A family history of coronary heart disease is an independent, common, actionable and perhaps under-appreciated risk factor for developing coronary heart disease in otherwise healthy people (1). In addition to shared genes, other factors such as blood lipid levels, blood pressure levels, body weight, type 2 diabetes, smoking habits, eating patterns, alcohol consumption, physical activity and socioeconomic status, also tend to cluster in families (2). Due to the fact that family health history captures the consequences of genetic, environmental and behavioral risk factors on cardiac health, it may be a better indicator of a person’s chances of developing CHD than many of the other risk factors that are more commonly relied upon for this purpose (1). Familial coronary heart disease accounts for a significant fraction of the burden of CHD in the population. In a large study of over 122,000 families who were not selected for CHD and were ascertained through high school health classes, 72% of early-onset CHD and 48% of all CHD were clustered in 14% of the families studied (3). Community-based preventive interventions that included visits by public health nurses, were shown to be effective in educating families about their risks, assisting in making appropriate referrals and supportive for long term behavior changes (4). Preventive interventions that focus on families therefore may have a significant impact on reducing cardiovascular disease risk factors in the population as a whole. In addition, the populations with the greatest familial risk for CHD also show the greatest risk reduction in response to preventive interventions (5).

Family history of CHD is also very commonly encountered in the population. In a recent national mail survey (Healthstyles) that collected information on the health attitudes, behaviors, conditions and knowledge of a population that is representative of the U.S. population, almost 50% of the respondents reported a family history of CHD in a close relative (parent or sibling), suggesting at least a moderate familial risk (6).

Considering the prevalence, predictive power and actionable nature of family history of CHD, it is important for health practitioners to be able to confidently interpret the significance of a family history of CHD, to understand the potential consequences for their patient’s health, and to determine appropriate follow-up and screening (7). In general, the risk of CHD increases as the age of onset of heart disease in the family gets younger and the number of relatives who are affected increases, especially if the relatives are female. In addition, the risk increases as the relationship of affected relatives gets closer. Other characteristics of familial susceptibility include the presence of multiple CHD risk factors in affected relatives or the presence of related disorders (e.g. type 2 diabetes, hypertension or stroke) in family members (7). In families with moderate histories of CHD, the cardiac health history of siblings seems to be even more predictive of CHD than that of parents (8).

Although there are no universal screening or follow up guidelines that are recommended for all individuals with a family history of CHD, one or more of a range of options may be appropriate and effective in addressing a familial risk of CHD. Interventions may range from counseling on relatively minor changes in behavior or diet to referral for further evaluation to a cardiologist or medical geneticist. In general, the aggressiveness of intervention is determined by the degree of the family history of CHD encountered and the underlying etiologies that are responsible. More detailed information on risk stratification and appropriate interventions for patients at risk for familial CHD are collected in a recent review (7). For more information on familial CHD or assistance for appropriate referrals for familial CHD contact the Chronic Disease Genomics Project at the Minnesota Department of Health at 651-201-3609.

1. Kardia SLR, et al. Family-centered approaches to understanding and preventing coronary heart disease. Am J Prev Med 2003; 24(2):143-151

2. Higgins M. Epidemiology and prevention of coronary heart disease in families. Am J Med 2000; 108(5):387-395

3. Williams RR, et al. Usefulness of cardiovascular family history data for population-based preventive medicine and medical research (The Health Family Tree Study and the NHLBI Family Heart Study). Am J Cardiol 2001; 87:129-135

4. Johnson J, et al. Utah’s Family High Risk Program: Bridging the gap between genomics and public health. Prev Chronic Dis [serial online] 2005 Apr.

5. Hunt SC, et al. Family history assessment: Strategies for prevention of cardiovascular disease. Am J Prev Med 2003; 24(2):136-142

6. McCusker ME, et al. Family history of heart disease and cardiovascular disease risk-reducing behaviors. Genet Med 2004; 6(3):153-158

7. Scheuner, MT. Clinical application of genetic risk assessment strategies for coronary artery disease: genotypes, phenotypes, and family history. Primary Care Clinics in Office Practice 2004; 31(3): 711-737

8. Nasir K, et al. Coronary artery calcification and family history of premature coronary heart disease: Sibling history is more strongly associated than parental history. Circulation 2004; 110:2150-2156

July 30, 2006

SACGHS seeks public comment on policy report

The Secretary's Advisory Committee on Genetics Health and Society (SACGHS) advises the Secretary of Health and Human Services on selected issues related to genetic research and applications, including the ethical, social and legal implications. The SACGHS issued a draft report entitled "Policy Issues Associated with Undertaking a Large U.S. Population Cohort Project on Genes, Environment, and Disease." The SACGHS is seeking public comment on this draft until July 31, 2006. The purpose of the report is to explore policy issues related to engaging in a very large study that is representative of the U.S. population to collect the necessary information for both biological and epidemiological studies that would help discern the relationship and interactions between genes and environmental factors that affect health. This would be a huge undertaking, so it is laudable that the SACGHS has begun to address this issue. They correctly observe that:

"A large population research project raises multiple policy issues because
1) it will involve an unprecedented number of participants and, thereby, will have a significant public profile and a direct impact on many people;
2) it requires a relatively large investment of public resources and, as such, warrants scrutiny of and deliberation about its relative value to science, society, and the Nation; and
3) the nature f the information that will be derived from it raises ethical, legal, social and public policy concerns that could be unique and/or significant, particularly in view of the number of potential participants”.

The SACGHS has identified five issue areas that need further exploration before a decision to engage in a large study of the U.S. population could even be made. These areas include issues related to:
1. Research policy
2. Research logistics
3. Regulatory and ethical considerations
4. Public health implications of the project
5. Social implications of the project

In the report, the SACGHS outlines the issues they have identified in each of these areas and some policy options for addressing each one. I will not re-cap the content further, but refer you to the report’s succinct executive summary. I will, however, offer a few brief observations on the report and its recommendations.

First of all, the report recognizes how important it will be that the public at large is and continues to be engaged in this project, should it occur. This is obviously very important, so it is good that the SACGHS clearly recognizes and addresses this.

Second, the report recognizes the existence of the many uses of this type of data and is sensitive to multiple perspectives of entities who may have interest in this information, including (but not limited to) the interests and concerns of racial groups, business interests, academia, ethicicists, policy makers, and public health.

Third, the areas related to issues on research policy and research logistics are especially detailed and well covered, offering very specific strategies for assuring that the project is multidisciplinary in nature and that the data generated is available for both public and private concerns, including issues related to protecting intellectual property.

Fourth, the sections on ethical issues and regulation, public health implications and social implications of the the project are, unfortunately, the least developed and the least specific. Although it is laudable that these issues were considered to be major enough to be considered part of the top five (all three are in the list detailed above), the recommendations provided by the SACGHS were vague and very nonspecific compared to the recommendations for the first two major issues, which were much better developed. Hopefully, in the next draft of this report, there will be a little more meat on the bones of this section.

The full report can be accessed here.

July 29, 2006

Dad's family history of breast cancer may get short shrift

In
families which have a familial tendency to develop breast cancer, this
inherited susceptibility can come from either the mother's or the
father's side of the family. In these families, the susceptibility
comes through the paternal lineage about as often it does through the
maternal side of the family. Many people (including some healthcare
providers) are surprised that you can inherit a susceptiblity from your
dad's side. After all, most men do not get breast cancer, even in
families with a very strong tendency for developing this disease, so
the idea that the susceptibility could pass through males to their
female descendants seems counter-intuitive.

The main finding
of a study that will be published in the September 2006 issue of the
American Journal of Preventive Medicine by Dr. John Quillen and
colleagues reports that women report fewer cases of breast cancer in
their paternal relatives than would be expected. The consequences of
this apparent under-reporting is that a woman's risk of breast cancer
may be underestimated, potentially affecting her access to appropriate
screening and/or cancer prevention strategies. Ultimately, her
likelihood of having a poor health outcome due to breast cancer may be
increased if the management of her risk is less aggressive than might
be warranted if the true extent of her family history of cancer was
considered.

The authors of the study report their results in the American Journal of Preventive Medicine.
The full text of this article will be published in the September 2006
issue. The article cite is “Paternal Relatives and Family History of
Breast Cancer” by John M. Quillin, PhD, Viswanathan Ramakrishnan, PhD,
Joseph Borzelleca, MD, Joann Bodurtha, MD, Deborah Bowen, PhD, and
Diane Baer Wilson, EdD. American Journal of Preventive Medicine, Volume
31, Issue 3 (September 2006).

An article
by Eric Nagourney in the New York Times on July 25, 2006 also reports
on this study. The full text of the article in the American Journal of
Preventive Medicine is available here. A press release from the publisher that summarizes the findings is available here

Beyond the Genome...Beyond the Individual: Genomics and Public Health

The National Societies of Genetic Counselors (NSGC) is sponsoring a one and one half day long course on public health genomics in conjunction with the Annual Education Conference in Nashville, TN on November 9-10, 2006.

According the NSGC, the purpose of the course is to help genetic counselors to increase their capacity to be prepared to play an important role as genomics is increasingly used in public health activities aimed at health promotion and disease prevention. More specifically, the purpose of the course is stated to be:

"Innovations in genetics and genomic research are influencing health risk assessment, treatment options, and disease prevention strategies. New knowledge based on the interactions of genetics with environmental and behavioral risk factors has resulted in expanded opportunities to understand and prevent common conditions, such as cardiovascular disease, cancer, and diabetes. As genomics further permeates medicine and public health, there is a growing need for genetic counselors to have expertise in both genomics and public health to help consumers and practitioners comprehend the implications of genomics in practice. The demand for genomics expertise in public health settings also provides new opportunities for expanding the practice of genetic counselors beyond individuals and families to the general population. For example, public health genomics is moving from the realm of newborn screening, education, and providing or funding care for vulnerable and underserved communities to dealing with family history as a population-based genomic tool, and incorporating genomics into chronic disease services and programs. Policies such as genetic nondiscrimination legislation and newborn screening expansion mandates are also affecting the practice of genetic counseling. Technological advances and elucidating their benefits and harms is another important part of public health genomics and genetic counseling.

To be maximally effective, genetic counselors must begin to strengthen their knowledge of public health principles, policy and practice. This short course will utilize plenary sessions and panel discussions to provide examples for using public health principles in genetic counseling, introduce the relevance of genomics to public health, discuss policy development, and explore ways in which genetic counselors can contribute to improving the health of populations. "

The course agenda is available. Online registration is available and you need not be a genetic counselor or a member of NSGC to participate.

National Office of Public Health Genomics at the CDC

The
Centers for Disease Control and Prevention has had an office working to
integrate genetics and genomics into public health since 1998. At its
inception, the office was known as the Office of Genetics and Disease
Prevention to reflect this mission of using genetic tools to improve
health. In 2002, the name was changed to the Office of Genomics and
Disease Prevention to reflect the growing importance of genomics and
other "omics" sciences in public health. On July 24, 2006, the name of
the office was changed again, to the National Office of Public Health
Genomics. According to the announcement on their website:

"Public
health genomics is a multidisciplinary field concerned with the
effective and responsible translation of genome-based knowledge and
technologies to improve population health. Public health genomics uses
population-based data on genetic variation and gene-environment
interactions to develop evidence-based tools for improving health and
preventing disease. Since 1998, our office has been at the leading edge
of this development in the United States and internationally. Thus, the
name change better reflects what we do."

July 27, 2006

New code in the DNA for nucleosome-wrapping

The most obvious information contained in our DNA is the information contained in the genetic code which allows us to predict the amino acid sequence of protein products that are coded by genes. Although the complete catalogue of proteins in the proteome is still incomplete, other more subtle structural and sequence patterns are being uncovered that may affect the regulation of gene expression and other genomic activities. This fledging understanding of how and when genes are transcribed is vital to understanding the biology that underlies health and disease. This understanding may have been significantly advanced by recently published work by Drs. Eran Segal, Jonathan Widom and colleagues that suggests that there may be a subtle, degenerate code in the DNA that determines where the DNA is likely to be pliable enough to wind around the structural protein complexes called nucleosomes. Published online in Nature on July 19, 2006, the authors present data that supports the existence of this new, non-obvious code which may help to explain how DNA wraps itself around the nucleosomes. This secondary genomic structure not only helps DNA package itself more compactly, but it also has an effect on gene expression by regulating access to transcription factor binding sites. It is believed that this discovery could provide some important insights into how, why and when specific genes are--or are not-- accessed for expression. Paid registration is required to access this article.

Nicholas Wade also reports on this new finding in the New York Times on July 26, 2006. Access is via free registration.

July 25, 2006

Genes, Gender and Scientific Ability

Nobody will ever say that males and females are exactly alike. At the level of the genome both males and females have 46 chromosomes in most cases, but males typically have an XY and females have an XX pair of chromosomes as part of the basic set. Phenotypically, male and female bodies have obvious physical differences. Some scientists are arguing that there are other constitutional differences between males and females that make females less able to compete and succeed at the highest levels of scientific endeavor due to a lack of innate ability and other "female" attributes.

A thoughtful essay in Nature (paid subscription required) by Dr. Ben Barres challenges some of these assertions. Dr. Barres is somewhat uniquely qualified to discuss these issues because, as a transgendered individual and an accomplished scientist, he has experienced life and career from both the perspectives of a woman and a man. Although he supplies his own experiences as anecdotes in this discussion, he does not consider them "data". Instead, he uses evidence from the published literature to support his argument that the differences between the observed levels of achievement between male and female scientists is due to a pervasive discrimination within academia that judges women as less competent than men.

Dr. Barres has also provided an interview to the New York Times, which was published on July 18, 2006, where he reviews and expands upon his comments in Nature. This article is available with free registration.

July 21, 2006

The Quest for the $1,000 Human Genome

The goal of the $1000 Human Genome is almost certainly a little closer with the advent of a new generation of DNA sequencers. Nicholas Wade reports on some of these new developments in the July 18, 2006, issue of the New York Times article The Quest for the $1,000 Human Genome.

However, even as we get closer to this NIH-supported goal, the bigger question still remains: What impact will access to the complete genome sequence really have for most people's medical care? The developers of this new technology acknowledge that there is no real demand for this information, at least not yet. They are banking that access to complete genome sequence information will become routinely relevant in healthcare in the next few years. The jury is still out as to what the value of this information will be for most people. So the question of whether the DNA sequence is likely to be so powerful and predictive that we all should have our genomes sequenced is a relevant one. By itself, the sequence is only potentially related to our health; it yields information about the probabilities of what our health is or will be, but not what our health actually is now or will be in the future. A prime example that illustrates this point are the hereditary cancer syndromes. Even in these families with inherited mutations in "cancer genes", many (if not most) of the individuals who inherit a cancer-predisposing mutation never get cancer. The probablilty that they will eventually develop cancer is higher, to be sure, but they are not sick simply because they inherited this strongly predisposing genetic element. This is even more true for the many less potent genetic elements that we all have that contribute to disease risk. The real story of health lies in the biological processes and interactions that are only partially due to the genome.

Our genes are only half (and sometimes significantly less than half) of our health story, both present and future. The other major players are all the extrinsic factors that make up our environment and the consequences of our behaviors. We are learning more and more about how our genome interacts with the myriad of elements within the genome itself and the almost infinite elements that are extrinsic to the genome. These interactions are more closely related to the health states we experience (both good and bad) than the sequence alone.

Of course, the DNA sequence obviously plays an important role--it is the foundation of our biology. However, the genome functions in an environmental context that regulates its activities at many levels. The technologies to elucidate the physiological consequences of these interactions between genes and environment are developing in parallel with the quest for the affordable genomic sequence. An understanding of how the genome is expressed and how non-genomic factors affect expression will ultimately be more directly relevant to managing the unique and dynamic physiological circumstances that contribute to a person's state of health or a particular disease process. As we close in on the quest for low-cost DNA sequencing, the genome sequence's greatest value may be in what it contributes to our understanding of the interactions between our genome and our environment, and thus, our health.

Minnesota Gene Pool Blog

July 31, 2006

Family history and coronary heart disease--common, actionable, under-appreciated