Determinants of hyperhomocysteinemia in healthy and hypertensive subjects: A population-based study and systematic review

doi:10.1016/j.clnu.2016.11.011

Clinical Nutrition

Volume 36, Issue 5, October 2017, Pages 1215-1230

https://doi.org/10.1016/j.clnu.2016.11.011 Get rights and content

Summary

Aims

Hyperhomocysteinemia (HHcy) is known to increase the risk of many diseases. Factors influencing HHcy in healthy and hypertensive subjects remain under-researched.

Methods

A large population-based study was conducted in 60 communities from Shenzhen, China. Responses to standardized questions on lifestyle factors and blood samples were collected from all participants after a 12-h overnight fast. Multiple linear and multivariate logistic regressions were used to explore risk factors for HHcy. Results were then compared to those from a systematic review of English-language articles listed in Pubmed, EBSCOhost, Web of Science, Embase and Cochrane libraries that investigated HHcy risk factors in healthy and hypertensive subjects.

Results

A total of 1586 healthy (Male/Female = 642/944) and 5935 hypertensive subjects (Male/Female = 2928/3007) participated in our population-based study. In logistic regression analyses, age, BMI and creatinine (Cr) were risk factors, while being female, fruit intake and physical activity were protective factors for HHcy in healthy subjects. In hypertensive subjects, seven [age, smoking, salt intake, systolic blood pressure (SBP), uric acid, triglycerides (TG), and Cr] and four [female, fruit intake, total cholesterol (TC), and glucose] factors were associated with higher and lower HHcy respectively. The review of 71 studies revealed that potential risk factors for Hcy included nutritional, physiologic, lifestyle habits, ethnicity, genetics, interactions between gene–environment, gene–gene, gene–nutritional, environment–environment, nutritional–nutritional.

Conclusion

Our study indicates the potential importance of increasing folic acid and vitamin B supplementation, daily fruit and vegetable intake, regular exercise and refraining from tobacco smoking and alcohol consumption as preventive strategies for Hcy.

Introduction

Homocysteine (Hcy) is a thiol-containing amino acid, an intermediate product of methionine and cysteine metabolism. Hcy can be methylated to methionine through the intermediate products including S-adenosylation and S-adenosylmethionine (SAM), and thus plays a dominant role in the methylation cycle [1]. Hcy levels are dynamically maintained by a complex metabolic pathway (transsulfuration or remethylation pathway) (Fig. 1) [2], involving folic acid, pyridoxine (vitamin B6), cobalamin (vitamin B12), methylene tetrahydrofolate reductase (MTHFR), methionine synthase (MS), and cystathionine beta synthase (CBS) [3]. Deficiency of vitamin B12, vitamin B6, folic acid and defective enzymes in homocysteine metabolism will lead to hyperhomocysteinemia (HHcy) [4]. Hcy contributes to elevated blood pressure through its effect on vascular endothelial integrity [5]. Increased plasma Hcy can cause atherosclerosis in the general population [6]. Independently of traditional coronary heart disease (CHD) risk factors, each 5 mmol/L increase in Hcy can add approximately 20% to CHD risk [7]. Elevation of plasma Hcy in hypertensive patients is associated with the risk of metabolic syndrome, cardiovascular events [8], and ischemic stroke [9].

HHcy prevalence in China has been increasing, particularly among males and the elderly [10]. HHcy prevalence in China is higher than that of many developed countries and this is likely because it lacks policies on fortified intake of folic acid in cereals and flour [10]. A community-based twin cohort study showed that elevated Hcy is prevalent in children and adults living in rural regions of China [11]. HHcy risk factors are under-researched and as existing evidence is observational, there is a threat of residual confounding. Optimal Hcy metabolism cannot only rely on the nutrients from food intake [12]. Risk factors for HHcy may include genetic factors and environmental factors. The risk factor contributions may be subject to effect measure modification by race and ethnic group [13], since the MTHFR 677T allele frequency (a genetic determinant of Hcy) varies substantially among different ethnic populations [3]. Although numerous studies have investigated the determinants of HHcy in healthy and hypertensive subjects, the results are inconsistent across different populations. The aim of our study was to enhance knowledge of HHcy risk factors in healthy and hypertensive subjects in China through a population survey, with the results contextualized via a systematic review of prior studies.

Section snippets

Study design

Our study enrolled 1586 healthy and 5935 hypertensive subjects from 60 community health service centers in Nanshan district, Shenzhen, Guangdong Province, China. The specific details of the study participants, recruitment, and baseline data collection have been described previously [9], [14]. All the subjects were over 20 years old and had lived in Shenzhen for at least 6 months, and they were enrolled consecutively from April 2010 to September 2011. All the hypertensive subjects were patients

Results from the population-based study

The internal-consistency reliability (Cronbach's alpha coefficient) for the questionnaire was 0.73. The content validity ratios were all higher than 0.79, and none of the questions were removed. The demographic characteristics of 1586 healthy and 5935 hypertensive subjects according to Hcy and HHcy are reported in Supplementary Tables 1 and 2, respectively. The Hcy and HHcy levels differ significantly concerning sex, age, smoking, alcohol consumption, salt intake, fruit intake, BMI, waistline,

Discussion

In our population-based study, the independent predictors of HHcy in logistic regression model include sex, age, fruit intake, physical activity, BMI, and Cr in total healthy subjects, while sex, age, smoking, salt intake, fruit intake, SBP, TC, UA, TG, glucose, and Cr in total hypertensive subjects. Among those factors, female, fruit intake, and physical activity are protective factors of HHcy in total healthy subjects, whereas female, fruit intake, TC, and glucose are protective factors in

Conflict of interest

The authors declare that they have no conflict of interests.

Acknowledgements

Liyuan Han and Shiwei Duan had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Donghui Duan, Nanjia Lu; acquisition of data: Guodong Xu, Kaiyue Wang, Lu Zhang, Kaibo Gu; analysis and interpretation of data: Qi Wen, Sihan Chen, Jianping Ma; drafting of the manuscript: Liyuan Han, Yanfen Liu, Changyi Wang, Dingyun You, Linlin Tang, Shiwei Duan; critical revision of the manuscript

References (111)

K.L. Schalinske et al.
Homocysteine imbalance: a pathological metabolic marker
Adv Nutr
(2012)
K.S. McCully
Homocysteine, vitamins, and vascular disease prevention
Am J Clin Nutr
(2007)
L.L. Humphrey et al.
Homocysteine level and coronary heart disease incidence: a systematic review and meta-analysis
Mayo Clin Proc
(2008)
C.Y. Wang et al.
Elevated plasma homocysteine level is associated with ischemic stroke in Chinese hypertensive patients
Eur J Intern Med
(2014)
D.J. Buysse et al.
The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research
Psychiatry Res
(1989)
C.B. Terwee et al.
Quality criteria were proposed for measurement properties of health status questionnaires
J Clin Epidemiol
(2007)
V. Ho et al.
Influence of thymidylate synthase gene polymorphisms on total plasma homocysteine concentrations
Mol Genet Metab
(2010)
A.E. Molero et al.
Total plasma homocysteine values among elderly subjects: findings from the Maracaibo Aging Study
Clin Biochem
(2006)
S. Lussier-Cacan et al.
Plasma total homocysteine in healthy subjects: sex-specific relation with biological traits
Am J Clin Nutr
(1996)
A. Battezzati et al.
Body composition: an important determinant of homocysteine and methionine concentrations in healthy individuals
Nutr Metab Cardiovasc Dis
(2007)

P. Berstad et al.

Dietary fat and plasma total homocysteine concentrations in 2 adult age groups: the Hordaland homocysteine study

Am J Clin Nutr

(2007)

K.S. Brown et al.

The 5,10-methylenetetrahydrofolate reductase C677T polymorphism interacts with smoking to increase homocysteine

Atherosclerosis

(2004)

G.V. Dedoussis et al.

Effect of interaction between adherence to a Mediterranean diet and the methylenetetrahydrofolate reductase 677C-->T mutation on homocysteine concentrations in healthy adults: the ATTICA Study

Am J Clin Nutr

(2004)

A.M. Devlin et al.

Interactions among polymorphisms in folate-metabolizing genes and serum total homocysteine concentrations in a healthy elderly population

Am J Clin Nutr

(2006)

D.J. Gaughan et al.

The methionine synthase reductase (MTRR) A66G polymorphism is a novel genetic determinant of plasma homocysteine concentrations

Atherosclerosis

(2001)

C. Lasheras et al.

Diet score is associated with plasma homocysteine in a healthy institutionalised elderly population

Nutr Metab Cardiovasc Dis

(2003)

E. Nurk et al.

Changes in lifestyle and plasma total homocysteine: the Hordaland homocysteine study

Am J Clin Nutr

(2004)

O. Nygard et al.

Coffee consumption and plasma total homocysteine: the Hordaland homocysteine study

Am J Clin Nutr

(1997)

O. Nygard et al.

Major lifestyle determinants of plasma total homocysteine distribution: the Hordaland Homocysteine Study

Am J Clin Nutr

(1998)

J.I. Pijoan Zubizarreta et al.

Population reference ranges and determinants of plasma homocysteine levels

Med Clin (Barc)

(2001)

J. Zittoun et al.

Plasma homocysteine levels related to interactions between folate status and methylenetetrahydrofolate reductase: a study in 52 healthy subjects

Metabolism

(1998)

R.A. Mahfouz et al.

Correlation of methylenetetrahydrofolate reductase polymorphisms with homocysteine metabolism in healthy Lebanese adults

Gene

(2012)

S.J. Oppeneer et al.

Genetic variation in folylpolyglutamate synthase and gamma-glutamyl hydrolase and plasma homocysteine levels in the Singapore Chinese health study

Mol Genet Metab

(2012)

R. Dankner et al.

Serum adiponectin is associated with homocysteine in elderly men and women, and with 5,10-methylenetetrahydrofolate reductase (MTHFR) in a sex-dependent manner

Metabolism

(2010)

L. Zhang et al.

The relation between nicotinamide N-methyltransferase gene polymorphism and plasma homocysteine concentration in healthy Japanese men

Thromb Res

(2007)

Y.H. Lin et al.

The influence of estimated creatinine clearance on plasma homocysteine in hypertensive patients with normal serum creatinine

Clin Biochem

(2007)

M.V. Gamble et al.

Folate and cobalamin deficiencies and hyperhomocysteinemia in Bangladesh

Am J Clin Nutr

(2005)

T. Huang et al.

MAT1A variants modulate the effect of dietary fatty acids on plasma homocysteine concentrations

Nutr Metab Cardiovasc Dis

(2012)

J. Golbahar et al.

Distribution of plasma total homocysteine concentrations in the healthy Iranians

Clin Biochem

(2004)

A. Brevik et al.

Plasma concentration of folate as a biomarker for the intake of fruit and vegetables: the Hordaland Homocysteine study

Am J Clin Nutr

(2005)

J. Loscalzo et al.

Epigenetic modifications: basic mechanisms and role in cardiovascular disease (2013 Grover Conference series)

Pulm Circ

(2014)

A. Baszczuk et al.

Hyperhomocysteinemia in patients with cardiovascular disease

Postepy Hig Med Dosw (Online)

(2014)

U. Lim et al.

Homocysteine and blood pressure in the third national health and nutrition examination survey, 1988–1994

Am J Epidemiol

(2002)

K.S. McCully

Homocysteine and the pathogenesis of atherosclerosis

Expert Rev Clin Pharmacol

(2015)

C. Catena et al.

Elevated homocysteine levels are associated with the metabolic syndrome and cardiovascular events in hypertensive patients

Am J Hypertens

(2015)

L. Han et al.

Homocysteine, ischemic stroke, and coronary heart disease in hypertensive patients: a population-based, prospective cohort study

Stroke

(2015)

B. Yang et al.

Prevalence of hyperhomocysteinemia in China: a systematic review and meta-analysis

Nutrients

(2015)

Y. Ji et al.

Distribution and determinants of plasma homocysteine levels in rural Chinese twins across the lifespan

Nutrients

(2014)

P. Ganguly et al.

Role of homocysteine in the development of cardiovascular disease

Nutr J

(2015)

S. Guo et al.

Ethnic differences in the prevalence of high homocysteine levels among low-income rural Kazakh and Uyghur adults in far western China and its implications for preventive public health

Int J Environ Res Public Health

(2015)

G. Mancia et al.

2007 guidelines for the management of arterial hypertension: the task force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC)

Eur Heart J

(2007)

I. Romera et al.

Factor analysis of the Zung self-rating depression scale in a large sample of patients with major depressive disorder in primary care

BMC Psychiatry

(2008)

M.R. Malinow et al.

Homocyst(e)ine, diet, and cardiovascular diseases: a statement for healthcare professionals from the Nutrition Committee, American Heart Association

Circulation

(1999)

D. Moher et al.

Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement

Syst Rev

(2015)

G.A. Wells et al.

The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses

Clin Epidemiol

(2012)

Y.M. Lee et al.

Association of homocysteine levels with blood lead levels and micronutrients in the US general population

J Prev Med Public Health

(2012)

C.M. Summers et al.

Genetic and lifestyle variables associated with homocysteine concentrations and the distribution of folate derivatives in healthy premenopausal women

Birth Defects Res A Clin Mol Teratol

(2010)

L. Ruan et al.

Plasma homocysteine is adversely associated with glomerular filtration rate in asymptomatic black and white young adults: the Bogalusa heart study

Eur J Epidemiol

(2009)

E.A. Angelova et al.

A study of plasma total homocysteine levels in healthy people

Folia Med (Plovdiv)

(2005)

A. Baccarelli et al.

Air pollution, smoking, and plasma homocysteine

Environ Health Perspect

(2007)

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This genetic association study included 150 hypertensive diabetic patients and 150 normotensives non-diabetic subjects. Glutathione S-transferases M1 and T1 (GSTM1/GSTT1) deletion polymorphisms and methylenetetrahydrofolate reductase (MTHFR) C677T SNP (rs1801133) genotyping were performed by SYBR Green multiplex real-time and RFLP-PCR, respectively. Both GSTM1 and GSTT1 null (OR = 4.52, p = 0.04, and OR = 4.27, p = 0.01) and mutant (677TT) genotypes (OR = 2.95, p = 0.02) conferred risk to hypertension susceptibility. The combined genotypes (MTHFR:GSTT1:GSTM1) revealed a significant association: W/−/+, W/+/−, H/−/−, H/−/+, M/+/−, and M/+/+. These findings suggesting a probable oxidative hypothesis for hypertensive diabetic patients from the interaction of the detoxification mechanism and the homocysteine metabolism. The imbalance in antioxidant enzymes contributes to the establishment of oxidative stress in conjunction with hyperhomocysteinemia and reactive oxygen species production. We concluded that these findings suggest that both polymorphisms may contribute to hypertension susceptibility in diabetic patients.
Causal effects of homocysteine levels on the changes of bone mineral density and risk for bone fracture: A two-sample mendelian randomization study
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Citation Excerpt :
Homocysteine (HCY), a sulfur containing amino acid, is produced as an essentially intermediate byproduct during the demethylation of methionine. Hyperhomocysteinemia has been recognized as a risk factor that was positively associated with cardiovascular disease (CVD) [7–10]. Emerging evidence have also suggested the possible role of HCY involving in bone, in which HCY could affect bone tissue formation through disturbing the formation of collagen cross-links and normal calcification process, as well as reducing bone blood flow [11–13].
Observational studies have demonstrated the relations of homocysteine (HCY) with bone mineral density (BMD) and bone fracture risk, but yielding contradictory results. The present study was conducted to evaluate whether the genetically predicted plasma HCY levels were causally associated with the change of BMD and the risk of bone fracture.
Genetic summary statistics were extracted from genome-wide association study (GWAS) meta-analysis of plasma HCY levels (n = 44,147), GWAS meta-analyses of measured forearm (FA), femoral neck (FN) and lumbar spine (LS) BMD (n = up to 32,735), UK Biobank estimated heel BMD (eBMD) (n = 426,824) and fracture (n = 426,795) GWAS data. Two Sample Mendelian Randomization (TSMR) analysis was performed to assess the causal effects of genetically determined plasma HCY on the BMD and bone fractures.
The MR analysis indicated that, genetically decreased plasma HCY was associated with the increased FA-BMD based on the inverse variance weighting (IVW) method (standard deviation [SD] = 0.348, 95% CI: 0.146 to 0.550, P = 7 × 10⁻⁴). However, there were no significant associations of genetically decreased plasma HCY with FN-BMD, LS-BMD, eBMD and the risk for bone fracture (SD = −0.041, 95% CI: −0.189 to 0.106, P = 0.582; SD = −0.053, 95% CI: −0.238 to 0.131, P = 0.572; SD = −0.030, 95% CI: −0.090 to 0.030, P = 0.328, odds ratio [OR]: 1.03, 95% CI: 0.94 to 1.13, P = 0.562, respectively). Moreover, the results also found that genetically determined HCY increase was not correlated with the changes of BMD and the risk for bone fracture.
Our study revealed that genetically decreased plasma HCY was associated with increase of FA-BMD.
Exploration of the risk factors of essential hypertension with hyperhomocysteinemia: A hospital-based study and nomogram analysis
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Citation Excerpt :
Moreover, various blood physiological indices have been found to be related to H-type hypertension. Wang et al. found that BMI and LDL levels are associated with H-type hypertension (1), while Han et al. indicated that uric acid, TG, and creatinine levels are associated with Hcy levels in patients with hypertension by logistic analysis (7). In the present study, high BMI, high TC levels, high glucose levels, and high creatinine levels were found to be risk factors of H-type hypertension in the healthy population; high BMI, high TC levels, and high glucose levels were risk factors of H-type hypertension in the HHcy population; and high creatinine levels were risk factors of H-type hypertension in the hypertension population.
To explore the risk factors of essential hypertension with hyperhomocysteinemia (H-type hypertension) and design a nomogram to predict this risk.
A hospital-based study was conducted on 1,712 individuals, including 282 patients with H-type hypertension, 105 patients with simple hypertension, 645 individuals with hyperhomocysteinemia, and 680 healthy controls. Logistic regression and nomogram models were applied to evaluate the risk factors.
Logistic regression showed that advanced age, male sex, high body mass index (BMI), high total cholesterol levels, high glucose levels, and high creatinine levels were risk factors of H-type hypertension in the healthy population and were integrated into the nomogram model. Advanced age, male sex, high BMI, high total cholesterol levels, and high glucose levels were shown to be risk factors of H-type hypertension in the hyperhomocysteinemia population. Male sex and high creatinine levels were shown to be risk factors of H-type hypertension in the hypertension population. Nomogram analysis showed that the total factor score ranged from 106 to 206, and the corresponding risk rate ranged from 0.05 to 0.95.
Men are more likely to have H-type hypertension, and advanced age, high BMI, high total cholesterol levels, and high glucose levels are risk factors of H-type hypertension in healthy and hyperhomocysteinemia populations. Furthermore, high creatinine level is a risk factor of H-type hypertension in healthy and hypertension populations. Nomogram models may be used to intuitively evaluate H-type hypertension risk and provide a basis for personalized interventions.
Value of triglyceride-glucose index for the estimation of ischemic stroke risk: Insights from a general population
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In 2013, stroke reached a prevalence of 1.60% and a mortality of 114.8 per 100,000 person-years in China [2]. Among the pathological subtypes of stroke, ischemic stroke was the most common subtype, constituting 77.8% of the prevalent strokes [2]. Consequently, stroke, especially ischemic stroke, has emerged as a major cause of death and disability in China [3,4].
Recent studies have recognized triglyceride-glucose index (TyG) as a practical surrogate of insulin resistance. Previous studies have demonstrated that insulin resistance contributes to ischemic stroke via multiple mechanisms. Our study aimed to investigate the association between TyG and prevalent ischemic stroke, exploring the value of TyG to optimize the risk stratification of ischemic stroke.
This cross-sectional study included 10,900 subjects (mean age: 59.95 years, 59.8% females) from rural areas of northeast China between September 2017 to May 2018. TyG was calculated as ln[fasting triglyceride (mg/dl) × fasting plasma glucose (mg/dl)/2]. The prevalence of ischemic stroke was 5.49%. After adjusting for all covariates, each SD increment of TyG caused 22.8% additional risk for ischemic stroke. When dividing TyG into quartiles, the top quartile had a 1.776 times risk for ischemic stroke against the bottom category. Furthermore, smoothing curve fitting demonstrated this association was linear in the whole range of TyG. Finally, AUC revealed an improvement when introducing TyG into clinical risk factors (0.746 vs 0.751, p = 0.029). Consistently, category-free net reclassification index (0.195, 95% CI: 0.112–0.277, P < 0.001) and integrated discrimination index (0.003, 95% CI: 0.001–0.004, P < 0.001) confirmed the improvement by TyG to stratify ischemic stroke risk.
The prevent ischemic stroke correlated proportionally with the increment of TyG, implicating the linearity of TyG as an indicator of ischemic stroke. Our findings suggest the potential value of TyG to optimize the risk stratification of ischemic stroke in a general population.
Associations of C-reactive protein and homocysteine concentrations with the impairment of intrinsic capacity domains over a 5-year follow-up among community-dwelling older adults at risk of cognitive decline (MAPT Study)
2019, Experimental Gerontology
Citation Excerpt :
Regarding the two parameters investigated in the present study, some aspects are worth noting. HHcy may be caused by – but not limited to – smoking (Chen et al., 2015), sedentary lifestyle (Han et al., 2017) and inadequate diets with deficient intake of vitamins B6, B12 and folate (Chen et al., 2015; Han et al., 2017). Also, diets rich in fruits and vegetables and with higher supply of vitamins B6 and folate are known to associate with lower Hcy (Brouwer et al., 1999; Gao et al., 2004) and CRP concentrations (Gao et al., 2004).
The World Health Organization (WHO) recently proposed an innovative model of care focusing on functional rather than disease-based perspectives, based on a construct of intrinsic capacity (IC).
This study aimed to analyze if low-grade inflammation (LGI) (chronically raised C-reactive protein – CRP) and hyperhomocysteinemia (HHcy) were associated with variation in IC domains (mobility, cognition, psychological and vitality) and in a combined IC Z-score over a 5-year follow-up among non-demented, community-dwelling older adults at risk of cognitive decline.
This observational study included 1516 subjects ≥70 years (64.5% female, mean age 75.4 years, SD = 4.5), volunteers from the interventional study Multidomain Alzheimer Preventive Trial (MAPT). Plasma CRP (at baseline, 6 and 12 months) and homocysteine (at baseline) concentrations were measured. LGI was defined as having ≥2 consecutively CRP readings >3 to 10 mg/L between baseline and 12 months, and HHcy was defined as homocysteine >15 μM/L. IC domains were operationalized as follows: Psychological. Depressive symptoms evaluated by the Geriatric Depression Scale (GDS); Mobility. Assessed by the Short Physical Performance Battery (SPPB); Cognitive function. Examined by a Z-score combining four tests; Vitality. Based on hand grip strength. Outcomes were combined into a composite IC Z-score.
IC Z-score decreased among groups with no inflammation and LGI after 5 years, but this decrease was more pronounced among the LGI group (unadjusted mean group difference: 0.09, 95%CI: 0.01 to 0.16; p = 0.032). Participants with HHcy also presented IC Z-score decreases over time. Combined conditions provided more pronounced declines, even after adjusting for potential confounders.
LGI and HHcy were both related with impairment on the combined IC levels among older adults after a 5-year follow-up. Identifying biomarkers that strongly associate with IC may help to settle strategies aiming to prevent the incidence and slow down the evolution of age-related functional decline and care dependency.
Effects of hyperhomocysteinaemia and metabolic syndrome on reproduction in women with polycystic ovary syndrome: a secondary analysis
2019, Reproductive BioMedicine Online
What is the association between hyperhomocysteinaemia (HHCY), metabolic syndrome, and reproductive outcomes among women with polycystic ovary syndrome (PCOS).
A secondary analysis of PCOSAct with 21 sites in China. A total of 1000 women with PCOS were enrolled; 936 women with baseline homocysteine (HCY) were analysed.
Higher HCY was associated with higher body mass index, free testosterone and lower FSH, fasting glucose (P < 0.001; P < 0.001; P = 0.005; P < 0.001) and ovulation rate among all participants (OR 0.59, 95% CI 0.41 to 0.86; OR 0.57, 95% CI 0.39 to 0.83 tertiles 2 and 3 versus tertile 1, respectively). The HHCY group had lower oestradiol and higher free testosterone (P = 0.04; P < 0.001) than the controls. In the metabolic syndrome group, LH, LH–FSH ratio and sex hormone-binding globulin were lowest in the metabolic syndrome group (all P < 0.001). In the HHCY group, ovulation rate decreased and the second or third trimester pregnancy loss rate increased compared with controls (OR 1.678, 95% CI 1.04 to 2.70; OR 0.03, 95% CI 0.00 to 0.42) with treatment adjustment. Compared with the controls, ovulation, conception, pregnancy, second or third trimester pregnancy loss and live birth rates were statistically lower in the metabolic syndrome group after adjusting treatment (OR 1.76, 95% CI 1.15 to 2.70; OR 1.75, 95% CI 1.15 to 2.65; OR 2.09, 95% CI 1.27 to 3.44; OR 0.02, 95% CI 0.00 to 0.33; OR 2.42 95% CI 1.42 to 4.10), and pregnancy, pregnancy loss and live birth rates remained significantly different after adjusting for treatment and sex-hormone factors (OR 1.77, 95% CI 1.05 to 2.99; OR 0.14, 95% CI 0.02 to 0.82; OR 2.02, 95% CI 1.16 to 3.50).
In women with PCOS, HHCY contributes to increased pregnancy loss and reduced ovulation, and metabolic syndrome was related to defects in ovulation, conception, pregnancy, pregnancy loss and live birth, indicating that the two conditions lead to defects at various reproductive stages.

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¹: Liyuan Han, Yanfen Liu and Changyi Wang are co-first authors of this work.

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ReviewDeterminants of hyperhomocysteinemia in healthy and hypertensive subjects: A population-based study and systematic review

Summary

Aims

Methods

Results

Conclusion

Introduction

Section snippets

Study design

Results from the population-based study

Discussion

Conflict of interest

Acknowledgements

Adv Nutr

Am J Clin Nutr

Mayo Clin Proc

Eur J Intern Med

Psychiatry Res

J Clin Epidemiol

Mol Genet Metab

Clin Biochem

Am J Clin Nutr

Nutr Metab Cardiovasc Dis

Am J Clin Nutr

Atherosclerosis

Am J Clin Nutr

Am J Clin Nutr

Atherosclerosis

Nutr Metab Cardiovasc Dis

Am J Clin Nutr

Am J Clin Nutr

Am J Clin Nutr

Med Clin (Barc)

Metabolism

Gene

Mol Genet Metab

Metabolism

Thromb Res

Clin Biochem

Am J Clin Nutr

Nutr Metab Cardiovasc Dis

Clin Biochem

Am J Clin Nutr

Epigenetic modifications: basic mechanisms and role in cardiovascular disease (2013 Grover Conference series)

Pulm Circ

Hyperhomocysteinemia in patients with cardiovascular disease

Postepy Hig Med Dosw (Online)

Homocysteine and blood pressure in the third national health and nutrition examination survey, 1988–1994

Am J Epidemiol

Homocysteine and the pathogenesis of atherosclerosis

Expert Rev Clin Pharmacol

Elevated homocysteine levels are associated with the metabolic syndrome and cardiovascular events in hypertensive patients

Am J Hypertens

Homocysteine, ischemic stroke, and coronary heart disease in hypertensive patients: a population-based, prospective cohort study

Stroke

Prevalence of hyperhomocysteinemia in China: a systematic review and meta-analysis

Nutrients

Distribution and determinants of plasma homocysteine levels in rural Chinese twins across the lifespan

Nutrients

Role of homocysteine in the development of cardiovascular disease

Nutr J

Ethnic differences in the prevalence of high homocysteine levels among low-income rural Kazakh and Uyghur adults in far western China and its implications for preventive public health

Int J Environ Res Public Health

2007 guidelines for the management of arterial hypertension: the task force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC)

Eur Heart J

Factor analysis of the Zung self-rating depression scale in a large sample of patients with major depressive disorder in primary care

BMC Psychiatry

Homocyst(e)ine, diet, and cardiovascular diseases: a statement for healthcare professionals from the Nutrition Committee, American Heart Association

Circulation

Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement

Syst Rev

The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses

Clin Epidemiol

Association of homocysteine levels with blood lead levels and micronutrients in the US general population

J Prev Med Public Health

Genetic and lifestyle variables associated with homocysteine concentrations and the distribution of folate derivatives in healthy premenopausal women

Birth Defects Res A Clin Mol Teratol

Plasma homocysteine is adversely associated with glomerular filtration rate in asymptomatic black and white young adults: the Bogalusa heart study

Eur J Epidemiol

A study of plasma total homocysteine levels in healthy people

Review
Determinants of hyperhomocysteinemia in healthy and hypertensive subjects: A population-based study and systematic review