DNA and You

Steven Pinker of the PGP in the NY Times Magazine

Very interesting article by Steven Pinker of the Personal Genome Project in the NY Times Magazine.  Check it out here.

If You Think Wired Is a Good Place to Go for Medical Advice, Think Again...

Andrew Yates at Think Gene wrote today about the new Wired Wiki home genomics how-to guide, "Check Yourself for Genomic Abnormalities."  Check out Andrew's post for a great discussion of the maturity, or, rather, the lack thereof, of the personal genomics market.

Something caught my eye though as I read through "Check Yourself for Genomic Abnormalities" at the Wired Wiki site.  The wiki post describes several options for "checking yourself for genomic abnormalities": 1) Visit a Genetic Counselor; 2) Scan Your Whole Genome; and 3) Perform Lab Tests at Home. 

Interestingly, the author(s), who otherwise did an ok job of briefly explaining what genetic counselors do, utilized consideration of a diagnosis of celiac sprue as an example of a situation in which someone would want to see a genetic counselor rather than "scanning their whole genome" or "performing lab tests at home."

I think the world of Wired, but in case it is not clear to the early adopters out there...

Wired is probably not where you want to get your medical advice.

Celiac disease (aka gluten-sensitive enteropathy or non-tropical sprue), the condition mentioned in the hypothetical scenario, is diagnosed via a blood antibody test and small intestinal biopsies.  Thus, rather than seeing your local genetic counselor if you think you might have CD, you would do well to discuss it with your primary care doctor and a gastroenterologist. 

The wiki writer's confusion likely stems from the fact that genetic factors do play a role in risk for Celiac disease; however, the genetics are complex, and the genes involved are not deterministic.  For example, risk of Celiac disease is higher if you have certain forms ("alleles") of HLA genes.  About 30% of the population has one of the Celiac disease-associated HLA alleles; however, only 3% of individuals with the Celiac disease-associated allele develop CD.

Is it heritable? Twin study evidence suggests acne can be inherited

Have you ever wondered whether acne risk can be inherited?  Twin studies can shed light on this question.

In a previous post, I discussed twin studies which are the genetic gold standard to determine whether the liklihood of developing a given medical condition (or trait) is subject to heritable (i.e., genetic) influences.  The concept is fairly simple: Identical twins share essentially 100% of their genetic material while fraternal twins share 50%.  If genetics plays a strong role in risk for a disease, when twin pairs in which one member has the disease are studied, both twins will have the same disease in a larger percentage of the identical twin pairs as compared to the fraternal twin pairs. 

One study applied this concept to the study of acne.  The results were clear: in this study, approximately 80% of the degree to which acne severity varied was due to genetic effects. 

Although the underlying causative genes are not known, the fact that genetics plays such a large role in the development of acne suggests that future efforts to find the underlying genes are likely to reveal new drug targets.

Rett Syndrome on Fox Show: "So You Think You Can Dance"

Tara Parker-Pope of the NY Times writes about an episode of the Fox reality show, "So You Think You Can Dance," in which Rett syndrome was featured.

For more on Rett Syndrome:

Rett Syndrome (MECP2-Related Disorders) GeneReview

International Rett Syndrome Foundation

Mandatory Waistline Measurement in Japan: Good Public Health Social Policy? Or Genetic Discrimination Against Fat People?

The NY Times has a really interesting piece on a new policy of mandatory waistline measurement in Japan.  With a goal of improving the public health, the government has established a state prescribed limit on male waistlines of 33.5 inches along with a limit of 35.4 inches for women...

No...I'm really not kidding.

Companies and local governments will apparently be required - under this new national law - to measure waistlines of those 40-74 years old during annual checkups.  Apparently, those not meeting the country's standard will be given dieting guidance if they do not meet the standard and do not lose the weight over 3 months (with subsequent escalation of the scrutiny and advice if folks are still too rotund at 6 months). 

Interestingly, the Japanese government intends to impose monetary penalties on entities (local governments and companies that fail to meet specific targets).

Although I am sure that the Japanese government has good intentions, this is a very interesting policy in light of the fact that obesity is a trait that can only be partially modified by behavioral change.  In other words, it is clear that obesity risk is to some extent a heritable trait, determined to some extent by one's genetic background, that can be difficult for some individuals to overcome.

Although this is an interesting and aggressive experiment aimed at reducing healthcare costs, it has the potential to result in further stigmatization of those affected by the obesity epidemic (something that is, no doubt, intended by the rule since it may result in public health benefits).  By imposing penalties on local governments and companies, the government is avoiding the appearance of discriminating against those with generous waistlines; however, this will create tremendous incentives on these entities to exert considerable pressure on individuals whose waists are over the limits. 

In sum, it's a bold social policy.  It may help with healthcare costs in the long-run, but is it genetic discrimination? 

What do you think?

COPD and Your Genes: New Study of Familial Risks for Chronic Obstructive Pulmonary Disease

Yesterday, at Cancer and Your Genes, I mentioned an interesting study assessing the degree to which survival in prostate cancer seems to run within families (and therefore may be genetic).  Some of the same authors, including Kari Hemminki, the lead author, also have a paper in the May 2008 issue of the Journal of Epidemiology and Community Health that assesses familial risks for chronic obstructive pulmonary disease (COPD) amongst siblings in Sweden.

The results basically showed that siblings of individuals with COPD had much higher risks of COPD themselves (Standardized Incidence Ratio [SIR] = ~4.6) as compared to spouses of individuals with COPD (SIR = ~1.6).  The fact that the SIR was much higher for sibling pairs than for spouses is consistent with genetics underlying at least some familial susceptibility to this disabling lung disease. 

Although there is a rare familial cause of COPD (alpha-antitrypsin deficiency), it seems unlikely that this would account for a significant fraction of the familial effect.  It will be interesting to see what we learn in the future about other genes underlying COPD risk--and also the extent to which they interact with a known environmental risk factor for this disease, smoking, which itself has a heritable component.  Very complicated!

More on Digital Clubbing...

I just noticed that there is a pretty good wikipedia article related to my earlier post on digital clubbing.

Digital Clubbing and Your Genes: Prostaglandin E2 in the Pathogenesis of Finger Clubbing (aka Hypertrophic Osteoarthropathy)

A new paper (abstract available here) published online in the journal Nature Genetics demonstrates the power of traditional Mendelian genetics to reveal clues to the underlying mechanisms of more common diseases.  Finger or digital clubbing, which is also known as hypertrophic osteoarthropathy, is one of the classic physical signs taught to medical students.  Hippocrates is commonly thought to have been the first to recognize digital clubbing in the fifth century BC.  The clubbing depicted in the figure below (from www.nail-disorders.com) is the hallmark of so-called pulmonary hypertrophic osteoarthropathy, a clinical sign that can develop in the context of a number of clinical conditions including intrathoracic neoplasms (i.e., cancers within the chest):

Some Clinical Conditions Associated with Digital Clubbing

• Lung Cancer
• Congenital Heart Disease
• Inflammatory Bowel Disease

Figure: Digital clubbing (aka hypertrophic osteoarthropathy).  From www.nail-disorders.com.

Despite the fact that the form of hypertrophic osteoarthropathy secondary to lung cancer and other disorders has been recognized for many centuries, its actual cause has remained remarkably enigmatic.  However, the new study in Nature Genetics breaks important new ground. 

The authors, led by Dr. David Bonthron of the Leeds Institute of Molecular Medicine and Yorkshire Regional Genetics Service, studied several families with a rare inherited form of digital clubbing, known as "primary (idiopathic) hypertrophic osteoarthropathy (PHO)."  They localized the gene responsible for PHO to the long arm of chromosome 4 and demonstrated that the responsible gene is HPGD, which provides the coding information to produce a protein called "15-hydroxyprostaglandin dehydrogenase."  The affected individuals in these families had mutations in both of their copies of HPGD, suggesting that the inheritance pattern is autosomal recessive (i.e., similar to cystic fibrosis in that a mutation in both copies of the gene are necessary to get the clinical condition). 

Importantly, 15-hydroxyprostaglandin dehydrogenase is the main enzyme responsible for breaking down prostaglandin E2 (PGE2, a lipid compound which has a number of functions in the lung, the GI tract, and in the uterus during pregnancy) and other prostaglandins and related compounds. 

The authors measured PGE2 levels in the urine of the study subjects and showed that they were elevated in the individuals from the families with mutations in both copies of HPGD.  Interestingly, intermediate elevations of urinary PGE2 levels were seen in some of the family members with one normal copy and one mutated copy of HPGD.  Some of these individuals had mild, late-onset digital clubbing, which is consistent with the degree of elevation of prostaglandin levels within the body determining the severity and age of onset of the digital clubbing.

In hindsight, the identification of HPGD, the key enzyme in prostaglandin degradation, as a disease gene for PHO makes a great deal of sense.  PGE2 is known to have a number of effects upon bone.  The demonstration, in this rare disorder, that mutations in the key enzyme of prostaglandin degradation lead to PHO suggests that elevated prostaglandin levels are critical in causing the much more common clubbing seen in pulmonary hypertrophic osteoarthropathy (the clubbing seen in association with lung cancer and other disorders).  As the lung is known to be a site of PGE2 clearance by HPGD, perhaps the lung diseases associated with pulmonary hypertrophic osteoarthropathy lead to decreased clearance and degradation of PGE2.

PGE2 is also known to be important in the context of a type of congenital heart disease known as "patent ductus arteriosus" (PDA).  Normally, the ductus arteriosus is closed after birth when circulating PGE2 levels fall significantly (due to exposure of the blood to HPGD in the newborn's lung).  One might expect that PGE2 levels would not drop as rapidly in individuals with mutations in HPGD, and, indeed, 4 of the 13 HPGD-deficient individuals in this study had patent ductus arteriosus.  Although, this association was previously recognized, it now makes much more sense given the association with a disruption in the capacity to metabolize PGE2.  It will be interesting to see if significant numbers of individuals with PDA have mutations in one or both copies of HPGD.

The authors point out that there were some previous clues to the involvement of prostaglandins in clubbing.  For example, liver transplant patients who received prostaglandin E therapy developed clubbing.  Nevertheless, this novel result suggests that PHO and the more common secondary pulmonary hypertrophic osteoarthropathy have a common cause: elevated prostaglandin levels. 

There are two important clinical implications for the future:

1. Strategies aimed at decreasing prostaglandin levels might be helpful in individuals with PHO.
2. For middle-aged or elderly individuals presenting to a physician with clubbing in the future, it may be worthwhile considering whether there are HPGD mutations, as their presence could help the patient avoid an extensive work-up looking for other underlying causes including malignancy.

A HOXA2 mutation is responsible for one type of autosomal recessive microtia (congenital deformity of the outer ear)

Congenital deformities of the outer ear, referred to as microtia, occur in about 1 out of every 9000 births and can be either unilateral (one-sided) or bilateral (both sides).  Most cases are unilateral, and interestingly, the right ear is more frequently affected in these cases.  Additionally, microtia occurs more frequently in males.

The condition is divided into four grades depending on the severity of the deformity.  Syndromic forms of microtia are seen in individuals in whom microtia occurs together with other congenital abnormalities.  Among the associated malformations in these syndromic cases are cleft lip or palate, kidney abnormalities, cardiac defects, and others, in addition to hearing loss.

Syndromes associated with microtia include the following:

• Oculo-auriculo-vertebral spectrum (which includes hemifacial microsomia aka Goldenhar radial defect syndrome
• Treacher Collins syndrome
• CHARGE association
• Nager syndrome

A new paper published online in the American Journal of Human Genetics reports the identification of a gene involved in an autosomal recessive form of microtia.  Fatemeh Alasti, Guy Van Camp, and colleagues studied a consanguineous Iranian family in which four cases of bilateral microtia were seen in association with hearing impairment (prelingual onset), and partial cleft palate. 

The authors performed linkage analysis and localized the disease gene to chromosome 7p between 7p14.3-p15.3.  Further fine mapping revealed an identical homozygous region that was approximately 10MB in length and contained >100 genes.  The authors chose to sequence genes from the HOXA gene cluster (HOX genes are homeobox genes which play a very important role in development).  A DNA sequence change in HOXA2 causing an amino acid change (Q186K) in the HOXA2 protein was found in the homozygous haplotype in all affected individuals in the family and in heterozygous fashion in the unaffected parents.  The authors demonstrated that this variant DNA sequence was absent from 231 Iranian and 109 Belgian control individuals (without microtia).   

Although the collective evidence from this study regarding the involvement of HOXA2 in ear malformations is very solid, ultimately further proof will be necessary from the identification of additional microtia patients with HOXA2 mutations and/or solid functional analysis of the mutant Q186K HOXA2 protein. 

It is difficult to speculate at this point about the percentage of autosomal recessive microtia that might be secondary to HOXA2 mutations.  Most likely, this will prove to be a fairly genetically heterogeneous condition with involvement of other genes (including other homeobox genes) in some cases.

Further Resources:

• OMIM microtia entry
• OMIM HOXA2 entry
• Children's Craniofacial Association microtia info
• Hereditary Hearing Loss Homepage
• UCSC Genome Browser HOXA2 page
• AJHG Abstract for F Alasti et al. paper

Gene Found for Ghosal Hematodiaphyseal Dysplasia Syndrome: A Rare Syndrome with Increased Bone Density

A paper published online on Sunday in the journal Nature Genetics (abstract available here) describes the identification of mutations in a gene causing the rare, autosomal recessive, genetic syndrome Ghosal hematodiaphyseal dysplasia syndrome (GHDS).  GHDS is a disorder of increased bone density. 

The authors had previously mapped the disease gene to a segment of chromosome 7 by studying two families from Algeria and Tunisia.  In this study, they identified mutations in TBXAS1 - which encodes the enzyme thromboxane synthase - in the two original families, in addition to two other families from Tunisia and Pakistan with GHDS. 

Thromboxane synthase is one of the terminal enzymes in the arachidonic acid cascade and is involved in the production of thromboxane A2, which is known to be a powerful inducer of blood platelet aggregation in addition to having other physiologically important effects. 

The demonstration that TBXAS1 mutations cause GHDS, a disorder of increased bone density, suggests that thromboxane synthase and thromboxane A2 may play an important role in bone remodeling. 

Additionally, as is often the case with the identification of disease genes causing rare Mendelian (see "Mendelian trait" section of this article) syndromes, this paper suggests a candidate gene for a related, but much more common, condition; the involvement of TBXAS1 in a disorder of increased bone density suggests that it may be a candidate gene worth investigating in osteoporosis in the future.