Vitamin K status, all-cause mortality, and cardiovascular disease in adults with chronic kidney disease: the Chronic Renal Insufficiency Cohort.

BACKGROUND: Vascular calcification contributes to cardiovascular disease (CVD) and mortality in individuals with chronic kidney disease (CKD). Vitamin K-dependent proteins function as calcification inhibitors in vascular tissue. OBJECTIVES: We sought to determine the association of vitamin K status with mortality and CVD events in adults with CKD. METHODS: Plasma dephospho-uncarboxylated matrix gla protein ((dp)ucMGP), which increases when vitamin K status is low, and plasma phylloquinone (vitamin K1), which decreases when vitamin K status is low, were measured in 3066 Chronic Renal Insufficiency Cohort participants (median age = 61 y, 45% female, 41% non-Hispanic black, median estimated glomerular filtration rate [eGFR] = 41 mL/min/1.73m2). The association of vitamin K status biomarkers with all-cause mortality and atherosclerotic-related CVD was determined using multivariable Cox proportional hazards regression. RESULTS: There were 1122 deaths and 599 atherosclerotic CVD events over the median 12.8 follow-up years. All-cause mortality risk was 21-29% lower among participants with plasma (dp)ucMGP <450 pmol/L (n = 2361) compared with those with plasma (dp)ucMGP ≥450 pmol/L (adjusted HRs [95% CIs]: <300 pmol/L = 0.71 [0.61, 0.83], 300-449 pmol/L = 0.77 [0.66, 0.90]) and 16-19% lower among participants with plasma phylloquinone ≥0.50 nmol/L (n = 2421) compared to those with plasma phylloquinone <0.50 nmol/L (adjusted HRs: 0.50, 0.99 nmol/L = 0.84 [0.72, 0.99], ≥1.00 nmol/L = 0.81 [0.70, 0.95]). The risk of atherosclerotic CVD events did not significantly differ across plasma (dp)ucMGP or phylloquinone categories. CONCLUSIONS: Two biomarkers of vitamin K status were associated with a lower all-cause mortality risk but not atherosclerotic CVD events. Additional studies are needed to clarify the mechanism underlying this association and evaluate the impact of improving vitamin K status in people with CKD.

Incremental Elevations in TNFα and IL6 in the Human Colon and Procancerous Changes in the Mucosal Transcriptome Accompany Adiposity.

BACKGROUND: Obesity, a risk factor for colorectal cancer, raises systemic levels of proinflammatory mediators. Whether increased levels also reside in the colons of obese individuals and are accompanied by procancerous alterations in the mucosal transcriptome is unknown. METHODS: Concentrations of TNFα, IL1ß, and IL6 in blood and colonic mucosa of 16 lean and 26 obese individuals were examined. Differences in the mucosal transcriptome between the two groups were defined. RESULTS: Plasma IL6 and TNFα were 1.4- to 3-fold elevated in obese subjects [body mass index (BMI) ≥ 34 kg/m2] compared with the lean controls (P < 0.01). Among individuals with BMI ≥ 34 kg/m2 colonic concentrations of IL6 and TNFα were 2- to 3-fold greater than in lean subjects (P < 0.03). In a general linear model, adjusted for NSAID use, colonic IL6 (partial r = 0.41; P < 0.01) and TNFα (partial r = 0.41; P = 0.01) increased incrementally over the entire range of BMIs (18.1-45.7). Regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) was associated with a reduction in colonic IL6 (ß = -0.65, P < 0.02). RNA sequencing (NSAID users excluded) identified 182 genes expressed differentially between lean and obese subjects. The two gene networks most strongly linked to changes in expression included several differentially expressed genes known to regulate the procarcinogenic signaling pathways, NFκB and ERK 1/2, in a pattern consistent with upregulation of each in the obese subjects. CONCLUSIONS: Incremental increases in two major proinflammatory colonic cytokines are associated with increasing BMI, and in the obese state are accompanied by procancerous changes in the transcriptome. IMPACT: These observations delineate means by which an inflammatory milieu may contribute to obesity-promoted colon cancer.

Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels.

Vitamin D is a steroid hormone precursor that is associated with a range of human traits and diseases. Previous GWAS of serum 25-hydroxyvitamin D concentrations have identified four genome-wide significant loci (GC, NADSYN1/DHCR7, CYP2R1, CYP24A1). In this study, we expand the previous SUNLIGHT Consortium GWAS discovery sample size from 16,125 to 79,366 (all European descent). This larger GWAS yields two additional loci harboring genome-wide significant variants (P = 4.7×10-9 at rs8018720 in SEC23A, and P = 1.9×10-14 at rs10745742 in AMDHD1). The overall estimate of heritability of 25-hydroxyvitamin D serum concentrations attributable to GWAS common SNPs is 7.5%, with statistically significant loci explaining 38% of this total. Further investigation identifies signal enrichment in immune and hematopoietic tissues, and clustering with autoimmune diseases in cell-type-specific analysis. Larger studies are required to identify additional common SNPs, and to explore the role of rare or structural variants and gene-gene interactions in the heritability of circulating 25-hydroxyvitamin D levels.

Circulating Vitamin K Is Inversely Associated with Incident Cardiovascular Disease Risk among Those Treated for Hypertension in the Health, Aging, and Body Composition Study (Health ABC).

Background: A role for vitamin K in coronary artery calcification (CAC), a subclinical manifestation of cardiovascular disease (CVD), has been proposed because vitamin K-dependent proteins, including the calcification inhibitor matrix Gla protein (MGP), are present in vascular tissue. Observational studies found that low circulating phylloquinone (vitamin K-1) was associated with increased CAC progression, especially in persons treated for hypertension. It is unknown whether hypertension treatment modifies this putative role of vitamin K in clinical CVD risk.Objective: We determined the association between vitamin K status and incident clinical CVD in older adults in the Health ABC (Health, Aging, and Body Composition Study) and whether the association differed by hypertension treatment status.Methods: Plasma phylloquinone was measured in 1061 participants free of CVD (70-79 y of age, 58% women, 39% black). Plasma uncarboxylated MGP [(dp)ucMGP] was measured in a subset of 635 participants. Multivariate Cox models estimated the HR for incident CVD over 12.1 follow-up years. Effect modification by hypertension was tested with the use of interaction terms.Results: Neither low plasma phylloquinone (<0.2 nmol/L) nor elevated (dp)ucMGP (≥574 pmol/L) was significantly associated with incident CVD [respective HRs (95% CIs): 1.27 (0.75, 2.13) and 1.02 (0.72, 1.45)]. In participants treated for hypertension (n = 489; 135 events), low plasma phylloquinone was associated with higher CVD risk overall (HR: 2.94; 95% CI: 1.41, 6.13). In those with untreated hypertension (n = 153; 48 events) and without hypertension (n = 418; 92 events), low plasma phylloquinone was not associated with incident CVD. The association between high (dp)ucMGP did not differ by hypertension treatment status (P-interaction = 0.72).Conclusions: Vitamin K status was not significantly associated with CVD risk overall, but low plasma phylloquinone was associated with a higher CVD risk in older adults treated for hypertension. Additional evidence from larger clinical studies is needed to clarify the importance of vitamin K to CVD in persons treated for hypertension, a segment of the population at high risk of clinical CVD events.

Potassium Bicarbonate Supplementation Lowers Bone Turnover and Calcium Excretion in Older Men and Women: A Randomized Dose-Finding Trial.

The acid load accompanying modern diets may have adverse effects on bone and muscle metabolism. Treatment with alkaline salts of potassium can neutralize the acid load, but the optimal amount of alkali is not established. Our objective was to determine the effectiveness of two doses of potassium bicarbonate (KHCO3 ) compared with placebo on biochemical markers of bone turnover, and calcium and nitrogen (N) excretion. In this double-blind, randomized, placebo-controlled study, 244 men and women age 50 years and older were randomized to placebo or 1 mmol/kg or 1.5 mmol/kg of KHCO3 daily for 3 months; 233 completed the study. The primary outcomes were changes in 24-hour urinary N-telopeptide (NTX) and N; changes in these measures were compared across the treatment groups. Exploratory outcomes included 24-hour urinary calcium excretion, serum amino-terminal propeptide of type I procollagen (P1NP), and muscle strength and function assessments. The median administered doses in the low-dose and high-dose groups were 81 mmol/day and 122 mmol/day, respectively. When compared with placebo, urinary NTX declined significantly in the low-dose group (p = 0.012, after adjustment for baseline NTX, gender, and change in urine creatinine) and serum P1NP declined significantly in the low-dose group (p = 0.004, adjusted for baseline P1NP and gender). Urinary calcium declined significantly in both KHCO3 groups versus placebo (p < 0.001, adjusted for baseline urinary calcium, gender, and changes in urine creatinine and calcium intake). There was no significant effect of either dose of KHCO3 on urinary N excretion or on the physical strength and function measures. KHCO3 has favorable effects on bone turnover and calcium excretion and the lower dose appears to be the more effective dose. Long-term trials to assess the effect of alkali on bone mass and fracture risk are needed.

25-Hydroxyvitamin D, parathyroid hormone, and mortality in black and white older adults: the health ABC study.

CONTEXT: Previous 25-hydroxyvitamin D [25(OH)D] and mortality studies have included mostly individuals of European descent. Whether the relationship is similar in Blacks and to what extent differences in 25(OH)D explain racial disparities in mortality is unclear. OBJECTIVE: The objective of the study was to examine the relationship between 25(OH)D, PTH, and mortality in Black and white community-dwelling older adults over 8.5 yr of follow-up. DESIGN AND SETTING: Health ABC is a prospective cohort study conducted in Memphis, TN, and Pittsburgh, PA. PARTICIPANTS: Well-functioning Blacks and whites aged 71-80 yr with measured 25(OH)D and PTH (n = 2638; 49% male, 39% Black) were included in the study. MAIN OUTCOME MEASURE: Multivariate-adjusted proportional hazards models estimated the hazard ratios (HR) for all-cause, cardiovascular, cancer, and noncancer, noncardiovascular mortality (n = 691 deaths). RESULTS: Mean 25(OH)D concentrations were higher in whites than in Blacks [mean (sd): 29.0 (9.9) and 20.8 (8.7) ng/ml, respectively; P < 0.001]. Serum 25(OH)D by race interactions were not significant, however. Lower 25(OH)D concentrations were associated with higher mortality in Blacks and whites combined [HR (95% confidence interval [CI] 2.27 (1.59-3.24), 1.48 (1.20-1.84), and 1.25 (1.02-1.52) for < 10, 10 to < 20, and 20 to < 30 vs. ≥30 ng/ml]. In the multivariate model without 25(OH)D, Blacks had 22% higher mortality than whites [HR (95% CI) 1.22 (1.01, 1.48)]; after including 25(OH)D in the model, the association was attenuated [1.09 (0.90-1.33)]. The mortality population attributable risks (95% CI) for 25(OH)D concentrations less than 20 ng/ml and less than 30 ng/ml in Blacks were 16.4% (3.1-26.6%) and 37.7% (11.6-55.1%) and in whites were 8.9% (3.9-12.7%) and 11.1% (-2.7 to 22.0%), respectively. PTH was also associated with mortality [HR (95% CI) 1.80 (1.33-2.43) for ≥70 vs. <23 pg/ml]. CONCLUSIONS: Low 25(OH)D and high PTH concentrations were associated with increased mortality in Black and white community-dwelling older adults. Because 25(OH)D concentrations were much lower in Blacks, the potential impact of remediating low 25(OH)D concentrations was greater in Blacks than whites.

Circulating phylloquinone concentrations of adults in the United States differ according to race and ethnicity.

Differences in micronutrient status are reported to contribute to racial and ethnic differences in chronic diseases. Diseases related to vitamin K are reported to differ by race and ethnicity, but it is unclear if circulating vitamin K concentrations similarly differ. We examined racial and ethnic differences in serum phylloquionone (K1) in the Multiethnic Study of Atherosclerosis (MESA) (mean ± SD age = 62 ± 10 y; 52% female; 262 white, 180 African American, 169 Hispanic, 93 Chinese American). Overall, 25% had serum K1 <0.1 nmol/L (the lower limit of detection). The prevalence of low serum K1 was 4% in Chinese Americans compared with 24% of whites, 29% of African Americans, and 33% of Hispanics. Compared with whites, Chinese Americans were significantly less likely to have serum K1 <0.1 nmol/L [OR (95% CI): 0.23 (0.09-0.23), adjusted for serum TG, K1 intake, age, sex, BMI, smoking, total cholesterol, site, season, and lipid-lowering medication use]. African Americans and Hispanics had similar odds to whites for having serum K1 <0.1 nmol/L [OR(95% CI): 1.30 (0.79-2.15) and 1.19 (0.66-2.15), respectively; fully adjusted]. In participants with detectable concentrations (n = 523), (natural log) serum K1 was higher in the Chinese Americans compared with whites, African Americans, and Hispanics (geometric mean ± SEM = 2.2 ± 0.1 nmol/L vs. 1.2 ± 0.1 nmol/L, 1.5 ± 0.1 nmol/L, and 1.1 ± 0.1 nmol/L, respectively, adjusted for serum TG, K1 intake, and additional covariates; all P < 0.001). These findings suggest circulating K1 differs by race and ethnicity in U.S. adults, especially among those of Chinese American descent, which merits consideration in the design and interpretation of future population-based and clinical studies of vitamin K and related diseases.

The effect of pioglitazone and resistance training on body composition in older men and women undergoing hypocaloric weight loss.

Age-related increases in ectopic fat accumulation are associated with greater risk for metabolic and cardiovascular diseases, and physical disability. Reducing skeletal muscle fat and preserving lean tissue are associated with improved physical function in older adults. PPARγ-agonist treatment decreases abdominal visceral adipose tissue (VAT) and resistance training preserves lean tissue, but their effect on ectopic fat depots in nondiabetic overweight adults is unclear. We examined the influence of pioglitazone and resistance training on body composition in older (65-79 years) nondiabetic overweight/obese men (n = 48, BMI = 32.3 ± 3.8 kg/m(2)) and women (n = 40, BMI = 33.3 ± 4.9 kg/m(2)) during weight loss. All participants underwent a 16-week hypocaloric weight-loss program and were randomized to receive pioglitazone (30 mg/day) or no pioglitazone with or without resistance training, following a 2 × 2 factorial design. Regional body composition was measured at baseline and follow-up using computed tomography (CT). Lean mass was measured using dual X-ray absorptiometry. Men lost 6.6% and women lost 6.5% of initial body mass. The percent of fat loss varied across individual compartments. Men who were given pioglitazone lost more visceral abdominal fat than men who were not given pioglitazone (-1,160 vs. -647 cm(3), P = 0.007). Women who were given pioglitazone lost less thigh subcutaneous fat (-104 vs. -298 cm(3), P = 0.002). Pioglitazone did not affect any other outcomes. Resistance training diminished thigh muscle loss in men and women (resistance training vs. no resistance training men: -43 vs. -88 cm(3), P = 0.005; women: -34 vs. -59 cm(3), P = 0.04). In overweight/obese older men undergoing weight loss, pioglitazone increased visceral fat loss and resistance training reduced skeletal muscle loss. Additional studies are needed to clarify the observed gender differences and evaluate how these changes in body composition influence functional status.

Vitamin K supplementation and progression of coronary artery calcium in older men and women.

BACKGROUND: Coronary artery calcification (CAC) is an independent predictor of cardiovascular disease. A preventive role for vitamin K in CAC progression has been proposed on the basis of the properties of matrix Gla protein (MGP) as a vitamin K-dependent calcification inhibitor. OBJECTIVE: The objective was to determine the effect of phylloquinone (vitamin K1) supplementation on CAC progression in older men and women. DESIGN: CAC was measured at baseline and after 3 y of follow-up in 388 healthy men and postmenopausal women; 200 received a multivitamin with 500 microg phylloquinone/d (treatment), and 188 received a multivitamin alone (control). RESULTS: In an intention-to-treat analysis, there was no difference in CAC progression between the phylloquinone group and the control group; the mean (+/-SEM) changes in Agatston scores were 27 +/- 6 and 37 +/- 7, respectively. In a subgroup analysis of participants who were > or =85% adherent to supplementation (n = 367), there was less CAC progression in the phylloquinone group than in the control group (P = 0.03). Of those with preexisting CAC (Agatston score > 10), those who received phylloquinone supplements had 6% less progression than did those who received the multivitamin alone (P = 0.04). Phylloquinone-associated decreases in CAC progression were independent of changes in serum MGP. MGP carboxylation status was not determined. CONCLUSIONS: Phylloquinone supplementation slows the progression of CAC in healthy older adults with preexisting CAC, independent of its effect on total MGP concentrations. Because our data are hypothesis-generating, further studies are warranted to clarify this mechanism. This trial was registered at clinicaltrials.gov as NCT00183001.

9-Cis retinoic acid reduces 1alpha,25-dihydroxycholecalciferol-induced renal calcification by altering vitamin K-dependent gamma-carboxylation of matrix gamma-carboxyglutamic acid protein in A/J male mice.

Matrix gamma-carboxyglutamic acid protein (MGP), a vitamin K-dependent protein, is involved in regulation of tissue calcification. We previously reported that 9-cis retinoic acid (RA) mitigates 1alpha,25-dihydroxycholecalciferol [1,25(OH)(2)D3]-induced renal calcification in a 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung cancer A/J male mouse model. This raised the question if the mechanism(s) underlying this calcification involves vitamin K. We assessed expression and vitamin K dependent gamma-carboxylation of MGP and vitamin K concentrations [phylloquinone (PK), as well as its conversion product, menaquinone-4 (MK-4)] in tissues obtained from NNK-injected A/J male mice fed 1,25(OH)(2)D3 (2.5 microg/kg diet; D group) +/- RA (15 mg/kg diet) for 20 wk. Renal calcification was only observed in the D group (2/10; 20% of the group). Renal MGP mRNA and uncarboxylated MGP (ucMGP) increased in response to D (P < 0.05) but not in response to RA or RA + D. In contrast, gamma-carboxylated MGP increased to 2.2-fold of the control in response to D+RA (P < 0.05) but not in response to RA or D alone. Although all diets contained equal amounts of PK, the kidney MK-4 concentration was higher in the D group (P < 0.05) and lower in the RA group (P < 0.05) compared with the RA+D or control groups. Renal PK concentrations were lower in the RA and RA+D groups than in the control and D groups (P < 0.05). These data suggest that 9-cis RA mitigated 1,25(OH)(2)D3-induced renal calcification by modifying the 1,25(OH)(2)D3-induced increase in ucMGP. The mechanisms by which 9-cis RA and 1,25(OH)(2)D3 alter vitamin K concentrations warrant further investigation.

Vitamin K, circulating cytokines, and bone mineral density in older men and women.

BACKGROUND: Vitamin K modulates cytokines involved in bone turnover, including interleukin-6 (IL-6) and osteoprotegerin in vitro. OBJECTIVE: The objective of this study was to assess 1) associations between measures of vitamin K status [plasma phylloquinone and serum percentage of undercarboxylated osteocalcin (%ucOC)] and IL-6, osteoprotegerin, and C-reactive protein (CRP) concentrations and 2) the effect of daily 500 mug phylloquinone supplementation for 3 y on cytokine concentrations. DESIGN: Concentrations of IL-6, osteoprotegerin, and CRP and bone mineral density (BMD) were measured at baseline and after 3 y of follow-up in 379 healthy men and women (60-81 y; 58.5% women) participating in a randomized trial that studied the effect of vitamin K supplementation on bone loss. RESULTS: Cross-sectionally, plasma phylloquinone was inversely associated with IL-6 and CRP, whereas serum %ucOC was inversely associated with IL-6. Osteoprotegerin was associated positively with plasma phylloquinone and inversely with %ucOC. No differences were observed in the 3-y change in IL-6, osteoprotegerin, and CRP concentrations between participants who received phylloquinone supplementation and those who did not. Overall, no association was observed between the 3-y changes in circulating cytokines and BMD. CONCLUSIONS: Poor vitamin K status was associated with high concentrations of cytokines involved in bone turnover, but vitamin K supplementation did not confer a decrease in cytokine concentrations. The healthy status of this cohort may explain a lack of effect of vitamin K supplementation on cytokine concentrations. This trial was registered with www.clinicaltrials.gov as NCT00183001.

Age and dietary form of vitamin K affect menaquinone-4 concentrations in male Fischer 344 rats.

Phylloquinone, the primary dietary form of vitamin K, is converted to menaquinone-4 (MK-4) in certain tissues. MK-4 may have tissue-specific roles independent of those traditionally identified with vitamin K. Fischer 344 male rats of different ages (2, 12, and 24 mo, n = 20 per age group) were used to compare the conversion of phylloquinone to MK-4 with an equivalent dose of another dietary form of vitamin K, 2',3'-dihydrophylloquinone. Rats were age- and diet-group pair-fed phylloquinone (198 +/- 9.0 microg/kg diet) or dihydrophylloquinone (172 +/- 13.0 microg/kg diet) for 28 d. MK-4 was the primary form of vitamin K in serum, spleen, kidney, testes, bone marrow, and brain myelin fractions, regardless of age group. MK-4 concentrations were significantly lower in kidney, heart, testes, cortex (myelin), and striatum (myelin) in the dihydrophylloquinone diet group compared with the phylloquinone diet group (P < 0.05). The MK-4 concentrations in 2-mo-old rats were lower in liver, spleen, kidney, heart, and cortex (myelin) but higher in testes compared with 24-mo-old rats (P < 0.05). However, there were no age-specific differences in MK-4 concentrations among the rats fed the 2 diets. These data suggest that dihydrophylloquinone, which differs from phylloquinone in its side phytyl chain, is absorbed but its intake results in less MK-4 in certain tissues. Dihydrophylloquinone may be used in models for the study of tissue-specific vitamin K deficiency.

Matrix Gla protein is associated with risk factors for atherosclerosis but not with coronary artery calcification.

OBJECTIVE: Atherosclerotic coronary artery calcification (CAC) is associated with increased coronary heart disease (CHD) risk. Matrix Gla protein (MGP) is an inhibitor of calcification in vivo. However, little is known regarding the distribution of circulating MGP and its associations with CHD risk factors or with CAC in humans. METHODS AND RESULTS: Serum MGP concentrations were determined in 2 independent populations of men and women free of clinically apparent cardiovascular disease: study A, n=316, mean age 58 years, and study B, n=452, mean age 68 years. CAC was determined by computed tomography. Mean MGP concentrations were 98.4 and 198 ng/mL in men, and 97.4 and 201 ng/mL in women, in study A and study B, respectively. In both cohorts, MGP levels were higher with increasing age. In age-adjusted analyses, there was an association of circulating MGP with increasing Framingham CHD risk score (in study A, P=0.003 in men and P=0.016 in women, respectively; in study B, a nonsignificant increase in men and P=0.05 in women, respectively). Significant associations of circulating MGP with high-density lipoprotein and other individual CHD risk factors were also noted in both cohorts. There were no consistent associations between MGP and CAC after adjustment for CHD risk score in the 2 cohorts. CONCLUSIONS: MGP is associated with individual CHD risk factors and the Framingham CHD risk score in men and women free of clinically apparent CHD. The relation of MGP with CAC deserves further study in larger populations.