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1.  Infant sex-specific placental cadmium and DNA methylation associations 
Environmental research  2015;138:74-81.
Background
Recent evidence suggests that maternal cadmium (Cd) burden and fetal growth associations may vary by fetal sex. However, mechanisms contributing to these differences are unknown.
Objectives
Among 24 maternal-infant pairs, we investigated infant sex-specific associations between placental Cd and placental genome-wide DNA methylation.
Methods
We used ANOVA models to examine sex-stratified associations of placental Cd (dichotomized into high/low Cd using sex-specific Cd median cutoffs) with DNA methylation at each cytosine-phosphate-guanine site or region. Statistical significance was defined using a false discovery rate cutoff (<0.10).
Results
Medians of placental Cd among females and males were 5 and 2 ng/g, respectively. Among females, three sites (near ADP-ribosylation factor-like 9 (ARL9), siah E3 ubiquitin protein ligase family member 3 (SIAH3), and heparin sulfate (glucosamine) 3-O-sulfotransferase 4 (HS3ST4) and one region on chromosome 7 (including carnitine O-octanoyltransferase (CROT) and TP5S target 1 (TP53TG1)) were hypomethylated in high Cd placentas. Among males, high placental Cd was associated with methylation of three sites, two (hypomethylated) near MDS1 and EVI1 complex locus (MECOM) and one (hypermethylated) near spalt-like transcription factor 1 (SALL1), and two regions (both hypomethylated, one on chromosome 3 including MECOM and another on chromosome 8 including rho guanine nucleotide exchange factor (GEF) 10 (ARHGEF10). Differentially methylated sites were at or close to transcription start sites of genes involved in cell damage response (SIAH3, HS3ST4, TP53TG1) in females and cell differentiation, angiogenesis and organ development (MECOM, SALL1) in males.
Conclusions
Our preliminary study supports infant sex-specific placental Cd-DNA methylation associations, possibly accounting for previously reported differences in Cd-fetal growth associations across fetal sex. Larger studies are needed to replicate and extend these findings. Such investigations may further our understanding of epigenetic mechanisms underlying maternal Cd burden with suboptimal fetal growth associations.
doi:10.1016/j.envres.2015.02.004
PMCID: PMC4385453  PMID: 25701811
placenta; cadmium; DNA methylation; infant-sex; fetal growth
2.  Use of statins and antihypertensive medications in relation to risk of longstanding persistent atrial fibrillation 
The Annals of pharmacotherapy  2015;49(4):378-386.
Background
After an initial episode of atrial fibrillation (AF), patients may develop longstanding persistent or permanent AF.
Objective
We evaluated whether use of statins, angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers is associated with lower risk of longstanding persistent AF after an initial AF episode.
Methods
We conducted a population-based inception cohort study of participants enrolled in Group Health, aged 30–84 with newly-diagnosed AF in 2001–2004. We included only participants whose initial AF episode terminated within six months of onset. We ascertained the primary outcome of longstanding persistent AF from medical records, electrocardiograms, and administrative data. We determined time-varying medication use from Group Health pharmacy data.
Results
Among 1,317 participants with incident AF, 304 developed longstanding persistent AF. Our study suggests that current statin use vs. never use may be associated with lower risk for longstanding persistent AF. However, the association was not statistically significant when adjusted for age, sex, cardiovascular risk factors, and current use of antiarrhythmic medication (hazard ratio [HR] = 0.77; 95% confidence interval [CI]: 0.57, 1.03). In lagged analyses intended to reduce healthy user bias, current statin use one year prior vs. never use one year prior was not associated with risk for longstanding persistent AF (HR = 0.91; 95% CI: 0.67, 1.24). ACE inhibitor, ARB, and beta-blocker use were not associated with risk for longstanding persistent AF.
Conclusions
Current statin use may confer protection that wanes after discontinuing use. Alternatively, healthy user bias or chance may explain the association. The association of statin use with longstanding persistent AF warrants further investigation.
doi:10.1177/1060028014568447
PMCID: PMC4562688  PMID: 25628466
antihypertensive agents; longstanding persistent atrial fibrillation; cohort studies; electrocardiography; hydroxymethylglutaryl-CoA reductase inhibitors; statins
3.  Obesity related risk of sudden cardiac death in the atherosclerosis risk in communities study 
Heart (British Cardiac Society)  2014;101(3):215-221.
Objective
To examine the association of body mass index (BMI), waist circumference (WC) and waist hip ratio (WHR) with sudden cardiac death (SCD) in community dwelling individuals.
Methods
Data from a multicentre, prospective, cohort study of 14 941 men and women (African American, and white), aged 45–64 years, participating in the Atherosclerosis Risk in Communities study was analysed. Obesity measures were assessed at baseline (1987–1989). SCD was adjudicated by a committee.
Results
At enrolment mean±SD age of the participants was 54±6 years (55% female; 26% African American). During 12.6±2.5 years of follow-up, 253 SCD occurred (incidence rate 1.34/100 person-years). The association between obesity and SCD differed by smoking status (interaction p≤0.01). In models adjusting for age, sex, race, study centre and education level, SCD risk was positively associated (p<0.001) with BMI, WC and WHR in non-smokers, but not in smokers. WHR was more strongly associated with SCD in non-smokers than was BMI or WC (HR per SD increment (95% CI) 2.00 (1.65 to 2.42); 1.34 (1.15 to 1.56) and 1.49 (1.28 to 1.74), respectively). After adjustment for potential mediators (hypertension, diabetes, lipid profile, prevalent coronary heart disease, heart failure, and LV hypertrophy), non-smokers in the highest WHR category (>0.95 in women; >1.01 in men) had double the risk of SCD (HR 2.03, 95% CI 1.19 to 3.46; incidence rate 1.43/1000 person-years) versus those with normal WHR.
Conclusions
General obesity is associated with increased risk of SCD in middle-aged, non-smoking individuals, mediated by traditional cardiovascular risk factors. Central obesity, however, is independently associated with SCD by pathways that remain to be elucidated.
doi:10.1136/heartjnl-2014-306238
PMCID: PMC4791977  PMID: 25410499
4.  Genome-Wide Association Study for Incident Myocardial Infarction and Coronary Heart Disease in Prospective Cohort Studies: The CHARGE Consortium 
PLoS ONE  2016;11(3):e0144997.
Background
Data are limited on genome-wide association studies (GWAS) for incident coronary heart disease (CHD). Moreover, it is not known whether genetic variants identified to date also associate with risk of CHD in a prospective setting.
Methods
We performed a two-stage GWAS analysis of incident myocardial infarction (MI) and CHD in a total of 64,297 individuals (including 3898 MI cases, 5465 CHD cases). SNPs that passed an arbitrary threshold of 5×10−6 in Stage I were taken to Stage II for further discovery. Furthermore, in an analysis of prognosis, we studied whether known SNPs from former GWAS were associated with total mortality in individuals who experienced MI during follow-up.
Results
In Stage I 15 loci passed the threshold of 5×10−6; 8 loci for MI and 8 loci for CHD, for which one locus overlapped and none were reported in previous GWAS meta-analyses. We took 60 SNPs representing these 15 loci to Stage II of discovery. Four SNPs near QKI showed nominally significant association with MI (p-value<8.8×10−3) and three exceeded the genome-wide significance threshold when Stage I and Stage II results were combined (top SNP rs6941513: p = 6.2×10−9). Despite excellent power, the 9p21 locus SNP (rs1333049) was only modestly associated with MI (HR = 1.09, p-value = 0.02) and marginally with CHD (HR = 1.06, p-value = 0.08). Among an inception cohort of those who experienced MI during follow-up, the risk allele of rs1333049 was associated with a decreased risk of subsequent mortality (HR = 0.90, p-value = 3.2×10−3).
Conclusions
QKI represents a novel locus that may serve as a predictor of incident CHD in prospective studies. The association of the 9p21 locus both with increased risk of first myocardial infarction and longer survival after MI highlights the importance of study design in investigating genetic determinants of complex disorders.
doi:10.1371/journal.pone.0144997
PMCID: PMC4780701  PMID: 26950853
6.  Acculturation and Plasma Fatty Acid Concentrations in Hispanic and Chinese-American Adults: The Multi-Ethnic Study of Atherosclerosis 
PLoS ONE  2016;11(2):e0149267.
Background
Acculturation to the U.S. is associated with increased risk of cardiovascular disease, but the etiologic pathways are not fully understood. Plasma fatty acid levels exhibit ethnic differences and are emerging as biomarkers and predictors of cardiovascular disease risk. Thus, plasma fatty acids may represent one pathway underlying the association between acculturation and cardiovascular disease. We investigated the cross-sectional relationship between acculturation and plasma phospholipid fatty acids in a diverse sample of Hispanic- and Chinese-American adults.
Methods and Findings
Participants included 377 Mexican, 320 non-Mexican Hispanic, and 712 Chinese adults from the Multi-Ethnic Study of Atherosclerosis, who had full plasma phospholipid assays and acculturation information. Acculturation was determined from three proxy measures: nativity, language spoken at home, and years in the U.S., with possible scores ranging from 0 (least acculturated) to 5 (most acculturated) points. α-Linolenic acid, linoleic acid, eicosapentaenoic acid, docosahexaenoic acid, and arachidonic acid were measured in fasting plasma. Linear regression models were conducted in race/ethnicity-stratified analyses, with acculturation as the predictor and plasma phospholipid fatty acids as the outcome variables. We ran secondary analyses to examine associations between acculturation and dietary fatty acids for comparison. Covariates included age, gender, education, and income. Contrary to our hypothesis, no statistically significant associations were detected between acculturation and plasma phospholipid fatty acids for Chinese, non-Mexican Hispanic, or Mexican participants. However, acculturation was related to dietary total n-6 fatty acids and dietary n-3/n-6 ratios in expected directions for Mexican, non-Mexican Hispanic, and combined Hispanic participants. In Chinese individuals, acculturation was unexpectedly associated with lower arachidonic acid intake.
Conclusion
Absence of associations between acculturation and plasma phospholipid fatty acids suggests that changes in the plasma phospholipid fatty acids studied do not account for the observed associations of acculturation to the U.S. and cardiovascular disease risk. Similar findings were observed for eicosapentaenoic acid and docosahexaenoic acid, when using dietary intake. However, the observed associations between dietary n-6 fatty acids and acculturation in Hispanic individuals suggest that dietary intake may be more informative than phospholipids when investigating acculturation effects. In Chinese individuals, acculturation may have a possible protective effect through decreased arachidonic acid intake. Further research on dietary fatty acids and other cardiovascular disease biomarkers is needed to identify possible etiologic mechanisms between acculturation and cardiovascular disease.
doi:10.1371/journal.pone.0149267
PMCID: PMC4752232  PMID: 26872329
7.  Potassium and Glucose Measures in Older Adults: The Cardiovascular Health Study 
Background.
We sought to determine the impacts of serum and dietary potassium measures on glucose metabolism and diabetes risk in older adults.
Methods.
Among participants of the Cardiovascular Health Study, a community-based cohort of older American adults, we examined a) cross-sectional associations between potassium and measures of insulin sensitivity and secretion estimated from oral glucose tolerance tests and b) longitudinal associations of serum and dietary potassium with diabetes risk.
Results.
Among 4,754 participants aged ≥65 years at baseline, there were 445 cases of incident diabetes during a median follow-up of 12 years. In multivariate models, baseline serum and dietary potassium were both associated with lower insulin sensitivity and greater insulin secretion. Compared with those with a serum potassium ≥4.5 mEq/L, participants with a serum potassium <4.0mEq/L had an adjusted mean difference in Matsuda insulin sensitivity index of −0.18 (−0.39, 0.02). Compared with those in the highest quartile, participants in the lowest quartile of dietary potassium intake had a corresponding adjusted mean difference in Matsuda insulin sensitivity index of −0.61 (−0.94, −0.29). In multivariate models, neither serum nor dietary potassium intake was associated with long-term diabetes risk.
Conclusions.
Although we did not identify serum and dietary potassium as risk factors for incident diabetes in older adults, results from cross-sectional analyses suggest that both may be associated with increased insulin resistance. This relationship with insulin resistance needs to be confirmed, and its importance on diabetes risk, cardiovascular risk, and conditions specific to older adults should be determined as well.
doi:10.1093/gerona/glu071
PMCID: PMC4366599  PMID: 24895271
Potassium; Glucose metabolism; Older adults.
8.  Association of Albumin-Creatinine Ratio and Cystatin C With Change in Ankle-Brachial Index: The Multi-Ethnic Study of Atherosclerosis (MESA) 
Background
Low ankle-brachial index (ABI) is a reflection of atherosclerotic disease, and high ABI is an indicator of calcified vessels. The associations of albuminuria and cystatin C with incidence of either low or high ABI are unknown.
Study Design
Prospective longitudinal cohort study.
Setting & Participants
The Multi-Ethnic Study of Atherosclerosis (MESA) enrolled community-dwelling adults (N=6,814) aged 45–84 years who were free of clinical cardiovascular disease (CVD) at baseline.
Predictors
Baseline albumin-creatinine ratio (ACR) and serum cystatin C levels.
Outcomes
Development of low (< 0.90), and high (> 1.40) ABI using multinomial regression among persons with ABI 0.90–1.40 at baseline.
Results
During 9.8 years of follow up, 221 and 89 participants progressed to low and high ABI, respectively. Baseline ACR and cystatin C were higher among progressors compared to non-progressors. In multivariable analyses, doubling of ACR was associated with increased risk of progression to low (OR, 1.08; 95% CI, 0.99–1.20) and high (OR, 1.16; 95% CI, 1.01–1.32) ABI. Compared to the lowest quintile, the highest quintile of ACR had a significantly increased risk of progression to low (OR, 1.79; 95% CI, 1.03–3.12) and high (OR, 2.76; 95% CI, 1.32–5.77) ABI. Higher cystatin C levels were associated with progression to low (OR per 1-SD greater, 1.12; 95% CI, 1.00–1.26) but not high (OR per 1-SD greater, 1.01; 95% CI, 0.81–1.25) ABI, but the highest quintile of cystatin C was not independently associated with either outcome.
Limitations
Single measure of albuminuria and low number of progressors to high ABI.
Conclusions
In adults free of clinical CVD, albuminuria was a strong, independent risk factor for the development of both high and low ABI, important and different measures of peripheral artery disease.
doi:10.1053/j.ajkd.2014.05.014
PMCID: PMC4272615  PMID: 24998036
Cystatin C; albuminuria; albumin-creatinine ratio (ACR); peripheral artery disease (PAD); ankle-brachial index (ABI); chronic kidney disease (CKD); cardiovascular disease (CVD); atherosclerotic disease
9.  FTO genetic variants, dietary intake and body mass index: insights from 177 330 individuals 
Qi, Qibin | Kilpeläinen, Tuomas O. | Downer, Mary K. | Tanaka, Toshiko | Smith, Caren E. | Sluijs, Ivonne | Sonestedt, Emily | Chu, Audrey Y. | Renström, Frida | Lin, Xiaochen | Ängquist, Lars H. | Huang, Jinyan | Liu, Zhonghua | Li, Yanping | Asif Ali, Muhammad | Xu, Min | Ahluwalia, Tarunveer Singh | Boer, Jolanda M.A. | Chen, Peng | Daimon, Makoto | Eriksson, Johan | Perola, Markus | Friedlander, Yechiel | Gao, Yu-Tang | Heppe, Denise H.M. | Holloway, John W. | Houston, Denise K. | Kanoni, Stavroula | Kim, Yu-Mi | Laaksonen, Maarit A. | Jääskeläinen, Tiina | Lee, Nanette R. | Lehtimäki, Terho | Lemaitre, Rozenn N. | Lu, Wei | Luben, Robert N. | Manichaikul, Ani | Männistö, Satu | Marques-Vidal, Pedro | Monda, Keri L. | Ngwa, Julius S. | Perusse, Louis | van Rooij, Frank J.A. | Xiang, Yong-Bing | Wen, Wanqing | Wojczynski, Mary K | Zhu, Jingwen | Borecki, Ingrid B. | Bouchard, Claude | Cai, Qiuyin | Cooper, Cyrus | Dedoussis, George V. | Deloukas, Panos | Ferrucci, Luigi | Forouhi, Nita G. | Hansen, Torben | Christiansen, Lene | Hofman, Albert | Johansson, Ingegerd | Jørgensen, Torben | Karasawa, Shigeru | Khaw, Kay-Tee | Kim, Mi-Kyung | Kristiansson, Kati | Li, Huaixing | Lin, Xu | Liu, Yongmei | Lohman, Kurt K. | Long, Jirong | Mikkilä, Vera | Mozaffarian, Dariush | North, Kari | Pedersen, Oluf | Raitakari, Olli | Rissanen, Harri | Tuomilehto, Jaakko | van der Schouw, Yvonne T. | Uitterlinden, André G. | Zillikens, M. Carola | Franco, Oscar H. | Shyong Tai, E. | Ou Shu, Xiao | Siscovick, David S. | Toft, Ulla | Verschuren, W.M. Monique | Vollenweider, Peter | Wareham, Nicholas J. | Witteman, Jacqueline C.M. | Zheng, Wei | Ridker, Paul M. | Kang, Jae H. | Liang, Liming | Jensen, Majken K. | Curhan, Gary C. | Pasquale, Louis R. | Hunter, David J. | Mohlke, Karen L. | Uusitupa, Matti | Cupples, L. Adrienne | Rankinen, Tuomo | Orho-Melander, Marju | Wang, Tao | Chasman, Daniel I. | Franks, Paul W. | Sørensen, Thorkild I.A. | Hu, Frank B. | Loos, Ruth J. F. | Nettleton, Jennifer A. | Qi, Lu
Human Molecular Genetics  2014;23(25):6961-6972.
FTO is the strongest known genetic susceptibility locus for obesity. Experimental studies in animals suggest the potential roles of FTO in regulating food intake. The interactive relation among FTO variants, dietary intake and body mass index (BMI) is complex and results from previous often small-scale studies in humans are highly inconsistent. We performed large-scale analyses based on data from 177 330 adults (154 439 Whites, 5776 African Americans and 17 115 Asians) from 40 studies to examine: (i) the association between the FTO-rs9939609 variant (or a proxy single-nucleotide polymorphism) and total energy and macronutrient intake and (ii) the interaction between the FTO variant and dietary intake on BMI. The minor allele (A-allele) of the FTO-rs9939609 variant was associated with higher BMI in Whites (effect per allele = 0.34 [0.31, 0.37] kg/m2, P = 1.9 × 10−105), and all participants (0.30 [0.30, 0.35] kg/m2, P = 3.6 × 10−107). The BMI-increasing allele of the FTO variant showed a significant association with higher dietary protein intake (effect per allele = 0.08 [0.06, 0.10] %, P = 2.4 × 10−16), and relative weak associations with lower total energy intake (−6.4 [−10.1, −2.6] kcal/day, P = 0.001) and lower dietary carbohydrate intake (−0.07 [−0.11, −0.02] %, P = 0.004). The associations with protein (P = 7.5 × 10−9) and total energy (P = 0.002) were attenuated but remained significant after adjustment for BMI. We did not find significant interactions between the FTO variant and dietary intake of total energy, protein, carbohydrate or fat on BMI. Our findings suggest a positive association between the BMI-increasing allele of FTO variant and higher dietary protein intake and offer insight into potential link between FTO, dietary protein intake and adiposity.
doi:10.1093/hmg/ddu411
PMCID: PMC4271061  PMID: 25104851
10.  African Ancestry Analysis and Admixture Genetic Mapping for Proliferative Diabetic Retinopathy in African Americans 
Purpose.
To examine the relationship between proportion of African ancestry (PAA) and proliferative diabetic retinopathy (PDR) and to identify genetic loci associated with PDR using admixture mapping in African Americans with type 2 diabetes (T2D).
Methods.
Between 1993 and 2013, 1440 participants enrolled in four different studies had fundus photographs graded using the Early Treatment Diabetic Retinopathy Study scale. Cases (n = 305) had PDR while controls (n = 1135) had nonproliferative diabetic retinopathy (DR) or no DR. Covariates included diabetes duration, hemoglobin A1C, systolic blood pressure, income, and education. Genotyping was performed on the Affymetrix platform. The association between PAA and PDR was evaluated using logistic regression. Genome-wide admixture scanning was performed using ANCESTRYMAP software.
Results.
In the univariate analysis, PDR was associated with increased PAA (odds ratio [OR] = 1.36, 95% confidence interval [CI] = 1.16–1.59, P = 0.0002). In multivariate regression adjusting for traditional DR risk factors, income and education, the association between PAA and PDR was attenuated and no longer significant (OR = 1.21, 95% CI = 0.59–2.47, P = 0.61). For the admixture analyses, the maximum genome-wide score was 1.44 on chromosome 1.
Conclusions.
In this largest study of PDR in African Americans with T2D to date, an association between PAA and PDR is not present after adjustment for clinical, demographic, and socioeconomic factors. No genome-wide significant locus (defined as having a locus-genome statistic > 5) was identified with admixture analysis. Further analyses with even larger sample sizes are needed to definitively assess if any admixture signal for DR is present.
In African Americans with type 2 diabetes, proportion of African ancestry was associated with proliferative diabetic retinopathy (PDR) but the association was no longer present with adjustment for clinical/socioeconomic variables. No genome-wide significant loci were found with admixture scanning.
doi:10.1167/iovs.15-16674
PMCID: PMC4477259  PMID: 26098467
genetics; diabetic retinopathy; proliferative diabetic retinopathy; African Americans; admixture; ancestry
11.  Associations of kidney injury markers with subclinical cardiovascular disease: the Multi-Ethnic Study of Atherosclerosis  
Clinical Nephrology  2015;84(6):358-364.
No abstract available.
doi:10.5414/CN108668
PMCID: PMC4776253  PMID: 26558369
kidney injury biomarkers; cardiovascular disease
12.  Risk Factors for Cardiovascular Disease across the Spectrum of Older Age: The Cardiovascular Health Study 
Atherosclerosis  2014;237(1):336-342.
Objective
The associations of some risk factors with cardiovascular disease (CVD) are attenuated in older age; whereas others appear robust. The present study aimed to compare CVD risk factors across older age.
Methods
Participants (n=4,883) in the Cardiovascular Health Study free of prevalent CVD, were stratified into three age groups: 65–74, 75–84, 85+ years. Traditional risk factors included systolic blood pressure (BP), LDL-cholesterol, HDL-cholesterol, obesity, and diabetes. Novel risk factors included kidney function, C-reactive protein (CRP), and N-terminal pro-B-type natriuretic peptide (NT pro-BNP).
Results
There were 1,498 composite CVD events (stroke, myocardial infarction, and cardiovascular death) over 5 years. The associations of high systolic BP and diabetes appeared strongest, though both were attenuated with age (p-values for interaction = 0.01 and 0.002, respectively). The demographic-adjusted hazard ratios (HR) for elevated systolic BP were 1.79 (95% confidence interval: 1.49, 2.15), 1.59 (1.37, 1.85) and 1.10 (0.86, 1.41) in participants aged 65–74, 75–84, 85+, and for diabetes, 2.36 (1.89, 2.95), 1.55 (1.27, 1.89), 1.51 (1.10, 2.09). The novel risk factors had consistent associations with the outcome across the age spectrum; low kidney function: 1.69 (1.31, 2.19), 1.61 (1.36, 1.90), and 1.57 (1.16, 2.14) for 65–74, 75–84, and 85+ years, respectively; elevated CRP: 1.54 (1.28, 1.87), 1.33 (1.13, 1.55), and 1.51 (1.15, 1.97); elevated NT pro-BNP: 2.67 (1.96, 3.64), 2.71 (2.25, 3.27), and 2.18 (1.43, 3.45).
Conclusions
The associations of most traditional risk factors with CVD were minimal in the oldest old, whereas diabetes, eGFR, CRP, and NT pro-BNP were associated with CVD across older age.
doi:10.1016/j.atherosclerosis.2014.09.012
PMCID: PMC4254262  PMID: 25303772
aging; epidemiology; risk factors
13.  Genome-wide association study of kidney function decline in individuals of European descent 
Gorski, Mathias | Tin, Adrienne | Garnaas, Maija | McMahon, Gearoid M. | Chu, Audrey Y. | Tayo, Bamidele O. | Pattaro, Cristian | Teumer, Alexander | Chasman, Daniel I. | Chalmers, John | Hamet, Pavel | Tremblay, Johanne | Woodward, Marc | Aspelund, Thor | Eiriksdottir, Gudny | Gudnason, Vilmundur | Harris, Tammara B. | Launer, Lenore J. | Smith, Albert V. | Mitchell, Braxton D. | O'Connell, Jeffrey R. | Shuldiner, Alan R. | Coresh, Josef | Li, Man | Freudenberger, Paul | Hofer, Edith | Schmidt, Helena | Schmidt, Reinhold | Holliday, Elizabeth G. | Mitchell, Paul | Wang, Jie Jin | de Boer, Ian H. | Li, Guo | Siscovick, David S. | Kutalik, Zoltan | Corre, Tanguy | Vollenweider, Peter | Waeber, Gérard | Gupta, Jayanta | Kanetsky, Peter A. | Hwang, Shih-Jen | Olden, Matthias | Yang, Qiong | de Andrade, Mariza | Atkinson, Elizabeth J. | Kardia, Sharon L.R. | Turner, Stephen T. | Stafford, Jeanette M. | Ding, Jingzhong | Liu, Yongmei | Barlassina, Cristina | Cusi, Daniele | Salvi, Erika | Staessen, Jan A | Ridker, Paul M | Grallert, Harald | Meisinger, Christa | Müller-Nurasyid, Martina | Krämer, Bernhard K. | Kramer, Holly | Rosas, Sylvia E. | Nolte, Ilja M. | Penninx, Brenda W. | Snieder, Harold | Del Greco, Fabiola | Franke, Andre | Nöthlings, Ute | Lieb, Wolfgang | Bakker, Stephan J.L. | Gansevoort, Ron T. | van der Harst, Pim | Dehghan, Abbas | Franco, Oscar H. | Hofman, Albert | Rivadeneira, Fernando | Sedaghat, Sanaz | Uitterlinden, André G. | Coassin, Stefan | Haun, Margot | Kollerits, Barbara | Kronenberg, Florian | Paulweber, Bernhard | Aumann, Nicole | Endlich, Karlhans | Pietzner, Mike | Völker, Uwe | Rettig, Rainer | Chouraki, Vincent | Helmer, Catherine | Lambert, Jean-Charles | Metzger, Marie | Stengel, Benedicte | Lehtimäki, Terho | Lyytikäinen, Leo-Pekka | Raitakari, Olli | Johnson, Andrew | Parsa, Afshin | Bochud, Murielle | Heid, Iris M. | Goessling, Wolfram | Köttgen, Anna | Kao, H. Linda | Fox, Caroline S. | Böger, Carsten A.
Kidney international  2014;87(5):1017-1029.
Genome wide association studies (GWAS) have identified multiple loci associated with cross-sectional eGFR, but a systematic genetic analysis of kidney function decline over time is missing. Here we conducted a GWAS meta-analysis among 63,558 participants of European descent, initially from 16 cohorts with serial kidney function measurements within the CKDGen Consortium, followed by independent replication among additional participants from 13 cohorts. In stage 1 GWAS meta-analysis, SNPs at MEOX2, GALNT11, IL1RAP, NPPA, HPCAL1 and CDH23 showed the strongest associations for at least one trait, in addition to the known UMOD locus which showed genome-wide significance with an annual change in eGFR. In stage 2 meta-analysis, the significant association at UMOD was replicated. Associations at GALNT11 with Rapid Decline (annual eGFRdecline of 3ml/min/1.73m2 or more), and CDH23 with eGFR change among those with CKD showed significant suggestive evidence of replication. Combined stage 1 and 2 meta-analyses showed significance for UMOD, GALNT11 and CDH23. Morpholino knockdowns of galnt11 and cdh23 in zebrafish embryos each had signs of severe edema 72 hours after gentamicin treatment compared to controls, but no gross morphological renal abnormalities before gentamicin administration. Thus, our results suggest a role in the deterioration of kidney function for the loci GALNT11 and CDH23, and show that the UMOD locus is significantly associated with kidney function decline.
doi:10.1038/ki.2014.361
PMCID: PMC4425568  PMID: 25493955
chronic kidney disease; kidney development
14.  Plasma phospholipid and dietary α-linolenic acid, mortality, CHD and stroke: the Cardiovascular Health Study 
The British journal of nutrition  2014;112(7):1206-1213.
Previous studies have suggested that long-chain n-3 fatty acids derived from seafood are associated with a lower risk of mortality, CHD and stroke. Whether α-linolenic acid (ALA, 18: 3n-3), a plant-derived long-chain essential n-3 fatty acid, is associated with a lower risk of these outcomes is unclear. The aim of the present study was to examine the associations of plasma phospholipid and dietary ALA with the risk of mortality, CHD and stroke among older adults who participated in the Cardiovascular Health Study, a cohort study of adults aged ≥65 years. A total of 2709 participants were included in the plasma phospholipid ALA analysis and 2583 participants were included in the dietary ALA analysis. Cox regression was used to assess the associations of plasma phospholipid and dietary ALA with the risk of mortality, incident CHD and stroke. In minimally and multivariable-adjusted models, plasma phospholipid ALA was found to be not associated with the risk of mortality, incident CHD or stroke. After adjustment for age, sex, race, enrolment site, education, smoking status, diabetes, BMI, alcohol consumption, treated hypertension and total energy intake, higher dietary ALA intake was found to be associated with a lower risk of total and non-cardiovascular mortality; on comparing the highest quintiles of dietary ALA with the lowest quintiles, the HR for total mortality and non-cardiovascular mortality were found to be 0·73 (95 % CI 0·61, 0·88) and 0·64 (95 % CI 0·52, 0·80), respectively. Dietary ALA was found to be not associated with the risk of cardiovascular mortality, incident CHD or stroke. In conclusion, the results of the present suggest study that dietary ALA, but not plasma phospholipid ALA, is associated with a lower risk of total and non-cardiovascular mortality in older adults.
doi:10.1017/S0007114514001925
PMCID: PMC4192018  PMID: 25159901
Fatty acids; α-Linolenic acid; Mortality; CVD
15.  Circulating Omega-6 Polyunsaturated Fatty Acids and Total and Cause-Specific Mortality: The Cardiovascular Health Study 
Circulation  2014;130(15):1245-1253.
Background
While omega-6 polyunsaturated fatty acids(n-6 PUFA) have been recommended to reduce CHD, controversy remains about benefits vs. harms, including concerns over theorized pro-inflammatory effects of n-6 PUFA. We investigated associations of circulating n-6 PUFA including linoleic acid(LA, the major dietary PUFA), γ-linolenic acid(GLA), dihomo-γ-linolenic acid(DGLA), and arachidonic acid(AA),with total and cause-specific mortality in the Cardiovascular Health Study, a community-based US cohort.
Methods and Results
Among 2,792 participants(age≥65y) free of CVD at baseline, plasma phospholipid n-6 PUFAwere measured at baseline using standardized methods. All-cause and cause-specific mortality, and total incident CHD and stroke, were assessed and adjudicated centrally. Associations of PUFA with risk were assessed by Cox regression. During 34,291 person-years of follow-up(1992–2010), 1,994 deaths occurred(678 cardiovascular deaths), with 427 fatal and 418 nonfatal CHD, and 154 fatal and 399 nonfatal strokes. In multivariable models, higher LA was associated with lower total mortality, with extreme-quintile HR=0.87(P-trend=0.005). Lower death was largely attributable to CVD causes, especially nonarrhythmic CHD mortality(HR=0.51, 95%CI=0.32–0.82, P-trend=0.001). Circulating GLA, DGLA, and AA were not significantly associated with total or cause-specific mortality; e.g., for AA and CHD death, the extreme-quintile HR was 0.97 (95%CI=0.70–1.34, P-trend=0.87). Evaluated semi-parametrically, LA showed graded inverse associations with total mortality(P=0.005). There was little evidence that associations of n-6 PUFA with total mortality varied by age, sex, race, or plasma n-3 PUFA. Evaluating both n-6 and n-3 PUFA, lowest risk was evident with highest levels of both.
Conclusions
High circulating LA, but not other n-6 PUFA, was inversely associated with total and CHD mortality in older adults.
doi:10.1161/CIRCULATIONAHA.114.011590
PMCID: PMC4189990  PMID: 25124495
Fatty Acids; Omega-6; Cardiovascular diseases; Epidemiology; Mortality
16.  Plasma vitamin D is associated with fasting insulin and HOMA-IR in young adult males, but not females, of the Jerusalem Perinatal Study 
Public health nutrition  2014;18(7):1324-1331.
Objective
To examine cross-sectional relationships between plasma vitamin D and Cardiometabolic Risk Factors in young adults.
Design
Data were collected from interviews, physical examinations, and biomarker measurements. Total plasma 25-hydroxyvitamin D (25[OH]D) was measured using liquid chromatography-tandem mass spectrometry. Associations between 25[OH]D and CMR were modeled using weighted linear regression with robust standard error estimates.
Setting
Individuals born in Jerusalem during 1974-1976.
Subjects
Participants of the Jerusalem Perinatal Study (n = 1,204) interviewed and examined at age 32 years. Participants were oversampled for low and high birthweight and for maternal pre-pregnancy obesity.
Results
Mean total 25[OH]D concentration among participants was 21.7 ng/mL (SD 8.9). Among males, 25[OH]D was associated with Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) (natural log-transformed, β = -0.011, p = 0.004) after adjustment for body mass index. However, these associations were not present among females (p for sex interaction = 0.005).
Conclusions
We found evidence for inverse associations of 25[OH]D with markers of insulin resistance among males, but not females, in a health, young adult Caucasian population. Prospective studies and studies conducted on other populations investigating sex specific effects of vitamin D on CMR are warranted.
doi:10.1017/S1368980014001475
PMCID: PMC4592940  PMID: 25145881
17.  Erythrocyte Very Long-Chain Saturated Fatty Acids Associated with Lower Risk of Incident Sudden Cardiac Arrest 
Prior studies suggest that circulating n-3 and trans-fatty acids influence the risk of sudden cardiac arrest (SCA). Yet, while other fatty acids also differ in their membrane properties and biological activities which may influence SCA, little is known about the associations of other circulating fatty acids with SCA. The aim of this study was to investigate the associations of 17 erythrocyte membrane fatty acids with SCA risk. We used data from a population-based case-control study of SCA in the greater Seattle, Washington, area. Cases, aged 25–74 years, were out-of-hospital SCA patients, attended by paramedics (n=265). Controls, matched to cases by age, sex and calendar year, were randomly identified from the community (n=415). All participants were free of prior clinically-diagnosed heart disease. Blood was obtained at the time of cardiac arrest by attending paramedics (cases) or at the time of an interview (controls). Higher levels of erythrocyte very long-chain saturated fatty acids (VLSFA) were associated with lower risk of SCA. After adjustment for risk factors and levels of n-3 and trans-fatty acids, higher levels of 20:0 corresponding to 1 SD were associated with 30% lower SCA risk (13%-43%, p=0.001). Higher levels of 22:0 and 24:0 were associated with similar lower SCA risk (ORs for 1 SD-difference: 0.71 [95% CI: 0.57–0.88, p=0.002] for 22:0; and 0.79 [95% CI: 0.63–0.98, p=0.04] for 24:0). These novel findings support the need for investigation of biologic effects of circulating VLSFA and their determinants.
doi:10.1016/j.plefa.2014.07.010
PMCID: PMC4156887  PMID: 25107579
cardiac arrest; fatty acids; epidemiology
18.  Low Serum Bicarbonate and Kidney Function Decline: The Multi-Ethnic Study of Atherosclerosis (MESA) 
Background
Among populations with established chronic kidney disease (CKD), metabolic acidosis is associated with more rapid progression of kidney disease. The association of serum bicarbonate concentrations with early declines in kidney function is less clear.
Study Design
Retrospective cohort study.
Setting & Participants
6380 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) with a baseline estimated glomerular filtration rate (eGFR) >60 mL/min/1.73m2 using the CKD-EPI (CKD Epidemiology Collaboration) creatinine–cystatin C equation.
Predictors
Serum bicarbonate concentrations.
Outcomes
Rapid kidney function decline (eGFR decline >5% per year) and incident reduced eGFR (eGFR<60 mL/min/1.73 m2 with minimum rate of eGFR loss of 1 mL/min/1.73 m2 per year).
Results
The average bicarbonate concentration was 23.2 ± 1.8 mEq/L. 1730 (33%) participants had rapid kidney function decline, and 487 had incident reduced eGFR during follow-up. Each 1-SD lower baseline bicarbonate concentration was associated with 12% higher adjusted odds of rapid kidney function decline (95% CI, 6%–20%) and higher risk of incident reduced eGFR (adjusted incidence rate ratio, 1.11; 95% CI, 1.03–1.20) in models adjusting for demographics, baseline eGFR, albuminuria, and CKD risk factors. The OR for the associations of bicarbonate <21mEq/L relative to 23–24 mEq/L was 1.35 (95% CI, 1.05–1.73) for rapid kidney function decline, and the incidence rate ratio was 1.16 (95% CI, 0.83–1.62) for incident reduced eGFR.
Limitations
Etiology of metabolic acidosis cannot be determined in this study.
Conclusions
Lower serum bicarbonate concentrations are independently associated with rapid kidney function decline independent of eGFR or albuminuria in community-living persons with a baseline eGFR >60 mL/min/1.73 m2. If confirmed, our findings suggest that metabolic acidosis may indicate either early kidney disease that is not captured by eGFR or albuminuria, or may have a causal role in the development of an eGFR <60 mL/min/1.73 m2.
doi:10.1053/j.ajkd.2014.05.008
PMCID: PMC4177290  PMID: 24953891
serum bicarbonate; metabolic acidosis; chronic kidney disease (CKD); kidney function; renal disease; disease progression; kidney disease trajectory
19.  Plasma Free Fatty Acids and Risk of Stroke in the Cardiovascular Health Study 
Background
While free fatty acids (FFA) have been positively associated with risk factors for stroke, the role of plasma FFA in the development of stroke has not been elucidated in older adults.
Aims
We sought to examine the association between plasma FFA and incident stroke.
Methods
Prospective cohort of 4,369 men and women ≥65 years of age in the Cardiovascular Health Study. Plasma levels of FFA were measured at the 1992–93 examination and stroke events were adjudicated by a committee of experts including neurologists and neuroradiologists. Cox regression was used to estimate the relative risk of stroke associated with FFA concentrations.
Results
The average age among participants was 75 ± 5.2 years. During a median follow-up of 11.4 years, 732 incident strokes occurred. The crude incidence rates of stroke were 14.5, 14.9, and 17.6 per 1,000 person-years across increasing tertiles of plasma FFA. The adjusted hazard ratio (95% CI) for incident stroke was 1.05 (0.97–1.14) per standard deviation (SD) increase in plasma FFA. Restriction to ischemic stroke did not alter the results [hazard ratio (95% CI): 1.04 (0.96–1.14) per SD higher FFA] and there was no effect modification by adiposity (p interaction = 0.18) or by diabetes (p interaction = 0.15).
Conclusion
Our data did not show an association of plasma FFA with incident stroke among community dwelling older adults.
doi:10.1111/ijs.12216
PMCID: PMC4105335  PMID: 24447493
20.  Plasma Free Fatty Acids, Fatty Acid-binding Protein 4, and Mortality in Older Adults (From the Cardiovascular Health Study) 
The American journal of cardiology  2014;114(6):843-848.
Plasma free fatty acids (FFA) are largely derived from adipose tissue. Elevated levels of FFA and fatty acid-binding protein 4 (FABP4), a key cytoplasmic chaperone of fatty acids, have been associated with adverse cardiovascular outcomes but limited data are available on the relation of these biomarkers with cardiovascular and total mortality. We studied 4,707 participants with a mean age of 75 years who had plasma FFA and FABP4 measured in 1992–1993 as part of the Cardiovascular Health Study, an observational cohort of community dwelling older adults. Over a median follow-up of 11.8 years, 3,555 participants died. Cox proportional hazard regression was used to determine the association between FFA, FABP4, and mortality. In fully adjusted models, FFA were associated with dose-dependent significantly higher total mortality (hazard ratio (HR) per standard deviation (SD): 1.14, 95% confidence interval (CI) 1.09–1.18), but FABP4 levels were not (HR 1.04, 95% CI 0.98–1.09). In a cause-specific mortality analysis, higher concentrations of FFA were associated with significantly higher risk of death due to cardiovascular disease, dementia, infection, and respiratory causes, but not cancer or trauma. We did not find evidence of an interaction between FFA and FABP4 (p=0.45), but FABP4 appeared to be associated with total mortality differentially among men and women (HR 1.17 (1.08–1.26) for men, HR 1.02 (0.96–1.07) for women, interaction p-value <0.001). In conclusion, in a cohort of community-dwelling older individuals, elevated plasma concentrations of FFA, but not FABP4, were associated with cardiovascular and non-cardiovascular mortality.
doi:10.1016/j.amjcard.2014.06.012
PMCID: PMC4162821  PMID: 25073566
Fatty acids; Mortality; Epidemiology
21.  Multiple rare alleles at LDLR and APOA5 confer risk for early-onset myocardial infarction 
Do, Ron | Stitziel, Nathan O. | Won, Hong-Hee | Jørgensen, Anders Berg | Duga, Stefano | Merlini, Pier Angelica | Kiezun, Adam | Farrall, Martin | Goel, Anuj | Zuk, Or | Guella, Illaria | Asselta, Rosanna | Lange, Leslie A. | Peloso, Gina M. | Auer, Paul L. | Girelli, Domenico | Martinelli, Nicola | Farlow, Deborah N. | DePristo, Mark A. | Roberts, Robert | Stewart, Alexander F.R. | Saleheen, Danish | Danesh, John | Epstein, Stephen E. | Sivapalaratnam, Suthesh | Hovingh, G. Kees | Kastelein, John J. | Samani, Nilesh J. | Schunkert, Heribert | Erdmann, Jeanette | Shah, Svati H. | Kraus, William E. | Davies, Robert | Nikpay, Majid | Johansen, Christopher T. | Wang, Jian | Hegele, Robert A. | Hechter, Eliana | Marz, Winfried | Kleber, Marcus E. | Huang, Jie | Johnson, Andrew D. | Li, Mingyao | Burke, Greg L. | Gross, Myron | Liu, Yongmei | Assimes, Themistocles L. | Heiss, Gerardo | Lange, Ethan M. | Folsom, Aaron R. | Taylor, Herman A. | Olivieri, Oliviero | Hamsten, Anders | Clarke, Robert | Reilly, Dermot F. | Yin, Wu | Rivas, Manuel A. | Donnelly, Peter | Rossouw, Jacques E. | Psaty, Bruce M. | Herrington, David M. | Wilson, James G. | Rich, Stephen S. | Bamshad, Michael J. | Tracy, Russell P. | Cupples, L. Adrienne | Rader, Daniel J. | Reilly, Muredach P. | Spertus, John A. | Cresci, Sharon | Hartiala, Jaana | Tang, W.H. Wilson | Hazen, Stanley L. | Allayee, Hooman | Reiner, Alex P. | Carlson, Christopher S. | Kooperberg, Charles | Jackson, Rebecca D. | Boerwinkle, Eric | Lander, Eric S. | Schwartz, Stephen M. | Siscovick, David S. | McPherson, Ruth | Tybjaerg-Hansen, Anne | Abecasis, Goncalo R. | Watkins, Hugh | Nickerson, Deborah A. | Ardissino, Diego | Sunyaev, Shamil R. | O’Donnell, Christopher J. | Altshuler, David | Gabriel, Stacey | Kathiresan, Sekar
Nature  2014;518(7537):102-106.
Summary
Myocardial infarction (MI), a leading cause of death around the world, displays a complex pattern of inheritance1,2. When MI occurs early in life, the role of inheritance is substantially greater1. Previously, rare mutations in low-density lipoprotein (LDL) genes have been shown to contribute to MI risk in individual families3–8 whereas common variants at more than 45 loci have been associated with MI risk in the population9–15. Here, we evaluate the contribution of rare mutations to MI risk in the population. We sequenced the protein-coding regions of 9,793 genomes from patients with MI at an early age (≤50 years in males and ≤60 years in females) along with MI-free controls. We identified two genes where rare coding-sequence mutations were more frequent in cases versus controls at exome-wide significance. At low-density lipoprotein receptor (LDLR), carriers of rare, damaging mutations (3.1% of cases versus 1.3% of controls) were at 2.4-fold increased risk for MI; carriers of null alleles at LDLR were at even higher risk (13-fold difference). This sequence-based estimate of the proportion of early MI cases due to LDLR mutations is remarkably similar to an estimate made more than 40 years ago using total cholesterol16. At apolipoprotein A-V (APOA5), carriers of rare nonsynonymous mutations (1.4% of cases versus 0.6% of controls) were at 2.2-fold increased risk for MI. When compared with non-carriers, LDLR mutation carriers had higher plasma LDL cholesterol whereas APOA5 mutation carriers had higher plasma triglycerides. Recent evidence has connected MI risk with coding sequence mutations at two genes functionally related to APOA5, namely lipoprotein lipase15,17 and apolipoprotein C318,19. When combined, these observations suggest that, beyond LDL cholesterol, disordered metabolism of triglyceride-rich lipoproteins contributes to MI risk.
doi:10.1038/nature13917
PMCID: PMC4319990  PMID: 25487149
22.  CIRCULATING LEVELS OF CARBOXY-METHYL-LYSINE (CML) ARE ASSOCIATED WITH HIP FRACTURE RISK 
Advanced glycation end products (AGE) in bone tissue are associated with impaired biomechanical properties and increased fracture risk. Here we examine whether serum levels of the AGE carboxy-methyl-lysine (CML) are associated with risk of hip fracture.
We followed 3373 participants from the Cardiovascular Health Study (age 78 years; 39.8% male) for a median of 9.22 years. Rates of incident hip fracture were calculated by quartiles of baseline CML levels, and hazard ratios were adjusted for covariates associated with hip fracture risk. A sub-cohort of 1315 participants had bone mineral density (BMD) measurement.
There were 348 hip fractures during follow-up, with incidence rates of hip fracture by CML quartiles of 0.94, 1.34, 1.18, and 1.69 / 100 participant-years. The unadjusted hazard ratio of hip fracture increased with each 1 SD increase (189 ng/ml) of CML level (1.27 [1.16, 1.40]; p<.001). Sequential adjustment for age, gender, race/ethnicity, BMI, smoking, alcohol consumption, prevalent CHD, energy expenditure, eGFR (based on cystatin C), and diabetes moderately attenuated the hazard ratio for fracture (1.17 [1.05, 1.31]; p=.006). In the cohort with BMD testing, total hip BMD was not significantly related to CML levels.
We conclude that increasing levels of CML are associated with hip fracture risk in older adults, independent of hip BMD. These results implicate AGE in the pathogenesis of hip fractures.
PMCID: PMC4523135  PMID: 24877243
Carboxy-methyl-lysine; hip fracture risk; bone quality; Cardiovascular Health Study; bone mineral density
23.  Estimated GFR and Circulating 24,25-Dihydroxyvitamin D3 Concentration: A Participant-Level Analysis of 5 Cohort Studies and Clinical Trials 
Background
Decreased glomerular filtration rate (GFR) leads to reduced production of 1,25-dihydroxyvitamin D3 from 25-hydroxyvitamin D3 (25(OH)D3). Effects of low GFR on vitamin D catabolism are less well understood. We tested associations of estimated GFR (eGFR) with the circulating concentration of 24,25-dihydroxyvitamin D3 (24,25(OH)2D3), the most abundant product of 25(OH)D3 catabolism, across populations with a wide range of GFR.
Study Design
Cross-sectional study.
Setting & Participants
9596 participants in 5 cohort studies and clinical trials: the Diabetes Control and Complications Trial (N=1193), Multi-Ethnic Study of Atherosclerosis (N=6470), Cardiovascular Health Study (N=932), Seattle Kidney Study (N=289), and Hemodialysis Study (N=712).
Predictor
eGFR.
Outcome
Circulating 24,25(OH)2D3 concentration.
Measurements
GFR was estimated from serum creatinine using the Chronic Kidney Disease Epidemiology Collaboration equation. Vitamin D metabolites were measured by mass spectrometry.
Results
Circulating 24,25(OH)2D3 concentration was correlated with circulating 25(OH)D3 concentration (Pearson r range, 0.64–0.88). This correlation was weaker with lower eGFR. Moreover, the increment in 24,25(OH)2D3 associated with higher 25(OH)D3 (“slope”) was lower with lower eGFR: 2.06 (95% CI, 2.01–2.10), 1.77 (95% CI, 1.74–1.81), 1.55 (95% CI, 1.48–1.62), 1.17 (95% CI, 1.05–1.29), 0.92 (95% CI, 0.74–1.10), 0.61 (95% CI, 0.22–1.00), and 0.37 (95% CI, 0.35–0.39) ng/mL 24,25(OH)2D3 per 10 ng/mL 25(OH)D3 for eGFR ≥90, 60–89, 45–59, 30–44, 15–29, and <15 mL/min/1.73 m2 and ESRD treated with hemodialysis, respectively. As a result, at a 25(OH)D3 concentration of 20 ng/mL, mean 24,25(OH)2D3 concentration was 2.92 (95% CI, 2.87–2.96), 2.68 (95% CI, 2.64–2.72), 2.35 (95% CI, 2.26–2.45), 1.92 (95% CI, 1.74–2.10), 1.69 (95% CI, 1.43–1.95), 1.14 (95% CI, 0.62–1.66), and 1.04 (95% CI,1.02–1.07) ng/mL for each category, respectively. This interaction was independent of other relevant clinical characteristics. Race, diabetes, urine albumin excretion, and the circulating concentrations of parathyroid hormone and fibroblast growth factor 23 more modestly modified the association of 24,25(OH)2D3 with 25(OH)D3.
Limitations
Lack of direct pharmacokinetic measurements of vitamin D catabolism.
Conclusions
Lower eGFR is strongly associated with reduced vitamin D catabolism as measured by circulating 24,25(OH)2D3 concentration.
doi:10.1053/j.ajkd.2014.02.015
PMCID: PMC4111986  PMID: 24703961
decreased renal function; low estimated glomerular filtration rate; vitamin D catabolism; 1,25-dihydroxyvitamin D3; 25-hydroxyvitamin D3; active vitamin D; chronic kidney disease (CKD); biomarker
24.  Life’s Simple 7 and Incidence of Diabetes Among American Indians: The Strong Heart Family Study 
Diabetes Care  2014;37(8):2240-2245.
OBJECTIVE
The American Heart Association’s recommendations for optimal health, summarized in Life’s Simple 7, have been associated with reduced risk of cardiovascular disease (CVD)-related end points, but no studies have examined the association of these goals with incident type 2 diabetes, which is associated with high risk for CVD. The purpose of this analysis was to examine the associations of Life’s Simple 7 goals with incident diabetes among American Indians, a population at high risk of cardiometabolic diseases.
RESEARCH DESIGN AND METHODS
Strong Heart Family Study participants without diabetes (n = 1,639) at baseline and who participated in a follow-up examination were included in the analysis. Risk scores ranging from 0 to 7 were created using physical activity, diet, BMI, smoking, blood pressure, fasting glucose, and cholesterol metrics in accordance with Life’s Simple 7 goals. Diabetes was defined using 2003 American Diabetes Association criteria, including use of insulin or oral antidiabetes medication or a follow-up fasting plasma glucose level ≥126 mg/dL. Generalized estimating equations were used to examine the association of risk scores with incident diabetes.
RESULTS
During a mean 5-year follow-up (range 4–8 years), we identified 210 cases of incident type 2 diabetes. Compared with participants who achieved 0–1 goals, those who achieved 2–3 or 4+ goals had lower odds of diabetes, with odds ratios = 0.40 (95% CI 0.29–0.56) and 0.11 (95% CI 0.05–0.21), respectively.
CONCLUSIONS
The adoption of as few as two or three Life’s Simple 7 goals is associated with a lower risk of diabetes.
doi:10.2337/dc13-2267
PMCID: PMC4113167  PMID: 24804696
25.  Parental Smoking during Pregnancy and Offspring Cardio-Metabolic Risk Factors at ages 17 and 32 
Atherosclerosis  2014;235(2):430-437.
Objective
To examine the association of maternal and/or paternal smoking during pregnancy with offspring cardio-metabolic risk (CMR) factors at adolescence and early adulthood, taking into account socio-demographic, medical and lifestyle characteristics of parents and offspring, as well as offspring common genetic variation.
Methods
We used a population-based cohort of all 17 003 births in Jerusalem during 1974–76, with available archival data on parental and birth characteristics. Measurements at age 17 were assessed at military induction examinations for 11 530 offspring. 1440 offspring from the original 1974–1976 birth cohort were sampled using a stratified sampling approach, and were interviewed and examined at age 32. Parental smoking during pregnancy (i.e. maternal, paternal and any parent) was primarily defined dichotomously (any number of cigarettes smoked daily by mother or father during pregnancy vs. non-smokers). Additionally, smoking was assessed by quantity of cigarettes smoked daily. Linear regression models were used to evaluate the associations of parental smoking during pregnancy with various offspring CMR factors, after controlling for potential confounders and for genetic variation in candidate genes.
Results
Prevalence of exposure to parental smoking in-utero (i.e. smoking of any parent) was 53.2% and 48.4% among the 17 years old and 32 years old samples, respectively. At age 17, smoking of at least one parent during pregnancy was significantly associated with weight (B=1.39), height (B=0.59), BMI (B=0.32) and pulse rate (B=−0.78) (p-values<0.001). At age 32, parental smoking, adjusted for covariates, was associated with 2.22 kg higher mean offspring weight, 0.95 cm higher mean offspring height, 0.57 kg/m2 higher BMI, and 1.46 cm higher waist-circumference (p-values≤0.02). Similar results, reflecting a dose response, were observed when maternal and paternal smoking were assessed by number of cigarettes smoked daily.
Conclusions
This prospective study demonstrates a potential long-term adverse effect of parental smoking during pregnancy on offspring health and calls for increasing efforts to promote smoking cessation of both parents before pregnancy.
doi:10.1016/j.atherosclerosis.2014.05.937
PMCID: PMC4123626  PMID: 24937467
cohort study; smoking; pregnancy; obesity; risk factors

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