03669nas a2200529 4500008004100000022001400041245007400055210006900129260001600198300001200214490000800226520220200234653001802436653001902454653002202473653001102495653001102506653001802517653002002535653000902555653001602564653000902580653002202589100003702611700002102648700002402669700003002693700001302723700001902736700002202755700002402777700002302801700001702824700002102841700002102862700001902883700002102902700001802923700002402941700002302965700001902988700002203007700001703029700001703046710004003063856003603103 2011 eng d a1533-440600aDiabetes mellitus, fasting glucose, and risk of cause-specific death.0 aDiabetes mellitus fasting glucose and risk of causespecific deat c2011 Mar 03 a829-8410 v3643 a

BACKGROUND: The extent to which diabetes mellitus or hyperglycemia is related to risk of death from cancer or other nonvascular conditions is uncertain.

METHODS: We calculated hazard ratios for cause-specific death, according to baseline diabetes status or fasting glucose level, from individual-participant data on 123,205 deaths among 820,900 people in 97 prospective studies.

RESULTS: After adjustment for age, sex, smoking status, and body-mass index, hazard ratios among persons with diabetes as compared with persons without diabetes were as follows: 1.80 (95% confidence interval [CI], 1.71 to 1.90) for death from any cause, 1.25 (95% CI, 1.19 to 1.31) for death from cancer, 2.32 (95% CI, 2.11 to 2.56) for death from vascular causes, and 1.73 (95% CI, 1.62 to 1.85) for death from other causes. Diabetes (vs. no diabetes) was moderately associated with death from cancers of the liver, pancreas, ovary, colorectum, lung, bladder, and breast. Aside from cancer and vascular disease, diabetes (vs. no diabetes) was also associated with death from renal disease, liver disease, pneumonia and other infectious diseases, mental disorders, nonhepatic digestive diseases, external causes, intentional self-harm, nervous-system disorders, and chronic obstructive pulmonary disease. Hazard ratios were appreciably reduced after further adjustment for glycemia measures, but not after adjustment for systolic blood pressure, lipid levels, inflammation or renal markers. Fasting glucose levels exceeding 100 mg per deciliter (5.6 mmol per liter), but not levels of 70 to 100 mg per deciliter (3.9 to 5.6 mmol per liter), were associated with death. A 50-year-old with diabetes died, on average, 6 years earlier than a counterpart without diabetes, with about 40% of the difference in survival attributable to excess nonvascular deaths.

CONCLUSIONS: In addition to vascular disease, diabetes is associated with substantial premature death from several cancers, infectious diseases, external causes, intentional self-harm, and degenerative disorders, independent of several major risk factors. (Funded by the British Heart Foundation and others.).

10aBlood Glucose10aCause of Death10aDiabetes Mellitus10aFemale10aHumans10aHyperglycemia10aLife Expectancy10aMale10aMiddle Aged10aRisk10aSurvival Analysis1 aSeshasai, Sreenivasa, Rao Kondap1 aKaptoge, Stephen1 aThompson, Alexander1 aDi Angelantonio, Emanuele1 aGao, Pei1 aSarwar, Nadeem1 aWhincup, Peter, H1 aMukamal, Kenneth, J1 aGillum, Richard, F1 aHolme, Ingar1 aNjølstad, Inger1 aFletcher, Astrid1 aNilsson, Peter1 aLewington, Sarah1 aCollins, Rory1 aGudnason, Vilmundur1 aThompson, Simon, G1 aSattar, Naveed1 aSelvin, Elizabeth1 aHu, Frank, B1 aDanesh, John1 aEmerging Risk Factors Collaboration uhttps://chs-nhlbi.org/node/127203099nas a2200481 4500008004100000022001400041245014200055210006900197260001600266520168500282100002201967700002301989700002402012700001702036700001302053700001202066700002202078700001702100700002002117700002002137700001802157700002402175700002002199700002102219700002202240700002002262700001902282700001402301700002202315700002202337700002002359700002102379700001702400700002202417700002402439700001802463700001702481700002702498700001602525700002102541700001902562856003602581 2017 eng d a1460-208300aDetection of genetic loci associated with plasma fetuin-A: A meta-analysis of genome-wide association studies from the CHARGE Consortium.0 aDetection of genetic loci associated with plasma fetuinA A metaa c2017 Apr 033 a

Plasma fetuin-A is associated with type 2 diabetes, and AHSG, the gene encoding fetuin-A, has been identified as a susceptibility locus for diabetes and metabolic syndrome. Thus far, unbiased investigations of the genetic determinants of plasma fetuin-A concentrations have not been conducted. We searched for single nucleotide polymorphisms (SNPs) related to fetuin-A concentrations by a genome-wide association study in six population-based studies.We examined the association of fetuin-A levels with ∼ 2.5 million genotyped and imputed SNPs in 9,055 participants of European descent and 2,119 African Americans. In both ethnicities, strongest associations were centered in a region with a high degree of LD near the AHSG locus. Among 136 genome-wide significant (p < 0.05x10-8) SNPs near the AHSG locus, the top SNP was rs4917 (p = 1.27x10-303), a known coding SNP in exon 6 that is associated with a 0.06 g/L (∼13%) lower fetuin-A level. This variant alone explained 14% of the variation in fetuin-A levels. Analyses conditioned on rs4917 indicated that the strong association with the AHSG locus stems from additional independent associations of multiple variants among European Americans. In conclusion, levels of fetuin-A in plasma are strongly associated with SNPs in its encoding gene, AHSG, but not elsewhere in the genome. Given the strength of the associations observed for multiple independent SNPs, the AHSG gene is an example of a candidate locus suitable for additional investigations including fine mapping to elucidate the biological basis of the findings and further functional experiments to clarify AHSG as a potential therapeutic target.

1 aJensen, Majken, K1 aJensen, Richard, A1 aMukamal, Kenneth, J1 aGuo, Xiuqing1 aYao, Jie1 aSun, Qi1 aCornelis, Marilyn1 aLiu, Yongmei1 aChen, Ming-Huei1 aKizer, Jorge, R1 aDjoussé, Luc1 aSiscovick, David, S1 aPsaty, Bruce, M1 aZmuda, Joseph, M1 aRotter, Jerome, I1 aGarcia, Melissa1 aHarris, Tamara1 aChen, Ida1 aGoodarzi, Mark, O1 aNalls, Michael, A1 aKeller, Margaux1 aArnold, Alice, M1 aNewman, Anne1 aHoogeeven, Ron, C1 aRexrode, Kathryn, M1 aRimm, Eric, B1 aHu, Frank, B1 aVasan, Ramachandran, S1 aKatz, Ronit1 aPankow, James, S1 aIx, Joachim, H uhttps://chs-nhlbi.org/node/732802519nas a2200217 4500008004100000022001400041245010400055210006900159260001600228520182600244100002402070700002102094700001902115700002302134700002202157700002402179700002402203700001802227700002002245856003602265 2022 eng d a1468-201X00aDysregulated carbohydrate and lipid metabolism and risk of atrial fibrillation in advanced old age.0 aDysregulated carbohydrate and lipid metabolism and risk of atria c2022 Dec 223 a

OBJECTIVE: Obesity and dysmetabolism are major risk factors for atrial fibrillation (AF). Fasting and postload levels of glucose and non-esterified fatty acids (NEFAs) reflect different facets of metabolic regulation. We sought to study their respective contributions to AF risk concurrently.

METHODS: We assessed levels of fasting and postload glucose and NEFA in the Cardiovascular Health Study to identify associations with AF incidence and, secondarily, with ECG parameters of AF risk available at baseline. Linear and Cox regressions were performed.

RESULTS: The study included 1876 participants (age 77.7±4.4). During the median follow-up of 11.4 years, 717 cases of incident AF occurred. After adjustment for potential confounders, postload glucose showed an association with incident AF (HR per SD increment of postload glucose=1.11, 95% CI 1.02 to 1.21, p=0.017). Both glucose measures, but not NEFA, were positively associated with higher P wave terminal force in V1 (PTFV1); the association remained significant only for postload glucose when the two measures were entered together (β per SD increment=138 μV·ms, 95% CI 15 to 260, p=0.028). Exploratory analyses showed significant interaction by sex for fasting NEFA (p=0.044) and postload glucose (p=0.015) relative to AF, with relationships stronger in women. For postload glucose, the association with incident AF was observed among women but not among men.

CONCLUSIONS: Among older adults, postload glucose was positively associated with incident AF, with consistent findings for PTFV1. In exploratory analyses, the relationship with AF appeared specific to women. These findings require further study but suggest that interventions to address postprandial dysglycaemia late in life might reduce AF.

1 aPellegrini, Cara, N1 aBůzková, Petra1 aOesterle, Adam1 aHeckbert, Susan, R1 aTracy, Russell, P1 aSiscovick, David, S1 aMukamal, Kenneth, J1 aDjoussé, Luc1 aKizer, Jorge, R uhttps://chs-nhlbi.org/node/925902596nas a2200217 4500008004100000022001400041245012300055210006900178260001300247300001100260490000700271520191500278100002502193700002402218700001902242700002002261700001902281700001802300700002402318856003602342 2023 eng d a2589-936800aThe determinants of fasting and post-load non-esterified fatty acids in older adults: The cardiovascular health study.0 adeterminants of fasting and postload nonesterified fatty acids i c2023 Dec a1002610 v203 a

AIM: Non-esterified fatty acids (NEFA) are potential targets for prevention of key cardiometabolic diseases of aging, but their population-level correlates remain uncertain. We sought to identify modifiable factors associated with fasting and post-load NEFA levels in older adults.

METHODS: We used linear regression to determine the cross-sectional associations of demographic, anthropometric, and lifestyle characteristics and medication use with serum fasting and post-load NEFA concentrations amongst community-dwelling older adults enrolled in the Cardiovascular Health Study (n = 1924).

RESULTS: Fasting NEFA levels generally demonstrated a broader set of determinants, while post-load NEFA were more consistently associated with metabolic factors. Waist circumference and weight were associated with higher fasting and post-load NEFA. Cigarette smoking and caffeine intake were associated with lower levels of both species, and moderate alcohol intake was associated with higher fasting levels whereas greater consumption was associated with lower post-load levels. Unique factors associated with higher fasting NEFA included female sex, higher age, loop and thiazide diuretic use and calcium intake, while factors associated with lower fasting levels included higher educational attainment, beta-blocker use, and protein intake. Hours spent sleeping during the daytime were associated with higher post-load NEFA, while DASH score was associated with lower levels.

CONCLUSION: Fasting and post-load NEFA have both common and unique modifiable risk factors, including sociodemographics, anthropometric, medications, and diet. Post-load NEFA were particularly sensitive to metabolic factors, while a broader range of determinants were associated with fasting levels. These factors warrant study as targets for lowering levels of NEFA in older adults.

1 aBene-Alhasan, Yakubu1 aSiscovick, David, S1 aIx, Joachim, H1 aKizer, Jorge, R1 aTracy, Russell1 aDjoussé, Luc1 aMukamal, Kenneth, J uhttps://chs-nhlbi.org/node/9582