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1.  Theoretical foundations of the Study of Latino (SOL) Youth: implications for obesity and cardiometabolic risk 
Annals of epidemiology  2013;24(1):10.1016/j.annepidem.2013.10.011.
This article describes the conceptual model developed for the Hispanic Community Health Study/Study of Latino Youth, a multisite epidemiologic study of obesity and cardiometabolic risk among U.S. Hispanic/Latino children.
Public health, psychology, and sociology research were examined for relevant theories and paradigms. This research, in turn, led us to consider several study design features to best represent both risk and protective factors from multiple levels of influence, as well as the identification of culturally relevant scales to capture identified constructs.
The Socio-Ecological Framework, Social Cognitive Theory, family systems theory, and acculturation research informed the specification of our conceptual model. Data are being collected from both children and parents in the household to examine the bidirectional influence of children and their parents, including the potential contribution of intergenerational differences in acculturation as a risk factor. Children and parents are reporting on individual, interpersonal, and perceived organizational and community influences on children's risk for obesity consistent with Socio-Ecological Framework.
Much research has been conducted on obesity, yet conceptual models examining risk and protective factors lack specificity in several areas. Study of Latino Youth is designed to fill a gap in this research and inform future efforts.
PMCID: PMC3879411  PMID: 24246265
Hispanic/Latino; Children; Obesity; Acculturation; Socio-Ecological Framework; Theory
2.  Cystatin C enhances GFR estimating Equations in Kidney Transplant Recipients 
American journal of nephrology  2014;39(1):59-65.
The glomerular filtration rate (GFR) estimating equation incorporating both cystatin C and creatinine perform better than those using creatinine or cystatin C alone in patients with reduced GFR. Whether this equation performs well in kidney transplant recipients cross-sectionally, and more importantly, over time has not been addressed.
We analyzed four GFR estimating equations in participants of the Angiotensin II Blockade for Chronic Allograft Nephropathy Trial (NCT 00067990): Chronic Kidney Disease Epidemiology Collaboration equations based on serum cystatin C and creatinine (eGFR (CKD-EPI-Creat+CysC)), cystatin C alone (eGFR (CKD-EPI-CysC)), creatinine alone (eGFR (CKD-EPI-Creat)) and the Modification of Diet in Renal Disease study equation (eGFR(MDRD)). Iothalamate GFR served as a standard (mGFR).
mGFR, serum creatinine, and cystatin C shortly after transplant were 56.1 ± 17.0 mL/min/1.73 m2, 1.2 ± 0.4 mg/dL, and 1.2 ± 0.3 mg/L respectively. eGFR (CKD-EPI-Creat+CysC) was most precise (R2=0.50) but slightly more biased than eGFR (MDRD); 9.0 ± 12.7 ml/min/1.73m2 vs. 6.4 ± 15.8 ml/min/1.73m2, respectively. This improved precision was most evident in recipients with mGFR >60 ml/min/1.73m2. For relative accuracy, eGFR (MDRD) and eGFR (CKD-EPI-Creat+CysC) had the highest percentage of estimates falling within 30% of mGFR; 75.8% and 68.9%, respectively. Longitudinally, equations incorporating cystatin C most closely paralleled the change in mGFR.
eGFR (CKD-EPI-Creat+CysC) is more precise and reflects GFR change over time reasonably well. eGFR (MDRD) had superior performance in recipients with mGFR between 30–60 ml/min/1.73m2.
PMCID: PMC4026030  PMID: 24457184
Glomerular filtration rate; Chronic Kidney Disease Epidemiology Collaboration; Modification of Diet in Renal Disease; cystatin C; kidney transplantation
3.  Association of Low-Grade Albuminuria with Adverse Cardiac Mechanics: Findings from the HyperGEN Study 
Circulation  2013;129(1):42-50.
Albuminuria is a marker of endothelial dysfunction and has been associated with adverse cardiovascular outcomes. The reasons for this association are unclear, but may be due to the relationship between endothelial dysfunction and intrinsic myocardial dysfunction.
Methods and Results
In the HyperGEN study, a population- and family-based study of hypertension, we examined the relationship between urine albumin-to-creatinine ratio (UACR) and cardiac mechanics (N=1894, all of whom had normal left ventricular ejection fraction and wall motion). We performed speckle-tracking echocardiographic analysis to quantify global longitudinal, circumferential, and radial strain (GLS, GCS, and GRS, respectively), and early diastolic (e′) tissue velocities. We used E/e′ ratio as a marker of increased LV filling pressures. We used multivariable-adjusted linear mixed effect models to determine independent associations between UACR and cardiac mechanics. The mean age was 50±14 years, 59% were female, and 46% were African-American. Comorbidities were increasingly prevalent among higher UACR quartiles. Albuminuria was associated with GLS, GCS, GRS, e′ velocity, and E/e′ ratio on unadjusted analyses. After adjustment for covariates, UACR was independently associated with lower absolute GLS (multivariable-adjusted mean GLS [95% CI] for UACR Quartile 1 = 15.3 [15.0–15.5]% vs. UACR Q4 = 14.6 [14.3–14.9]%, P for trend <0.001) and increased E/e′ ratio (Q1 = 25.3 [23.5–27.1] vs. Q4 = 29.0 [27.0–31.0], P= 0.003). The association between UACR and GLS was present even in participants with UACR < 30 mg/g (P<0.001 after multivariable adjustment).
Albuminuria, even at low levels, is associated with adverse cardiac mechanics and higher E/e′ ratio.
PMCID: PMC3888488  PMID: 24077169
albuminuria; cardiac mechanics; strain; echocardiography
4.  The effects of angiotensinogen gene polymorphisms on cardiovascular disease outcomes during antihypertensive treatment in the GenHAT study 
Previous studies have reported that risk of cardiovascular morbidity and mortality substantially increases in hypertensive patients, especially among those with inadequate blood pressure control. Two common antihypertensive drug classes including thiazide diuretics and angiotensin-converting enzyme (ACE) inhibitors affect different enzymes in the renin-angiotensin-aldosterone system (RAAS). In the RAAS, angiotensinogen is converted into angiotensin II which increases blood pressure through vasoconstriction. Using a case-only design with 3448 high-risk hypertensive individuals from the Genetics of Hypertension Associated Treatment (GenHAT) study, we examined whether seven single nucleotide polymorphisms (SNPs) in the angiotensinogen gene (AGT) interact with three classes of antihypertensive drugs including chlorthalidone (a thiazide diuretic), lisinopril (an ACE inhibitor), and amlodipine (a calcium channel blocker) to modify the risk of incident coronary heart disease (CHD) and heart failure (HF) among Caucasian and African American participants, separately. We found no gene by treatment interactions to be statistically significant after correction for multiple testing. However, some suggestive results were found. African American participants with the minor allele of rs11122576 had over two-fold higher risk of CHD when using chlorthalidone compared to using amlodipine, or lisinopril compared to amlodipine (p = 0.006 and p = 0.01, respectively). Other marginal associations are also reported among both race groups. The findings reported here suggest that rs11122576 could contribute to future personalization of antihypertensive treatment among African Americans though more studies are needed.
PMCID: PMC4165277  PMID: 25278896
AGT gene; antihypertensive drugs; hypertension; coronary heart disease; heart failure
5.  Trends in the Prevalence of Reduced GFR in the United States: A Comparison of Creatinine- and Cystatin C-Based Estimates 
The US prevalence of reduced estimated glomerular filtration rate (eGFR) based on serum creatinine increased over the decade ending in 2002. National Health and Nutrition Examination Survey (NHANES) cystatin C measurements were recently calibrated to the international standard, allowing for an independent test of the trend in prevalence of reduced eGFR using cystatin C.
Study Design
Cross-sectional surveys performed during two periods.
Setting & Participants
Nationally representative subsamples of adult participants from NHANES III (1988–1994) and the NHANES 1999–2002 surveys.
Survey period.
Prevalence of reduced GFR, defined as eGFR<60ml/min/1.73m2 based on serum creatinine, cystatin C, or both (eGFRcr, eGFRcys, eGFRcr-cys), using estimating equations developed by the Chronic Kidney Disease Epidemiology Collaboration (CKDEPI).
Serum cystatin C, measured from stored samples in 2006, calibrated to the international standard in 2012.
Between 1988–1994 and 1999–2002, the prevalence of reduced eGFRcr, eGFRcys and eGFRcr-cys increased from 4.7% (95% CI, 4.1%–5.3%) to 6.5% (95% CI, 5.9%–7.1%; p<0.001), from 5.5% (95% CI, 4.6%–6.5%) to 8.7% (95% CI, 7.5%–10.0%; p<0.001), and from 4.4% (95% CI, 3.7%–5.2%) to 7.1% (95% CI, 6.2%–8.0%; p<0.001), respectively. The higher prevalence of reduced GFR in the later period was observed in all subgroups of age, race, sex, and GFR categories. After adjusting for changes in the US population by age, sex, race, diabetes, hypertension, and body mass index, the prevalence ratio of reduced GFR in the later versus earlier survey was 1.24 (95% CI, 1.09–1.45), 1.34 (95% CI, 1.15–1.67), and 1.33 (95% CI, 1.17–1.65) using eGFRcr, eGFRcys, and eGFRcr-cys, respectively.
Likely under-ascertainment of persons with GFR<15 ml/min/1.73m2; GFR was estimated and not measured; comparability of laboratory assays based on a calibration subsample.
The prevalence of reduced eGFRcys in the US civilian, non-institutionalized population increased between 1988–1994 and 1999–2002, confirming the increase observed in the prevalence of reduced eGFRcr.
PMCID: PMC3723746  PMID: 23619125
cystatin C; chronic kidney disease; estimating equations; prevalence
6.  Association Between Celiac Disease and Iron Deficiency in Caucasians, but not Non-Caucasians 
Background & Aims
Celiac disease is an increasingly recognized disorder in Caucasian populations of European origin. Little is known about its prevalence in non-Caucasians. Although it is thought to be a cause of iron deficiency anemia, little is known about the extent to which celiac disease contributes to iron deficiency in Caucasians, and especially non-Caucasians. We analyzed samples collected from participants in the Hemochromatosis and Iron Overload Screening (HEIRS) study to identify individuals with iron deficiency and assess the frequency of celiac disease.
We analyzed serum samples from white men (25 y old or older) and women (50 y old or older) who participated the HEIRS study; cases were defined as individuals with iron deficiency (serum level of ferritin ≤12 mg/L) and controls were those without (serum level of ferritin >100 mg/L in men and >50 mg/L in women). All samples were also analyzed for human recombinant tissue transglutaminase immunoglobulin A; positive results were confirmed by an assay for endomysial antibodies. Patients with positive results from both celiac disease tests were presumed to have untreated celiac disease, and those with a positive result from only 1 test were excluded from analysis. We analyzed HLA genotypes and frequencies of celiac disease between Caucasians and non-Caucasians with iron deficiency.
Celiac disease occurred in 14 of 567 of cases (2.5%) and in only 1 of 1136 controls (0.1%; Fisher’s exact test, P=1.92 × 10−6). Celiac disease was more common in Caucasian cases (14/363, 4%) than non-Caucasian cases (0/204; P=.003). Only 1 Caucasian control and no non-Caucasian controls had celiac disease. The odds of celiac disease in individuals with iron deficiency was 28-fold (95% confidence interval, 3.7–212.8) that of controls; 13/14 cases with celiac disease carried the DQ2.5 variant of the HLA genotype.
Celiac disease is associated with iron deficiency of Caucasians. Celiac disease is rare among non-Caucasians—even among individuals with features of celiac disease, such as iron deficiency. Celiac disease is also rare among individuals without iron deficiency. Men and post-menopausal women with iron deficiency should be tested for celiac disease.
PMCID: PMC3843318  PMID: 23416278
SNP; risk factor; gluten allergy; intestine; absorption
7.  HFE mutations in Caucasian participants of the Hemochromatosis and Iron Overload Screening study with serum ferritin level <1000 μg/L 
Many patients referred for an elevated serum ferritin level <1000 μg/L are advised that they likely have iron overload and hemochromatosis.
To determine the prevalence of HFE mutations in the hemochromatosis gene for 11 serum ferritin concentration intervals from 200 μg/L to 1000 μg/L in Caucasian participants in a primary care, population-based study.
The Hemochromatosis and Iron Overload Screening study screened 99,711 participants for serum ferritin levels, transferrin saturation and genetic testing for the C282Y and H63D mutations of the HFE gene. This analysis was confined to 17,160 male and 27,465 female Caucasian participants because the HFE C282Y mutation is rare in other races. Post-test likelihood was calculated for prediction of C282Y homozygosity from a ferritin interval. A subgroup analysis was performed in participants with both an elevated serum ferritin level and transferrin saturation.
There were 3359 male and 2416 female participants with an elevated serum ferritin level (200 μg/L to 1000 μg/L for women, 300 μg/L to 1000 μg/L for men). There were 69 male (2.1%) and 87 female (3.6%) C282Y homozygotes, and the probability of being a homozygote increased as the ferritin level increased. Post-test likelihood values were 0.3% to 16% in men and 0.3% to 30.4% in women.
Iron loading HFE mutations are unlikely to be the most common cause of an elevated serum ferritin level in patients with mild hyperferritinemia. Patients should be advised that there are many causes of an elevated serum ferritin level including iron overload.
PMCID: PMC3956024  PMID: 23862168
Ferritin; Haemochromatosis; Hemochromatosis; Iron overload
8.  Fibroblast Growth Factor‐23 and Incident Coronary Heart Disease, Heart Failure, and Cardiovascular Mortality: The Atherosclerosis Risk In Communities Study 
Fibroblast growth factor‐23 (FGF‐23) is a hormone involved in phosphorous regulation and vitamin D metabolism that may be associated with cardiovascular risk, and it is a potential target for intervention. We tested whether elevated FGF‐23 is associated with incident coronary heart disease, heart failure, and cardiovascular mortality, even at normal kidney function.
Methods and Results
A total of 11 638 Atherosclerosis Risk In Communities study participants, median age 57 at baseline (1990–1992), were followed through 2010. Cox regression was used to evaluate the independent association of baseline serum active FGF‐23 with incident outcomes. Models were adjusted for traditional cardiovascular risk factors and estimated glomerular filtration rate. During a median follow‐up of 18.6 years, 1125 participants developed coronary heart disease, 1515 developed heart failure, and 802 died of cardiovascular causes. For all 3 outcomes, there was a threshold, whereby FGF‐23 was not associated with risk at <40 pg/mL but was positively associated with risk at >40 pg/mL. Compared with those with FGF‐23 <40 pg/mL, those in the highest FGF‐23 category (≥58.8 pg/mL) had a higher risk of incident coronary heart disease (adjusted hazard ratio, 95% CIs: 1.65, 1.40 to 1.94), heart failure (1.75, 1.52 to 2.01), and cardiovascular mortality (1.65, 1.36 to 2.01). Associations were modestly attenuated but remained statistically significant after further adjustment for estimated glomerular filtration rate. In stratified analyses, similar results were observed in African Americans and among persons with normal kidney function.
High levels of serum FGF‐23 were associated with increased risk of coronary heart disease, heart failure, and cardiovascular mortality in this large, biracial, population‐based cohort. This association was independent of traditional cardiovascular risk factors and kidney function.
PMCID: PMC4309096  PMID: 24922628
Atherosclerosis Risk In Communities; cardiovascular mortality; coronary heart disease; epidemiology; fibroblast growth factor 23; heart failure
9.  RYR3 gene polymorphisms and cardiovascular disease outcomes in the context of antihypertensive treatment 
The pharmacogenomics journal  2012;13(4):330-334.
Nearly one-third of adults in the U.S. have hypertension, which is associated with increased cardiovascular disease (CVD) morbidity and mortality. The goal of antihypertensive pharmacogenetic research is to enhance understanding of drug response based on the interaction of individual genetic architecture and antihypertensive therapy to improve blood pressure control and ultimately prevent CVD outcomes. In the context of the Genetics of Hypertension Associated Treatment (GenHAT) study and using a case-only design, we examined whether single nucleotide polymorphisms in RYR3 interact with four classes of antihypertensive drugs, particularly the calcium channel blocker amlodipine versus other classes, to modify the risk of coronary heart disease (CHD; fatal CHD and non-fatal myocardial infarction combined) and heart failure in high-risk hypertensive individuals. RYR3 mediates the mobilization of stored Ca+2 in cardiac and skeletal muscle to initiate muscle contraction. There was suggestive evidence of pharmacogenetic effects on heart failure, the strongest of which was for rs877087, with the smallest p-value =.0005 for the codominant model when comparing amlodipine versus all other treatments. There were no pharmacogenetic effects observed for CHD. The findings reported here for the case-only analysis of the antihypertensive pharmacogenetic effect of RYR3 among 3,058 CHD cases and 1,940 heart failure cases show that a hypertensive patient’s genetic profile may help predict which medication(s) might better lower cardiovascular disease risk.
PMCID: PMC3435442  PMID: 22664477
RYR3 gene; calcium channel blocker; hypertension; coronary heart disease; heart failure; genetic interaction
10.  Estimated plasma Stearoyl Co-A Desaturase-1 activity and risk of incident diabetes: the Atherosclerosis Risk in Communities (ARIC) study 
Evidence from pre-clinical studies suggests inhibition of Stearoyl Co-A Desaturase-1 (SCD-1) activity improves insulin sensitivity. Translation of these findings to humans remains less defined. The purpose of this research was to evaluate the association between different measures of SCD-1 activity and incident diabetes in a large, prospective human study.
In 2738 white participants (aged 45-64 yrs, 47% men) who were free of diabetes at baseline, SCD-1 activity was estimated at baseline by plasma fatty acid ratios in cholesterol esters (SCD16c=16:1n-7/16:0, SCD18c =18:1n-9/18:0) and in phospholipids (SCD16p=16:1n-7/16:0, SCD18p=18:1n-9/18:0). Incident diabetes was ascertained during 3 follow-up visits. Cox proportional hazards regression was used to determine the association between estimated SCD-1 activity and incident diabetes.
During follow-up (mean 8.0 ± SE 2.1 years), 207 (7.6%) participants developed diabetes. After adjusting for age and sex, higher SCD16c, higher SCD16p, and lower SCD18p were significantly associated with incident diabetes. After additional adjustment for education, parental history of diabetes, smoking, dietary intake (carbohydrate, fiber, saturated/monounsaturated/polyunsaturated fat), alcohol use, physical activity, body mass index (BMI), waist-hip ratio, blood pressure, and lipid composition – only SCD16c remained significantly associated with incident diabetes (Hazard Ratio=1.1 linearly across decreasing quintiles, 95% CI 1.01-1.30; p =0.03) which remained nominally associated after adjusting for insulin resistance (p=0.05).
In a large community-based prospective cohort study, the estimate of SCD-1 activity by SCD16c had the strongest association with incident diabetes. Refinement of SCD-1 measurement and replication of its association with incident diabetes in an independent cohort is recommended.
PMCID: PMC3518662  PMID: 22819528
fatty acid ratio; Type 2 Diabetes; prospective study
11.  Pharmacogenetic effect of the stromelysin (MMP3) polymorphism on stroke risk in relation to antihypertensive treatment: The GenHAT Study 
Stroke; a journal of cerebral circulation  2010;42(2):10.1161/STROKEAHA.110.593798.
Background and Purpose
Atherothrombotic diseases including stroke share a common etiology of atherosclerosis, and susceptibility to atherosclerosis has a genetic component. Stromelysin-1 (MMP3) regulates arterial matrix composition and is a candidate gene for atherothrombosis. A common polymorphism of MMP3 alters expression levels and affects atherosclerotic progression and plaque stability. As part of the GenHAT study, ancillary to ALLHAT, we evaluated the 5A/6A polymorphism in MMP3 to determine its association with stroke and determine if it modifies clinical outcome response to blood pressure lowering drugs.
The effect of the MMP3 5A/6A polymorphism on stroke rates were examined using multivariate-adjusted Cox regression models including testing interactions between genotype and antihypertensive drug class.
Compared to participants treated with chlorthalidone with the 6A/6A genotype, individuals with the 6A/6A genotype randomized to lisinopril had higher stroke rates (HR, 1.32; 95% CI, 1.08-1.61; P = 0.007), 5A/6A individuals taking lisinopril had lower stroke rates (HRinteraction = 0.74; Pinteraction = 0.08; 95% CI, 0.53-1.04), while 5A/5A individuals taking lisinopril had the lowest stroke rate (HRinteraction=0.51; Pinteraction=0.009; 95% CI, 0.31-0.85). There were no pharmacogenetic differences in stroke rate by genotype in patients taking amlodipine or doxazosin versus chlorthalidone.
The MMP3 6A/6A genotype is associated with an increased risk of stroke in hypertensive subjects taking lisinopril compared to patients treated with chlorthalidone, while a protective effect was found for 5A/5A individuals treated with lisinopril. Genetic screening for the MMP3 5A/6A genotype might be a useful tool to select optimal antihypertensive therapy if this finding is replicated.
PMCID: PMC3859235  PMID: 21183746
hypertension; pharmacogenetics; genetic polymorphism; cardiovascular; Stroke; Matrix Metalloproteinase 3; Antihypertensive Agents
12.  Tumor necrosis factor-alpha promoter variants and iron phenotypes in 785 Hemochromatosis and Iron Overload Screening (HEIRS) Study participants 
Blood cells, molecules & diseases  2010;44(4):10.1016/j.bcmd.2010.01.007.
We sought to determine if TNF promoter variants could explain iron phenotype heterogeneity in adults with previous HFE genotyping. HEIRS Study participants genotyped for C282Y and H63D were designated as high transferrin saturation (TS) and/or serum ferritin (SF) (high TS/SF), low TS/SF, or controls. We grouped 191 C282Y homozygotes as high TS/SF, low TS/SF, or controls, and 594 other participants by race/ethnicity as high TS/SF or controls. Using denaturing high-performance liquid chromatography (DHPLC), we screened the TNF promoter region in each participant. We performed multiple regression analyses in C282Y homozygotes using age, sex, HEIRS Study Field Center, and positivity for TNF −308G→A and −238G→A to determine if these attributes predicted ln TS or ln SF. DHPLC analyses were successful in 99.3% of 791 participants and detected 9 different variants; TNF −308G→A and −238G→A were the most prevalent. Most subjects positive for variants were heterozygous. The phenotype frequencies of each variant did not differ significantly (p <0.05) across subgroups of C282Y homozygotes, or across white, black, Hispanic, and Asian non-C282Y homozygotes subgrouped as high TS/SF phenotypes and controls. TNF −308G→A positivity was a significant predictor of initial screening ln TS but not ln SF; TNF −238G→A predicted neither ln TS nor ln SF. We conclude that TNF promoter variants have little, if any, effect on initial screening SF values in adults with or without C282Y homozygosity. We cannot exclude a possible association of homozygosity for TNF promoter variants on TS and SF values.
PMCID: PMC3836206  PMID: 20178892
iron; iron overload; hemochromatosis; phenotype; tumor necrosis factor
13.  Heritability of Serum Iron Measures in the Hemochromatosis and Iron Overload Screening (HEIRS) Family Study 
American journal of hematology  2010;85(2):10.1002/ajh.21585.
Heritability is the proportion of observed variation in a trait among individuals in a population that is attributable to hereditary factors. The HEIRS Family Study estimated heritability of serum iron measures. Probands were HFE C282Y homozygotes or non-C282Y homozygotes with elevated transferrin saturation (TS > 50%, men; TS > 45%, women) and serum ferritin concentration (SF > 300 μg/L, men; SF > 200 μg/L, women). Heritability (h2) was estimated by variance component analysis of TS, natural logarithm (ln) of SF, and unsaturated iron-binding capacity (UIBC). Participants (N=942) were 77% Caucasians, 10% Asians, 8% Hispanics, and 5% other race/ethnicities. Average age (SD) was 49 (16) y; 57% were female. For HFE C282Y homozygote probands and their family members, excluding variation due to HFE C282Y and H63D genotype and measured demographic and environmental factors, the residual h2 (SE) was 0.21 (0.07) for TS, 0.37 (0.08) for ln SF, and 0.34 (0.08) for UIBC (all P < 0.0004 for comparisons with zero). For the non-C282Y homozygote proband group, residual h2 was significant with a value of 0.64 (0.26) for ln SF (p=0.0096). In conclusion, serum iron measures have significant heritability components, after excluding known genetic and non-genetic sources of variation.
PMCID: PMC3816512  PMID: 20095037
HFE; familial aggregation; transferrin saturation; serum ferritin concentration
14.  Serum Concentration of Cystatin C and Risk of End-Stage Renal Disease in Diabetes 
Diabetes Care  2012;35(11):2311-2316.
Patients with diabetes have a high risk of end-stage renal disease (ESRD). We examined whether prediction of this outcome, according to chronic kidney disease (CKD) staging by creatinine-based estimates of the glomerular filtration rate (eGFRcreat), is improved by further staging with serum cystatin C–based estimates (eGFRcyst).
Patients with diabetes in CKD stages 1–3 were selected from three cohorts: two from Joslin Diabetes Center, one with type 1 diabetes (N = 364) and one with type 2 diabetes (N = 402), and the third from the Finnish Diabetic Nephropathy (FinnDiane) Study of type 1 (N = 399). Baseline serum concentrations of creatinine and cystatin C were measured in all patients. Follow-up averaged 8–10 years and onsets of ESRD (n = 246) and death unrelated to ESRD (n = 159) were ascertained.
Although CKD staging by eGFRcyst was concordant with that by eGFRcreat for 62% of Joslin patients and 73% of FinnDiane patients, those given a higher stage by eGFRcyst than eGFRcreat had a significantly higher risk of ESRD than those with concordant staging in all three cohorts (hazard ratio 2.3 [95% CI 1.8–3.1]). Similarly, patients at a lower stage by eGFRcyst than by eGFRcreat had a lower risk than those with concordant staging (0.30 [0.13–0.68]). Deaths unrelated to ESRD followed the same pattern, but differences were not as large.
In patients with diabetes, CKD staging based on eGFRcyst significantly improves ESRD risk stratification based on eGFRcreat. This conclusion can be generalized to patients with type 1 and type 2 diabetes and to diabetic patients in the U.S. and Finland.
PMCID: PMC3476893  PMID: 22851596
15.  Genetic and Adverse Health Outcome Associations with Treatment Resistant Hypertension in GenHAT 
Treatment resistant hypertension (TRH) is defined as uncontrolled hypertension (HTN) despite the use of ≥3 antihypertensive medication classes or controlled HTN while treated with ≥4 antihypertensive medication classes. Risk factors for TRH include increasing age, diminished kidney function, higher body mass index, diabetes, and African American (AA) race. Importantly, previous studies suggest a genetic role in TRH, although the genetics of TRH are largely understudied. With 2203 treatment resistant cases and 2354 treatment responsive controls (36% AA) from the Genetics of Hypertension Associated Treatment Study (GenHAT), we assessed the association of 78 candidate gene polymorphisms with TRH status using logistic regression. After stratifying by race and adjusting for potential confounders, there were 2 genetic variants in the AGT gene (rs699, rs5051) statistically significantly associated with TRH among white participants. The Met allele of rs699 and the G allele of rs5051 were positively associated with TRH: OR = 1.27 (1.12–1.44), P = 0.0001, and OR = 1.36 (1.20–1.53), P < 0.0001, respectively. There was no similar association among AA participants (race interaction P = 0.0004 for rs699 and P = 0.0001 for rs5051). This research contributes to our understanding of the genetic basis of TRH, and further genetic studies of TRH may help reach the goal of better clinical outcomes for hypertensive patients.
PMCID: PMC3833110  PMID: 24288596
16.  Epistatic effects of ACE I/D and AGT gene variants on left ventricular mass in hypertensive patients: The HyperGEN Study 
Journal of human hypertension  2011;26(2):133-140.
Identifying predictors of left ventricular hypertrophy has been an active study topic because of its association with cardiovascular morbidity and mortality. We examined the epistatic effect (gene-gene interaction) of two genes (ACE I/D; AGT -6G-A, M235T, -20A-C) in the renin-angiotension system (RAS) on left ventricular mass (LVM) among hypertensive participants in the HyperGEN study.
Included were 2156 participants aged 20–87 years (60% women, 63% African American). We employed mixed linear regression models to assess main effects of four genetic variants on echocardigraphically determined LVM (indexed for height), and ACE-by-AGT epistatic effects. There was evidence that AGT -6G-A was associated with LVM among white participants: Adjusted mean LVM (g/m2.7) increased with ‘G’ allele copy number (‘AA’:41.2, ‘AG’:42.3, ‘GG’:44.0; p=0.03). There was also evidence of an ACE I/D-by-AGT -20A-C epistatic effect among white participants (interaction p=0.03): Among ACE ‘DD’ participants, AGT -20A-C ‘C’ allele carriers had lower mean LVM than ‘AA’ homozygotes (‘DD/CC’:39.2, ‘DD/AC’:39.9, ‘DD/AA’:43.9), with no similar significant effect among ACE ‘I’ allele carriers (‘ID/CC’:47.2, ‘ID/AC’:43.4, ‘ID/AA’:42.6; ‘II/CC’: NA, ‘II/AC’:41.3, ‘II/AA’:43.1).
These findings indicate that RAS variants in at least two genes may interact to modulate LVM.
PMCID: PMC3775641  PMID: 21248783
Left ventricular mass; left ventricular hypertrophy; ACE gene; AGT gene; epistasis; hypertension
17.  Characteristics of participants with self-reported hemochromatosis or iron overload at HEIRS Study initial screening 
American journal of hematology  2008;83(2):126-132.
There are few descriptions of young adults with self-reported hemochromatosis or iron overload (H/IO). We analyzed initial screening data in 7,343 HEmochromatosis and IRon Overload Screening (HEIRS) Study participants ages 25–29 years, including race/ethnicity and health information; transferrin saturation (TS) and ferritin (SF) measurements; and HFE C282Y and H63D genotypes. We used denaturing high-pressure liquid chromatography and sequencing to detect mutations in HJV, TFR2, HAMP, SLC40A1, and FTL. Fifty-one participants reported previous H/IO; 23 (45%) reported medical conditions associated with H/IO. Prevalences of reports of arthritis, diabetes, liver disease or liver cancer, heart failure, fertility problems or impotence, and blood relatives with H/IO were significantly greater in participants with previous H/IO reports than in those without. Only 7.8% of the 51 participants with previous H/IO reports had elevated TS; 13.7% had elevated SF. Only one participant had C282Y homozygosity. Three participants aged 25–29 years were heterozygous for potentially deleterious mutations in HFE2, TFR2, and HAMP promoter, respectively. Prevalences of self-reported conditions, screening iron phenotypes, and C282Y homozygosity were similar in 1,165 participants aged 30 years or greater who reported previous H/IO. We conclude that persons who report previous H/IO diagnoses in screening programs are unlikely to have H/IO phenotypes or genotypes. Previous H/IO reports in some participants could be explained by treatment that induced iron depletion before initial screening, misdiagnosis, or participant misunderstanding of their physician or the initial screening questionnaire.
PMCID: PMC3773364  PMID: 17726683
18.  Serum ferritin concentrations and body iron stores in a multicenter, multiethnic primary-care population 
American journal of hematology  2008;83(8):618-626.
How often elevated serum ferritin in primary-care patients reflects increased iron stores (normally 0.8 g in men, 0.4 g in women) is not known. The Hereditary Hemochromatosis and Iron Overload Screening (HEIRS) study screened 101,168 primary-care participants (44% Caucasians, 27% African-Americans, 14% Asians/Pacific Islanders, 13% Hispanics, 2% others). Follow-up clinical evaluation was performed in 302 of 333 HFE C282Y homozygotes regardless of iron measures and 1,375 of 1,920 nonhomozygotes with serum ferritin >300 μg/L (men), >200 μg/L (women) and transferrin saturation >50% (men), >45% (women). Quantitative phlebotomy was conducted in 122 of 175 C282Y homozygotes and 122 of 1,102 nonhomozygotes with non-transfusional serum ferritin elevation at evaluation. The estimated prevalence in the Caucasian population of C282Y homozygotes with serum ferritin >900 μg/L at evaluation was 20 per 10,000 men and 4 per 10,000 women; this constellation was predictive of iron stores >4 g in men and >2 g in women. The estimated prevalence per 10,000 of non-C282Y homozygotes with serum ferritin >900 μg/L at evaluation was 7 among Caucasians, 13 among Hispanics, 20 among African Americans, and 38 among Asians and Pacific Islanders, and this constellation was predictive of iron stores >2 g but <4 g. In conclusion, serum ferritin >900 μg/L after initial elevations of both serum ferritin and transferrin saturation is predictive of mildly increased iron stores in multiple ethnic populations regardless of HFE genotype. Serum ferritin >900 μg/L in male C282Y homozygotes is predictive of moderately increased iron stores.
PMCID: PMC3773165  PMID: 18429050
19.  Probability of C282Y homozygosity decreases as liver transaminase activities increase in participants with hyperferritinemia in the HEIRS Study 
Hepatology (Baltimore, Md.)  2012;55(6):1722-1726.
Hemochromatosis is considered by many to be an uncommon disorder, although the prevalence of HFE C282Y homozygosity is relatively high in Caucasians. Liver disease is one of the most consistent findings in advanced iron overload due to hemochromatosis. Liver clinics are often thought to be ideal venues for diagnosis of hemochromatosis, but diagnosis rates are often low.
The Hemochromatosis and Iron Overload Screening (HEIRS) Study screened 99, 711 primary care participants in North America for iron overload using serum ferritin and transferrin saturation measurements and HFE genotyping. In this HEIRS substudy, serum hepatic transaminases activities (ALT, AST) were compared between 162 C282Y homozygotes and 1,367 non-homozygotes with a serum ferritin > 300 μg/L in men and > 200 μg/L in women and transferrin saturation > 45 % in women and 50 % in men. The probability of being a C282Y homozygote was determined for AST and ALT ranges.
Mean ALT and AST activities were significantly lower in C282Y homozygotes than non-homozygotes. The probability of being a C282Y homozygote increased as the ALT and AST activities decreased.
Patients with hyperferritinemia are more likely to be C282Y homozygotes if they have normal liver transaminase activities. This paradox could explain the low yields of hemochromatosis screening reported by some liver clinics.
PMCID: PMC3355194  PMID: 22183642
20.  Dietary iron intake and serum ferritin concentration in 213 patients homozygous for the HFEC282Y hemochromatosis mutation 
HFEC282Y homozygotes have an increased risk for developing increased iron stores and related disorders. It is controversial whether dietary iron restrictions should be recommended to such individuals.
To determine whether dietary iron content influences iron stores in HFEC282Y homozygotes as assessed by serum ferritin concentration.
Serum ferritin concentration was measured and a dietary iron questionnaire was completed as part of the evaluation of 213 HFEC282Y homozygotes who were identified through screening of >100,000 primary care patients at five HEmochromatosis and IRon Overload Screening (HEIRS) Study Field Centers in the United States and Canada.
No significant relationships between serum ferritin concentration and dietary heme iron content, dietary nonheme iron content or reports of supplemental iron use were found.
These results do not support recommending dietary heme or nonheme iron restrictions for HFEC282Y homozygotes diagnosed through screening in North America.
PMCID: PMC3378281  PMID: 22720276
Haemochromatosis; Hemochromatosis; Iron overload; Iron supplementation
21.  The effects of freeze–thaw on β-trace protein and β2-microglobulin assays after long-term sample storage 
Clinical biochemistry  2012;45(9):694-696.
To evaluate the effect of a freeze–thaw cycle on β-trace protein (βTP) and β2-microglobulin (β2M).
Design and methods
We compared βTP and β2M concentrations before and after a single freeze–thaw cycle in long-term stored samples from 172 participants of the Third National Health and Nutrition Examination Survey (NHANES III).
Measurements of βTP and β2M before and after freeze–thaw were highly correlated with Spearman’s coefficients of 0.90 and 0.99, respectively. Serum concentrations of βTP were slightly lower after freeze–thaw (−0.05 mg/L, P=0.006). Measurements of β2M did not differ before and after freeze–thaw (P=0.35).
βTP and β2M measurements were robust to a single freeze–thaw cycle, although β2M appeared more stable than βTP. These results have implications for future studies of these biomarkers.
PMCID: PMC3575740  PMID: 22425605
β-trace protein (βTP); β2-microglobulin; National Health and Nutrition Examination Survey; Freeze–thaw; Kidney filtration marker
22.  Gene panels to help identify subgroups at high and low risk of CHD among those randomized to antihypertensive treatment: The GenHAT Study 
Pharmacogenetics and Genomics  2012;22(5):355-366.
To identify panels of genetic variants that predict treatment-related coronary heart disease (CHD) outcomes in hypertensive patients on one of four different classes of initial antihypertensive treatment. The goal was to identify subgroups of people based on their genetic profile who benefit most from a particular treatment.
Candidate genetic variants (n=78) were genotyped in 39,114 participants from GenHAT, ancillary to ALLHAT. ALLHAT randomized hypertensive participants (>=55 years) to one of four treatments (amlodipine, chlorthalidone, doxazosin, lisinopril). The primary outcome was fatal CHD or non-fatal MI (mean follow-up=4.9 years). A pharmacogenetic panel was derived within each of the four treatment groups. ROC curves estimated the discrimination rate between those with and without a CHD event, based on the addition of the genetic panel risk score.
For each treatment group, we identified a panel of genetic variants that collectively improved prediction of CHD to a small but statistically significant extent. Chlorthalidone (A): NOS3, rs3918226; SELE, rs5361; ICAM1, rs1799969; AGT, rs5051; GNAS, rs7121; ROC comparison p=.004; Amlodipine (B): MMP1, rs1799750; F5, rs6025; NPPA, rs5065; PDE4D, rs6450512; MMP9, rs2274756; ROC comparison p=.006; Lisinopril (C): AGT, rs5051; PON1, rs705379; MMP12, rs652438; F12, rs1801020; GP1BA, rs6065; PDE4D, rs27653; ROC comparison p=.01; Doxazosin (D): F2, rs1799963; PAI1, rs1799768; MMP7, rs11568818; AGT, rs5051; ACE, rs4343; MMP2, rs243865; ROC comparison p=.007. Each panel was tested for a pharmacogenetic effect; panels A, B and D showed such evidence (p=.009, .006, and .001 respectively), panel C did not (p=.09).
Because each panel was associated with CHD in a specific treatment group but not the others, this research provides evidence that it may be possible to use gene panel scores as a tool to better assess antihypertensive treatment choices to reduce CHD risk in hypertensive individuals.
PMCID: PMC3325375  PMID: 22388798
pharmacogenetics; antihypertensive pharmacogenetics; CVD; gene panels
Hypertension  2012;59(5):926-933.
Concerns exist that diuretic-induced changes in serum potassium may have adverse effects in hypertensive patients. ALLHAT, a large practice-based clinical trial made it possible to examine consequences of observed changes in potassium during care in conventional practice settings. Normokalemic participants randomized to chlorthalidone versus amlodipine or lisinopril as first-step drug were stratified by year-1 potassium. Post-year-1 outcomes among hypokalemics (potassium<3.5mmol/L) and hyperkalemics (potassium>5.4mmol/L) were compared to normokalemics (potassium 3.5–5.4 mmol/L). Year-1 hypokalemia incidence was 6.8%; incidence in chlorthalidone (12.9%) differed from amlodipine (2.1%; p<0.001) and lisinopril (1.0%; p<0.01). Hyperkalemia incidence (2.0%) was greater in lisinopril (3.6%) than chlorthalidone (1.2%; p<0.01) or amlodipine (1.9%; p<0.01). Coronary heart disease occurred in 8.1% with hypokalemia, 8.0% with normokalemia, and 11.1% with hyperkalemia. Overall, mortality was higher in hypokalemics than normokalemics (Cox hazard ratio =1.21; 95% confidence interval=1.02–1.44) with statistically significant (interaction p<0.01) disparity in hazard ratios for the three treatment arms (hazard ratios: chlorthalidone=1.21, amlodipine=1.60, lisinopril=3.82). Hyperkalemia was associated with increased risk of combined cardiovascular disease (hazard ratio=1.58; 1.15–2.18) without significant treatment interactions. In conventional practice settings, the uncommon appearance of hyperkalemia was associated with increased cardiovascular disease risk. Hypokalemia was associated with increased mortality; however, the statistically significant heterogeneity in hazard ratios across treatment groups strongly suggests that the observed increase in mortality is unrelated to the specific effects of chlorthalidone. Thus, for most patients, concerns about potassium levels should not influence clinician’s decision about initiating hypertension treatment with low-moderate doses of thiazide diuretics (12.5–25 mg of chlorthalidone).
PMCID: PMC3373273  PMID: 22431578
hypertension; hypokalemia; hyperkalemia; diuretic; calcium-channel blocker; ACE-inhibitor
24.  Novel Association between Plasma Matrix Metalloproteinase-9 and Risk of Incident Atrial Fibrillation in a Case-Cohort Study: The Atherosclerosis Risk in Communities Study 
PLoS ONE  2013;8(3):e59052.
Previous cross-sectional studies have suggested that biomarkers of extracellular matrix remodelling are associated with atrial fibrillation (AF), but no prospective data have yet been published. Hence, we examine whether plasma matrix metalloproteinases (MMP) and their inhibitors are related to increased risk of incident AF.
We used a case-cohort design in the context of the prospective Atherosclerosis Risk in Communities (ARIC) study. From 13718 eligible men and women free from AF in 1990-92, we selected a stratified random sample of 500 individuals without and 580 with incident AF over a mean follow-up of 11.8 years. Using a weighted proportional hazards regression model, the relationships between MMP-1, MMP-2, MMP-9, tissue inhibitor of matrix metalloproteinase (TIMP)-1, TIMP-2 and C-terminal propeptide of collagen type-I with incident AF were examined after adjusting for confounders.
In models adjusted for age, sex and race, all biomarkers were associated with AF, but only the relationship between plasma MMP-9 remained significant in the fully-adjusted model: each one standard deviation increase in MMP-9 was associated with 27% (95% Confidence Interval: 7% to 50%) increase in risk of AF with no evidence of an interaction with race or sex. Individuals with above mean levels of MMP-9 were more likely to be male, white and current smokers.
The findings suggest that elevated levels of MMP-9 are independently associated with increased risk of AF. However, given the lack of specificity of MMP-9 to atrial tissue, it remains to be determined whether the observed relationship reflects the impact of atrial fibrosis or more generalized fibrosis on risk of incident AF.
PMCID: PMC3598956  PMID: 23554968
25.  Associations between Single Nucleotide Polymorphisms in Iron-Related Genes and Iron Status in Multiethnic Populations 
PLoS ONE  2012;7(6):e38339.
The existence of multiple inherited disorders of iron metabolism suggests genetic contributions to iron deficiency. We previously performed a genome-wide association study of iron-related single nucleotide polymorphisms (SNPs) using DNA from white men aged ≥25 y and women ≥50 y in the Hemochromatosis and Iron Overload Screening (HEIRS) Study with serum ferritin (SF) ≤12 µg/L (cases) and controls (SF >100 µg/L in men, SF >50 µg/L in women). We report a follow-up study of white, African-American, Hispanic, and Asian HEIRS participants, analyzed for association between SNPs and eight iron-related outcomes. Three chromosomal regions showed association across multiple populations, including SNPs in the TF and TMPRSS6 genes, and on chromosome 18q21. A novel SNP rs1421312 in TMPRSS6 was associated with serum iron in whites (p = 3.7×10−6) and replicated in African Americans (p = 0.0012).Twenty SNPs in the TF gene region were associated with total iron-binding capacity in whites (p<4.4×10−5); six SNPs replicated in other ethnicities (p<0.01). SNP rs10904850 in the CUBN gene on 10p13 was associated with serum iron in African Americans (P = 1.0×10−5). These results confirm known associations with iron measures and give unique evidence of their role in different ethnicities, suggesting origins in a common founder.
PMCID: PMC3382217  PMID: 22761678

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