area using computed tomography. High renal sinus fat (“fatty kidney”) was defined using sex-specific 90th percentiles in a healthy referent sub-sample. Multivariable linear and logistic regression was used to model metabolic risk factors as a function of fatty kidney and log-transformed renal sinus fat. Multivariable models were adjusted for age, sex, outcome-specific covariates, and then additionally adjusted for body mass index (BMI) or abdominal visceral adipose tissue (VAT). The prevalence of fatty kidney was 30.1% (n=879). Individuals with fatty kidney had a higher odds ratio (OR) of hypertension (OR 2.12, p<0.0001), which persisted after adjustment for BMI (OR 1.49, p<0.0001) and VAT (OR 1.24, p=0.049). Fatty kidney was also associated with an increased odds ratio for CKD (OR 2.30, p=0.005), even after additionally adjusting for BMI (OR 1.86, p=0.04) or VAT (OR 1.86, p=0.05). We observed no association between fatty kidney and diabetes after adjusting for VAT. In conclusion, fatty kidney is a common condition that is associated with an increased risk of hypertension and chronic kidney disease. Renal sinus fat may play a role in blood pressure regulation and CKD.

Objective

To examine whether fatty liver, and abdominal visceral adipose tissue (VAT) are jointly associated with cardiometabolic abnormalities.

Methods and Results

African American participants were from the Jackson Heart Study (n=2882, 65% women) who underwent computed tomography. Fatty liver was measured by liver attenuation in Hounsfield Units (LA) and VAT was quantified volumetrically. Cross-sectional associations between LA, VAT, and cardiometabolic risk factors were assessed using linear and logistic regression, and their joint associations were further examined in 4 subgroups - (High-LA/Low-VAT [n=1704], Low-LA/Low-VAT [n=422], High-LA/High-VAT [n=436] and Low-LA/High-VAT [n=320]). Both LA and VAT were associated with most cardiometabolic traits (all p<0.0001), which persisted after additional adjustment for each other (LA, p < 0.01-0.0001 and VAT, p<0.0001). In bootstrap analyses, the regression coefficient of VAT was significantly greater than LA for triglycerides, HDL-C, impaired glucose and metabolic syndrome (MetS) (p range 0.009-0.0001). The interaction between LA and VAT was significant for HDL-C (p=0.002), impaired glucose (p=0.003) and MetS (p=0.04). Among 4 subgroups, participants with higher VAT and lower LA had higher prevalence of cardiometabolic traits than those with each condition alone.

Conclusion

Both fatty liver and VAT are independent correlates of cardiometabolic risk, but the associations are stronger for VAT than for fatty liver.

Serum urate concentrations are highly heritable and elevated serum urate is a key risk factor for gout. Genome-wide association studies (GWAS) of serum urate in African American (AA) populations are lacking. We conducted a meta-analysis of GWAS of serum urate levels and gout among 5820 AA and a large candidate gene study among 6890 AA and 21 708 participants of European ancestry (EA) within the Candidate Gene Association Resource Consortium. Findings were tested for replication among 1996 independent AA individuals, and evaluated for their association among 28 283 EA participants of the CHARGE Consortium. Functional studies were conducted using 14C-urate transport assays in mammalian Chinese hamster ovary cells. In the discovery GWAS of serum urate, three loci achieved genome-wide significance (P< 5.0 × 10−8): a novel locus near SGK1/SLC2A12 on chromosome 6 (rs9321453, P= 1.0 × 10−9), and two loci previously identified in EA participants, SLC2A9 (P= 3.8 × 10−32) and SLC22A12 (P= 2.1 × 10−10). A novel rare non-synonymous variant of large effect size in SLC22A12, rs12800450 (minor allele frequency 0.01, G65W), was identified and replicated (beta −1.19 mg/dl, P= 2.7 × 10−16). 14C-urate transport assays showed reduced urate transport for the G65W URAT1 mutant. Finally, in analyses of 11 loci previously associated with serum urate in EA individuals, 10 of 11 lead single-nucleotide polymorphisms showed direction-consistent association with urate among AA. In summary, we identified and replicated one novel locus in association with serum urate levels and experimentally characterize the novel G65W variant in URAT1 as a functional allele. Our data support the importance of multi-ethnic GWAS in the identification of novel risk loci as well as functional variants.

Background

Early detection of individuals at high risk for chronic kidney disease (CKD) may aid prevention. Urinary levels of trefoil factor 3 (TFF3) are associated with acute kidney injury in animal models, but the association of TFF3 levels with incident CKD in humans is unknown.

Methods

We conducted a case-control study nested within the Atherosclerosis Risk in Communities (ARIC) Study and the ARIC Carotid MRI Study to determine whether urinary TFF3 levels predict incident CKD over 8.6 years of follow-up. A total of 143 participants with incident CKD (eGFR decreasing by ≥25% to <60 ml/min/1.73 m2) were matched on age, sex and race to 143 non-cases.

Results

Higher TFF3 levels at baseline were strongly associated with Black race, diabetes (both p = 0.002), and antihypertensive medication use (p = 0.02). Compared to participants with TFF3 levels in the lowest quartile, the odds ratio (OR) of incident CKD was 1.84 (95% confidence interval (CI): 0.80, 4.22) for individuals with TFF3 levels in the second quartile, 2.43 (95% CI: 1.06, 5.53) for the third quartile, and 2.77 (95% CI: 1.22, 6.28) for the fourth quartile (p trend = 0.02). Adjustment for covariates, including urinary albumin: creatinine ratio, did not markedly change the associations. Twofold higher TFF3 levels were strongly associated with incident CKD after adjustment for CKD risk factors (adjusted OR = 1.35; 95% CI: 1.11, 1.64).

Conclusions

Higher urinary TFF3 levels may indicate ongoing repair of damage in the kidney. Additional studies are needed to confirm whether TFF3 can be useful as a marker of increased risk for CKD.

Natriuretic peptides have important roles in the regulation of vasomotor tone, salt homeostasis, and ventricular remodeling. Lower natriuretic peptide levels observed in obese individuals may underlie the greater cardiovascular risk associated with obesity. Thus, the aim of this study was to determine whether lower natriuretic peptide levels in obesity are attributable to differences in regional fat distribution. We investigated the relationship of plasma N-terminal pro-B-type natriuretic peptide (N-BNP) with regional adiposity in 1,873 community-based individuals (46% women; mean age 45 years). Subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) volumes were measured by multi-detector computed tomography. In sex-specific, multivariable analyses adjusting for age and blood pressure, log N-BNP was inversely associated with VAT in both men (β −0.11, P<0.001) and women (β −0.19, P<0.001). Log N-BNP was inversely associated with SAT in women only (β −0.14, P<0.001). In models containing both VAT and SAT, only VAT was significantly associated with log N-BNP (men, β −0.137, P<0.001; women, β −0.184, P<0.001). VAT remained associated with log N-BNP even after adjustment for body mass index and waist circumference (β −0.119, P<0.001), and in analyses restricted to non-obese individuals (β −0.114; P<0.001). Adjustment for insulin resistance attenuated the associations of N-BNP with both VAT and SAT. In conclusion, this study demonstrates that circulating N-BNP is related to variation in regional and particularly visceral adiposity. These findings suggest that excess visceral adiposity and concomitant hyperinsulinemia may contribute to the natriuretic peptide “deficiency” observed in obesity.

OBJECTIVE

Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology.

RESEARCH DESIGN AND METHODS

We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates.

RESULTS

Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10−8). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10−4), improved β-cell function (P = 1.1 × 10−5), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10−6). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets.

CONCLUSIONS

We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis.

OBJECTIVE

Many genetic variants have been associated with glucose homeostasis and type 2 diabetes in genome-wide association studies. Zinc is an essential micronutrient that is important for β-cell function and glucose homeostasis. We tested the hypothesis that zinc intake could influence the glucose-raising effect of specific variants.

RESEARCH DESIGN AND METHODS

We conducted a 14-cohort meta-analysis to assess the interaction of 20 genetic variants known to be related to glycemic traits and zinc metabolism with dietary zinc intake (food sources) and a 5-cohort meta-analysis to assess the interaction with total zinc intake (food sources and supplements) on fasting glucose levels among individuals of European ancestry without diabetes.

RESULTS

We observed a significant association of total zinc intake with lower fasting glucose levels (β-coefficient ± SE per 1 mg/day of zinc intake: −0.0012 ± 0.0003 mmol/L, summary P value = 0.0003), while the association of dietary zinc intake was not significant. We identified a nominally significant interaction between total zinc intake and the SLC30A8 rs11558471 variant on fasting glucose levels (β-coefficient ± SE per A allele for 1 mg/day of greater total zinc intake: −0.0017 ± 0.0006 mmol/L, summary interaction P value = 0.005); this result suggests a stronger inverse association between total zinc intake and fasting glucose in individuals carrying the glucose-raising A allele compared with individuals who do not carry it. None of the other interaction tests were statistically significant.

CONCLUSIONS

Our results suggest that higher total zinc intake may attenuate the glucose-raising effect of the rs11558471 SLC30A8 (zinc transporter) variant. Our findings also support evidence for the association of higher total zinc intake with lower fasting glucose levels.

Background. Elevations in serum phosphorus are associated with renal decline in animal models and progression of established chronic kidney disease (CKD) in human observational studies. We examined whether serum phosphorus levels increase the risk of incident CKD or end-stage renal disease (ESRD) in two population-based prospective cohort studies.

Methods. Overall, 2269 participants free of CKD [estimated glomerular filtration rate (eGFR) <60 mL/min/1.732] from the Framingham Heart Study (FHS; mean age 42 years; 53% women) and 13 372 participants from the Third National Health and Nutrition Examination Survey (NHANES III; mean age 44.3 years, 52% women) contributed to the present study. In the FHS, we evaluated the relationship between baseline phosphorus category (<2.5 mg/dL, 2.5–3.49 mg/dL, 3.5–3.99 mg/dL and ≥4 mg/dL) and incident CKD (n = 267). In NHANES, we examined the relationship between phosphorus below and above 4 mg/dL in relation to incident ESRD (n = 65).

Results. FHS participants in the highest phosphorus category had an increased risk of CKD [odds ratio 2.14; 95% confidence interval (CI), 1.07–4.28; P = 0.03] in multivariable-adjusted models when compared to the referent group (2.5–3.49 mg/dL). Similarly, NHANES III participants with phosphorus levels ≥4 mg/dL demonstrated an increased risk of incident ESRD compared to those <4 mg/dL (relative risk 1.90; 95% CI 1.03–3.53; P = 0.04).

Conclusions. In prospective studies of the general population, serum phosphorus levels in the upper-normal range were associated with a doubling in the risk of developing incident CKD and ESRD.

OBJECTIVE

Diabetic and prediabtic states, including insulin resistance, fasting hyperglycemia, and hyperinsulinemia, are associated with metabolic dysregulation. These components have been individually linked to increased risks of cognitive decline and Alzheimer’s disease. We aimed to comprehensively relate all of the components of metabolic dysregulation to cognitive function and brain magnetic resonance imaging (MRI) in middle-aged adults.

RESEARCH DESIGN AND METHODS

Framingham Offspring participants who underwent volumetric MRI and detailed cognitive testing and were free of clinical stroke and dementia during examination 7 (1998–2001) constituted our study sample (n = 2,439; 1,311 women; age 61 ± 9 years). We related diabetes, homeostasis model assessment of insulin resistance (HOMA-IR), fasting insulin, and glycohemoglobin levels to cross-sectional MRI measures of total cerebral brain volume (TCBV) and hippocampal volume and to verbal and visuospatial memory and executive function. We serially adjusted for age, sex, and education alone (model A), additionally for other vascular risk factors (model B), and finally, with the inclusion of apolipoprotein E-ε4, plasma homocysteine, C-reactive protein, and interleukin-6 (model C).

RESULTS

We observed an inverse association between all indices of metabolic dysfunction and TCBV in all models (P < 0.030). The observed difference in TCBV between participants with and without diabetes was equivalent to approximately 6 years of chronologic aging. Diabetes and elevated glycohemoglobin, HOMA-IR, and fasting insulin were related to poorer executive function scores (P < 0.038), whereas only HOMA-IR and fasting insulin were inversely related to visuospatial memory (P < 0.007).

CONCLUSIONS

Metabolic dysregulation, especially insulin resistance, was associated with lower brain volumes and executive function in a large, relatively healthy, middle-aged, community-based cohort.

Objective

Parental history of diabetes and specific gene variants are risk factors for type 2 diabetes, but the extent to which these factors are associated is unknown.

Methods

We examined the association between parental history of diabetes and a type 2 diabetes genetic risk score (GRS) in two cohort studies from Finland (population-based PPP-Botnia Study) and the US (family-based Framingham Offspring Study).

Results

Mean (95% CI) GRS increased from 16.8 (16.8–16.9) to 16.9 (16.8–17.1) to 17.1 (16.8–17.4) among PPP-Botnia participants with 0, 1, and 2 parents with diabetes, respectively (ptrend=0.03). The trend was similar among Framingham Offspring but was not statistically significant (p=0.07). The meta-analyzed p value for trend from the two studies was 0.005.

Conclusions

The very modest associations reported above suggest that the increased risk of diabetes in offspring of parents with diabetes is largely the result of shared environmental/lifestyle factors and/or hitherto unknown genetic factors.