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The Implications of a Newly Discovered  CYP2J2 Gene Polymorphism  Associated with Coronary Vascular Disease in the Uygur Chinese Population

Author, Curator: Larry H Bernstein, MD, FCAP

This is an interesting genomic study of the relationship of genetic polymorphism in the Chinese Uygur population that highlights the difficulty in CVD genomics, and casts a promising light on difficulties over
1.  possibly no more than 8 genetic signatures to account for all of human CVD conditions
2.  genetic signatures may no be equally distributed over studied populations
3.  genetic signatures may be more pronounced in different populations
4.  there is little predictable validity in such studies over large assimilated populations (such as African-Americans
5.  the best genomic evidence for meaningful associations does appear to tie in with endothelial metabolism
6.  the greatest difficulty in all studies is the small dose of information provided by an such linkage
7.  there has been too little information provided in studies of the effect of dietary factors on the affected population, which would entail nutrigenomics.
8.  there is an association between certain distinct CVD’s and later development of coronary heart disease (CHD).
This study concepts, methods and difficulties were recently reviewed in the following articles:
Synthetic Biology: On Advanced Genome Interpretation for Gene Variants and Pathways: What is the Genetic Base of Atherosclerosis and Loss of Arterial Elasticity with Aging
Aviva Lev-Ari, PhD, RN
Genomics & Genetics of Cardiovascular Disease Diagnoses: A Literature Survey of AHA’s Circulation Cardiovascular Genetics, 3/2010 – 3/2013
Aviva Lev-Ari, PhD, RN and Larry H Bernstein, MD, FCAP
Diagnosis of Cardiovascular Disease, Treatment and Prevention: Current & Predicted Cost of Care and the Promise of Individualized Medicine Using Clinical Decision Support Systems
Aviva Lev-Ari, PhD, RN and Larry H Bernstein, MD, FCAP
Hypertension and Vascular Compliance: 2013 Thought Frontier – An Arterial Elasticity Focus
Justin D. Pearlman, MD, PhD, and Aviva Lev-Ari, PhD, RN
Clinical Trials Results for Endothelin System: Pathophysiological role in Chronic Heart Failure, Acute Coronary Syndromes and MI – Marker of Disease Severity or Genetic Determination?
Aviva Lev-Ari, PhD, RN
Vascular Medicine and Biology: CLASSIFICATION OF FAST ACTING THERAPY FOR PATIENTS AT HIGH RISK FOR MACROVASCULAR EVENTS Macrovascular Disease – Therapeutic Potential of cEPCs
Aviva Lev-Ari, PhD, RN
Endothelial Function and Cardiovascular Disease
Larry H Bernstein, MD, FCAP
Reversal of Cardiac Mitochondrial Dysfunction
Larry H Bernstein, MD, FCAP
A Second Look at the Transthyretin Nutrition Inflammatory Conundrum
Larry H Bernstein, MD, FCAP

A Novel Polymorphism of the CYP2J2 Gene is Associated with Coronary Artery Disease in Uygur Population in China

Qing Zhu, Zhenyan Fu, Yitong Ma, Hong Yang, Ding Huang, Xiang Xie, Fen Liu, Yingying Zheng, Erdenbat Cha
PII: S0009-9120(13)00174-4    Available online 15 May 2013
Reference: CLB 8375
To appear in: Clinical Biochemistry
Received date: 17 February 2013
Revised date: 13 April 2013
Accepted date: 3 May 2013
Background: Cytochrome P450 (CYP) 2J2 is expressed in the vascular endothelium and metabolizes arachidonic acid to biologically active epoxyeicosatrienoic acids (EETs).
  • The EETs are potent endogenous vasodilators and
  • inhibitors of vascular inflammation.
The aim of the present study was to assess the association between the human CYP2J2 gene polymorphism and coronary artery disease (CAD) in a Han and Uygur population of China.
We use two independent case-control studies:
  1. a Han population (206 CAD patients and 262 control subjects) and
  2. a Uygur population (336 CAD patients and 448 control subjects).
All CAD patients  and controls were genotyped for the same three single nucleotide polymorphisms (SNPs)
  1. rs890293
  2. rs11572223
  3. rs2280275
of CYP2J2 gene by a Real-time PCR instrument.
Results: In the Uygur population, for total, the distribution of SNP3 (rs2280275) genotypes showed a significant difference between CAD and control participants (P=0.048).
For total and men, the distribution of SNP3 (rs2280275) alleles and the dominant model (CC vs CT + TT)
  • showed a significant difference between CAD and control participants (for allele: P=0.014 and P=0.035, respectively; for dominant model: P=0.014 and P=0.034, respectively).
The significant difference in dominant model was retained after adjustment for covariates (OR: 0.279, 95% confidence interval [CI]: 0.176-0.440, P=0.001; OR: 0.240, 95% CI: 0.128-0.457, P=0.001, respectively).
Conclusions: The CC genotype of rs2280275 in CYP2J2 gene could be a protective genetic marker of CAD and T allele may be a risk genetic marker of CAD in men of Uygur population in China.
Highlights:
1. We used two independent case-control studies: one was in a Han population and the other was in a Uygur population.
2. The CC genotype of rs2280275 in CYP2J2 gene could be a protective genetic marker of CAD and T allele may be a risk genetic marker of CAD in men of Uygur population in China.
3. Polymorphism of the CYP2J2 gene can affect the synthesis of epoxyeicosatrienoic acids (EETs).
Reviewer Observations:
This article describes the association between CYP2J2 polymorphism(SNP1, SNP2 and SNP3) and coronary artery disease (CAD) in two populations of China (Han and Uygur).
Results show that
  1. the frequency of T allele of rs2280275 (SNP3 of the CYP2J2) is higher in CAD patients than in control subjects and
  2. that CC genotype of rs 2280275 is significantly lower in CAD patients than in control subjects.
  3. “T allele of rs2280275 was significantly higher in CAD patients than in control participants. CC genotype of rs2280275 was significantly lower in CAD patients than in control participants.”;
  4. It appears that CC is the homozygous and dominant state of this SNP3 sequence in a pairing-combination.
  5. The effect of decreased CHD is seen only in the CC double combination, in men and not women. The difference between men and women with CAD is in LDL.
For Uygur population,
(1) after adjusting major confounding factors such as Glu、LDL、EH、DM and smoking, the effect of decreased CAD is seen only in the CC double combination, in men and not women.
(2) for men, the LDL level is higher in CAD than in control, for women, there isn’t a difference of LDL level between CAD and control.
(3) for men, the distribution of T and C allele is different between CAD and control (p=0.035), and not in women (p=0.118).
The T allele of SNP3 is increased in CAD. So the C allele is important, and a CT pair is neutral. Neither SNP1 or SNP2, or presumably both have lower incidence.

I might conjecture that having(heterozygous rs2280275), a C & a T, and eating a lot of fish and/or flax seed would show a difference

  • because of the intimal enzymatic conversion of arachidonic acid to EETs.

Arachidonic acid is a derivative of linoleic acid,an n-6 PUFA, while linolenic acid is an omega-3 PUFA. Substantial documentation of the effect of EETs is given. The anti-inflammatory advantage of an n-3 PUFA is also known.
It appears that the intimal conversion results in an omega-3 product.  In addition, the EET activates eNOS, so that there is endothelial NO produced.

The studies of both Spiecker and Ping Yin Liu showed the polymorphism of CYP2J2 (rs890293, SNP1) has relation with CAD. However, in this study, the authors found there was no association between the polymorphism of CYP2J2 (rs890293, SNP1) and CAD in Han population and Uygur population. We found (rs 2280275, SNP3) has association with CAD.
  • “The CC genotype of rs2280275 in CYP2J2 gene could be a protective genetic marker of CAD and T allele may be a risk genetic marker of CAD in men of Uygur population in China”
All participants had a differential diagnosis for chest pain encountered in the Cardiac Catheterization Laboratory of First Affiliated Hospital of Xinjiang Medical University. We recruited randomly CAD group and control group, subjects with valvular disease were excluded, control subjects were not healthy individuals, some of them have hypertension, some of them have DM, some of them have hyperlipidemia, which means control group expose to the same risk factors of CAD while the results of coronary angiogram is normal. All control subjects underwent a coronary angiogram and have no coronary artery stenosis.
The analysis was a logistic regression analysis, we used the major variables of CAD to analysis and found the CC genotype was the dependent useful factor after adjusting for major confounding factors such as Glu、LDL、EH、DM and smoking.
Schematic of EET interactions with cardiovascularion channels.
A: In the cardiac myocyte, EETs activate sarcolemmal or mitochondrial KATP channels.
B: In the vasculature, EETs activate endothelial small-(SKCa) or intermediate (IKCa)–conductance calcium-activated channels to cause hyperpolarization, which can be transmitted to the vascular smooth muscle via myoendothelial gap junctions. EETs also activate TRPV4 channels to activate Ca2+influx. In the vascular smooth muscle, EETs activate large conductance, calcium-activated (BK-Ca) channels through a G protein-Coupled event.
C: In platelets, EETs activate BK-Ca channels.calcium-activated (BK-Ca) channels through a G-protein-coupled event. C, In platelets, EETs activate BK-Ca channels.

Association of the ADRA2A polymorphisms with the risk of type 2 diabetes: A meta-analysis

Xi Chen, Lei Liu, Wentao He, Yu Lu, Delin Ma, Tingting Du, Qian Liu, Cai Chen, Xuefeng Yu
Clinical Biochemistry 2013;  46 (9): 722–726   http://dx.doi.org/10.1016/j.clinbiochem.2013.02.004
Results from the published studies on the association of ADRA2A (adrenoceptor alpha 2A) variants with type 2 diabetes (T2D) are conflicting and call for further assessment. The aim of this meta-analysis was to quantitatively summarize the effects of the two recently reported ADRA2A single nucleotide polymorphisms (SNPs) rs553668 and rs10885122 on T2D risk.
Results
Twelve studies with 40,828 subjects from seven eligible papers were included in the meta-analysis. Overall, the present meta-analysis failed to support a positive association between ADRA2A SNPs (rs553668 and rs10885122) and susceptibility to T2D (OR = 1.05, p = 0.17, 95% CI: 0.98, 1.12; and OR = 1.06, p = 0.11, 95% CI: 0.99, 1.13; respectively).
However, in the subgroup analysis by ethnicity, the significant association between rs553668 and the risk of T2D was obtained in Europeans under the recessive genetic model (OR = 1.36, p = 0.02, 95% CI: 1.05, 1.76).
Conclusion
The results of the meta-analyses indicated that both SNPs were associated with CHD in Caucasians (P < 0.05) but not in Asians. The results from our case-control study and meta-analyses might be explained by genetic heterogeneity in the susceptibility of CHD and ethnic differences between Asians and Caucasians.

Association between PCSK9 and LDLR gene polymorphisms with coronary heart disease: Case-control study and meta-analysis

Lina Zhang, Fang Yuan, Panpan Liu, Lijuan Fei, Yi Huang, Limin Xu, et al.
Clinical Biochemistry 2013; 46 (9): 727–732
► Association of rs11206510 and rs1122608 with CHD in 813 Chinese participants.
► The first association test of rs1122608 with the risk of CHD in Han Chinese.
► Meta-analyses were performed for rs11206510 and rs1122608.
► The two SNPs were associated with CHD in Caucasians but not in Asians.
Objective
To explore the association of rs11206510 (PCSK9 gene) and rs1122608 (LDLR gene) polymorphisms with coronary heart disease (CHD) in Han Chinese.
Methods
A total of 813 participants (290 CHD cases, 193 non-CHD controls and 330 healthy controls) were recruited in the case-control study. DNA genotyping was performed on the SEQUENOM® Mass–ARRAY iPLEX® platform. χ2-test was used to compare the genotype distribution and allele frequencies. Two meta-analyses were performed to establish the association between the two polymorphisms with CHD.
Results
No significant associations between the two SNPs and the risk of CHD were observed in the present study. The meta-analysis of rs11206510 of PCSK9 gene comprises 11 case-control studies with a total of 69,054 participants. Significant heterogeneity was observed in Caucasian population in subgroup analysis of the association studies of rs11206510 with CHD (P = 0.003, I2 = 67.2%). The meta-analysis of LDLR gene rs1122608 polymorphism comprises 7 case-control studies with a total of 20,456 participants and the heterogeneity of seven studies was minimal (P = 0.148, I2 = 36.7%).
Conclusion
The results of the meta-analyses indicated that both SNPs were associated with CHD in Caucasians (P < 0.05) but not in Asians.

The effect of hyperhomocysteinemia on aortic distensibility in healthy individuals

I Eleftheriadou, P Grigoropoulou, I Moyssakis, A Kokkinos. et al.
Nutrition 18 Feb 2013; 29 (6): 876-880, PII: S0899-9007(13)00015-4
Elevated plasma homocysteine (HCY) levels have been associated with increased risk for cardiovascular disease. Aortic distensibility and aortic pulse wave velocity (PWV) are indices of aortic elasticity. The aim of the present study was to determine the effect of acute methionine-induced HHCY on aortic distensibility and PWV in healthy individuals and the effect of acute HHCY on myocardial performance of the left ventricle (Tei index).
Thirty healthy volunteers were included in this crossover study. Aortic distensibility and Tei index were determined non-invasively by ultrasonography at baseline and 3 h after methionine or water consumption, while PWV was measured by applanation tonometry at baseline and every 1 h for the same time interval.
Oral methionine induced an increase in total plasma HCY concentrations (P < 0.001), whereas HCY concentrations did not change after water consumption. Aortic distensibility decreased 3 h after methionine load (P < 0.001) and Tei index increased (P < 0.001), suggesting worsening compared with baseline values. Water consumption had no effect on aortic distensibility or Tei index values. PWV values did not change after either methionine or water consumption.
Acute methionine-induced HHCY reduces aortic distensibility and worsens myocardial performance in healthy individuals. Further research is warranted to examine in the long term the direct effects of HHCY on cardiovascular function and the indirect effects on structural remodeling.
Micrograph of an artery that supplies the hear...

Micrograph of an artery that supplies the heart with significant atherosclerosis and marked luminal narrowing. Tissue has been stained using Masson’s trichrome. (Photo credit: Wikipedia)

Estimated propability of death or non-fatal my...

Estimated propability of death or non-fatal myocardial-infarction over one year corresponding ti selectet values of the individual scores. Ordinate: individual score, abscissa: Propability of death or non-fatal myocardial infarction in 1 year (in %) (Photo credit: Wikipedia)

 

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Reporter: Aviva Lev-Ari, PhD, RN

Gordon H. Sun, M.D., Jeffrey D. Steinberg, Ph.D., and Reshma Jagsi, M.D., D.Phil.

N Engl J Med 2012; 367:687-690   August 23, 2012

Since the founding of the National Institutes of Health (NIH) and the National Science Foundation (NSF) more than six decades ago, the United States has maintained a preeminent position as a government sponsor of medical research. That primacy is being tested, however, by potent economic challenges. The NIH’s proposed budget for fiscal year 2013 would freeze baseline funding at 2012 levels, continuing a decade-long failure to keep pace with the rising costs of conducting medical research. Across-the-board cuts mandated by the Budget Control Act (BCA) of 2011 will also affect medical research, with the NIH, NSF, and other federal research sponsors sustaining budgetary reductions of about 8% next year.

Cuts to government-funded research will have adverse long-term effects on the health care system and the economy and may irreversibly compromise the work of laboratories long accustomed to receiving stable federal support. Moreover, many medical researchers could transfer their knowledge and resources abroad. In fact, five emerging Asian economic or technological powers — China, India, South Korea, Taiwan, and Singapore — already have medical research policies in place that are filling the void being created by ever more restrictive U.S. funding.

Several U.S.-based economists have justified increasing research budgets on the premise that medical discoveries have intrinsically high economic value. For example, Murphy and Topel have suggested that eliminating deaths related to heart disease had an estimated worth of $48 trillion, and a 1% reduction in cancer-related mortality could save $500 billion.1 Beyond these ambitious goals, however, are more practical arguments favoring support for medical research.

Local and regional economic benefits are one example. A June 2008 analysis by Families USA showed that during the NIH’s fiscal year 2007, nearly $23 billion in grants and contracts supported more than 350,000 jobs, with each dollar generating more than twice as much in direct state economic output in the form of goods and services. The NIH reported that almost 1 million Americans worked in for-profit medical businesses in 2008, earning $84 billion and generating $90 billion in goods and services, reinforcing the importance of preserving the U.S. position as a “knowledge hub” for medical research.2 Nevertheless, BCA cuts next year could result in at least 2500 fewer NIH grants, 33,000 fewer jobs, and a $4.5 billion loss in economic activity.3 Since the NIH’s budget represents less than 1% of overall federal spending, policymakers must reconsider whether shaving 8% from NIH outlays will have a noticeable positive effect on the national deficit or economy.

Fallout from funding cuts could include shifts in the U.S. medical research workforce. In 2000, the National Research Council noted both an overall shortage of medical researchers and inadequate funding for scientists working in the United States, which coincided with a decline in the number of funded NIH grant applications from 31% in fiscal year 2002 to 19% in 2010. This change is particularly critical for postdoctoral researchers, who represent the majority of the U.S. biomedical science workforce. According to the NSF, nearly half the 14,601 new postdoctoral-level researchers who were trained in the United States in 2009 were not U.S. citizens or permanent residents. If U.S. institutions are willing to devote money, training, and infrastructure to support talented, committed researchers, it would be an illogical waste of resources and poor long-term strategy to reduce federal grant mechanisms and wipe out potential job opportunities. Indeed, declining financial support may well encourage medical researchers to seek employment elsewhere.

As compared with the United States, China, India, South Korea, Taiwan, and Singapore have taken a sharply different view of medical research and have developed policies that foster medical research as an engine for economic growth and intellectual innovation (see tableMajor Government Agencies in Asia and Their Budgets for Medical Research.). Their national budgets are heavily based on scientific research and development, and funding is increasing, with budgetary targets ranging from 2 to 5% of their gross domestic products (GDPs). India’s funding goal for medical research alone is 2% of its GDP.

Increased funding for research infrastructure attracts scientists and organizations interested in high-quality research, including clinical trials. During the past two decades, increasing numbers of clinical trials have moved overseas, where benefits can include decreased costs of doing business, fewer administrative regulations, and greater enrichment of international relationships among researchers. The average annual rate of growth in clinical trials has been highest in China — 47% — while the number conducted in the United States has decreased by an average of 6.5% annually.4 In addition, the increased attention paid to Asia by private firms and other nongovernmental organizations has spurred rapid policy-level responses to concerns about the lack of informed consent, transparency, and other ethical issues, thus further strengthening the appeal of conducting research in the region.

Asian policies reflect a recognition of the extrinsic economic benefits of medical research. China and India have advocated for more government-funded medical research to improve health-related outcomes. China has espoused increased spending as part of achieving xiaokang, a Confucian term meaning a moderately prosperous society. In 2007, India inaugurated its Department of Health Research, which coordinates biomedical science and health-services research programs and translates their findings to address public health concerns. Since the signing of the Korean War Armistice Agreement in 1953, South Korea has leaned heavily on government-funded research to reduce poverty, allowing the country to gradually acquire advanced technologies and expertise. Medical research is part of at least two core technology areas in South Korea’s “577 Initiative”: medical technologies, such as neuroimaging, to address the needs of an aging population and research on issues pertaining to national safety and public health, such as infectious-disease preparedness and food safety.

National research and development programs have been a fundamental component of Taiwan’s economic policy for at least five decades. In 2005, the country began developing “intelligent medical care” — similar to earlier U.S. initiatives — which integrates medical information technology with quality-improvement measures. In Singapore, medical research and economic oversight are administratively linked. For example, the Biomedical Sciences Group of the Economic Development Board supports researchers financially and designs strategies that enhance Singapore’s status as a knowledge center, and the private firm Bio*One Capital invests directly in promising medical technologies.

The diverse strategies outlined above allow Asian countries to systematically recruit medical researchers from both home and abroad. China is particularly proactive in enticing Chinese-born, U.S.-educated researchers to return to their native country by offering generous financial and material incentives under its Knowledge Innovation Program. As the vice president of the Chinese Academy of Sciences stated more than a decade ago, modern “research and development is actually a war for more talented people.”5 In 2000, Singapore jump-started its Biomedical Sciences Initiative to attract medical researchers worldwide with a direct $2 billion investment, as well as with tax incentives for internal biotechnology start-ups and global pharmaceutical firms. In Singapore and India, English is the primary language for scientific communications, which alleviates concerns about language barriers.

For two decades, emerging Asian countries have been designing long-term strategies to reap the benefits of medical research. Meanwhile, the United States is relying on short-term solutions to support its medical research infrastructure, such as those offered by the Patient Protection and Affordable Care Act and the American Recovery and Reinvestment Act. Decreased investment in U.S. medical research could lead to long-term economic damage for the United States and the loss of its stature as a global leader in the field. Powerful incentives that can retain an elite biomedical-research workforce are necessary to strengthen the U.S. health care system and economy.

The views expressed in this article are those of the authors and do not necessarily reflect those of the Robert Wood Johnson Foundation, the Department of Veterans Affairs, or the Agency for Science, Technology, and Research.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

SOURCE INFORMATION

From the Robert Wood Johnson Foundation Clinical Scholars Program (G.H.S., R.J.), the Department of Otolaryngology (G.H.S.), and the Department of Radiation Oncology (R.J.), University of Michigan, and the Health Services Research and Development Service, VA Ann Arbor Healthcare System (G.H.S.) — both in Ann Arbor, MI; and the Singapore Bioimaging Consortium, Agency for Science, Technology, and Research, Singapore (J.D.S.).

http://www.nejm.org/doi/full/10.1056/NEJMp1206643?query=TOC

 

 

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