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  • Genetic Involvement in Common Disorders

    Edwin M. Knights Jr., M.D.

    WHY SHOULD WE KNOW OUR MEDICAL PEDIGREES?

    There are compelling reasons why knowing your family’s history of inherited disorders can be of great value, both to the present generation and even more for future ones. We like to say that DNA can unlock our past and provide keys to the future. It all started back in 1908, when Garrod reported that a disease called alkaptonuria was being inherited in a way that followed Mendel’s laws. About 50 years later, similar observations were made about sickle cell disease and after that reports on inherited disorders appeared increasingly often.

    We’ve come a long way in about a century, and it was well summarized by Ezekowitz in his editorial in the New England Journal of Medicine in 2001:
    “It seems that we are at the threshold of real advances in therapies for inherited disorders. The ability to purify and manipulate stem cells from bone marrow may provide new approaches to somatic gene therapy. The possibility that single-gene defects could be repaired in autologous stem cells ex vivo and, on return to the patient, home selectively to the organ of choice seems within our reach. These new techniques may allow the cure of a wide range of inherited disorders in the next decade.”

    SEARCHING THE GENETIC FLEA MARKETS

    Even a casual glance at medical literature today reveals the frantic molecular biological search for significant genes. To the genealogist whose dabbling in DNA was confined to Introductory Genetics and gazing at chromosomes, the whole scene has to be a bit scarey. Admittedly, it’s fun to create a pedigree chart and follow the inheritance of some unpleasant x-linked recessive trait, especially if it’s in somebody else’s family, but some time ago scientists were forced to conclude that humans aren’t pea pods or fruit flies, which is why our inheritance patterns, along with accompanying mutations, are just beginning to be understood. Of course, Dr.Victor McKusick was telling us this right along, but now that the medical establishment is in an all-out global race to find genetic applications for diagnosis, treatment, monitoring and possible prevention of diseases, it’s becoming apparent even to those of us who merely sit on the sidelines. But rather than being spectators, are there ways for us to help benefit our families from some of these marvelous new discoveries? What can we do to make this possible?

    THE GENETIC DISEASE SPECTRUM

    We now realize there’s a broad spectrum of genetic diseases. Although about 4,000 of them seem to arise from mutatations in single genes, that’s because those were the diseases that were easiest to study and identify. Now we’re faced with increasing degrees of complexity.
    • Simplest are single-gene diseases, e.g., sickle cell anemia. Many other genetic variations will or won’t cause anemia.
    • Next would be genetic mutations which can cause disease, but only later in life, such as Huntington’s disease.
    • We have other genes which carry susceptiiblity to disease, such as BRA-1 and BRA-2, associated with breast and ovarian cancers.
    • Other diseases can be associated with multiple genes which have moderate or weak effects, such as in asthma. In these conditions, it may also require specific environmental influences to cause the disease.
    • Mitochondrial DNA, inherited through the maternal line, can participate in many diseases through its energy production functions. Its influence is being recognized in more and more diseases, one of the most recent being bipolar disease.
    • Genetic linkage has been found between some vastly different
    diseases having close proximity of atypical genetic loci.

    How Do We Make Use of Genetics?

    It’s all very fascinating, but how can we be involved without being overwhelmed? We need to consider what our objectives should be and then we can look for ways to achieve them. We have to bear in mind that we’re looking at a new, rapidly expanding scientific field when the buzz-word is CHANGE. Genealogists who bravely pioneered in using DNA to research their family pedigrees discovered to their dismay that their sources for processing genetic information were continually emerging, merging and sometimes submerging and even the nomenclature for DNA loci had not been standardized.

    Some reliable sources are gradually developing from this chaotic situation, including excellent molecular genetics facilities in univerities, commercial laboratories, or combined ventures. They are striving to create a database of linked and unlinked allele frequencies which can be used for paternity testing and studying more distant relationships, such as first and second cousins. A second goal is to develop a human DNA population database useful for genealogical and geographical migration studies.
    If you’ve been confused about developments in this arena, join the club!

    Early pronouncements about the Human Genome Project included detailed descriptions about the vastness of this new scientific playground but the concepts seemed almost beyond comprehension. Fortunately, we were told, much of this newly mapped DNA consisted of “junk” which seemed to have little relevance to our daily existence. While molecular biology and its newly created partner, bioinformatics, continued to drown us in data, the genomics industry shrewdly concentrated on those aspects which showed the greatest promise for commercial success. The emphasis, and the press releases, focused on the medical potential, but newly created companies discovered the paper-trails to fiscal viability were paved with cost over-runs.
    Although genealogical uses were obviously not a high priority, we began to hear more about DNA’s little cousin, mitochondrial DNA (mtDNA). Y-chromosomes were now being used to track our family pedigrees very efficiently and the methodology blended beautifully with classic traditions of recognizing a family by its surname. That was certainly good news, although not really unexpected. And there was more good news to follow. Genealogists, always frustrated by early records which failed to identify the spouses, were delighted by possibilities of following maternal lines using mtDNA. Currently, the Y-chromosomes and mtDNA are the keys to genealogical research, but there will be other types of markers from cells other than those in the germ lines which will enhance our capabilities.

    Medical Pedigree Possibilities

    There’s been continual interest in determining our medical pedigrees, because documentation of birth, death and serious illnesses were integral parts of every person’s genealogical file. If the same illnesses or causes of death recurred frequently, it raised questions about their importance to both past and current family members. DNA opened the gates to an entirely new level of understanding family medical history. It confirmed that our lives represented a balance of multiple genetic and environmental influences and began to explain how much each was contributing over the course of a lifetime.

    Generation after generation, each family has encounted serious medical events, many inter-related and others sporadic or unique. We already knew that certain conditions tended to affect one generation after another and we are told that some which we once considered environmental also show evidence of genetic heritability. And we are continually learning about specific DNA which may not cause a disease but definitely predisposes someone to acquire it, or results in greater susceptibility to the disease.
    All the while, it’s getting ever more complex! We learned that mighty mtDNA, which exists in little non-nuclear power plants in the cytoplasm of cells, probably first arrived there as an invading virus or micro-organism but now plays an integral role in our metabolism and can participate by means of multi-organ involvement in some diseases, especially affecting the energy needs of some of our tissues. Our mtDNA duplicates some of the functions carried out by nuclear DNA but uses very different mechanisms. And while mtDNA is almost exclusively of female origin in humans, this is not true in plants and some other animal species and mutated human male mtDNA may actually occur in rare instances.

    It’s Not All “Junk”!

    It’s also becoming apparent that some of that “junk” DNA isnt junk after all and it’s opened up a vast chromosomal flea market. We are also beginning to understand more about some heritable familial tendencies which can combine seemingly unrelated conditions, leading to more intense investigation of the phenomenon known as “genetic linkage.” Because some of these links imply susceptibility rather than a direct connection, the research promises to be prolonged and complex.

    The amount of research on any condition depends directly upon the funding, whether by private sources or government grants. Private sources can include foundations, trusts, personal donations, the biotechnology industry or pharmaceutical companies. Federal funding is available in many nations.

    There are many sources available to research a certain disease. The printed literature includes recognized scientific journals, books, specialty magazines and daily newspapers. The field advances so rapidly that we are almost overwhelmed by research data, so our discussions include few references to exact loci, mutations or even some of the biochemical reactions. The latest findings are almost always on the internet, plus there are marvelous web sites available for almost any popular subject. Abstracts of recent seminars or papers will also be found there. Almost every disease has spawned one or more charitable foundations devoted to disseminating information about the condition, plus encouraging, coordinating, financing and directing the associated research. These foundations have web sites which usually provide the latest press releases on their research projects and sometimes abstracts of seminars or publications.

    Caution! Genealogists have already learned, to their keen disappointment, how much misinformation pervades the internet. Anybody can promote just about anything and include some wildly inaccurate statements, plus prejudicial or distorted judgment. In contrast, articles submitted to recognized medical journals are routinely subjected to careful editing and peer review, as professional organizations don’t want to be blamed (or liable) for spreading misinformation. One complication arising from disseminating inaccurate data is that it is widely quoted and misinterpreted, especially by the news media, whose standards for reliability have become very suspect. Televised newscasts frequently present news gleaned from a scientific journal which has not yet reached its subscribers. Several years ago the news media featured a study published by the Journal of the American Medical Society which proclaimed that 100,000 Americans died annually from adverse drug reactions. This would mean that one of every 300 hospital patients dies from an ADR. Having practiced pathology for nearly 50 years, I found this extremely difficult to believe. This statistic was seriously questioned in later careful reviews of the subject, but these follow-up reports received little attention.

    If you are seeking medical information from any article on any web site, be sure to note when the site was last updated, as it may be years out of date! Remember that medical advice is best obtained from your personal physician, not published sources or advertisements. Also, as we noted previously, the types of testing required for medical evaluation are not available from the laboratories which genealogists use for establishing a pedigree. There are excellent reasons why such studies should be carried out in an environment where professional interpretation, genetic counseling and other assistance is available to the client, all protected by confidentiality. Genetic tests can only give an indication of the risk of inheriting a disease, not precise predictions, and you will need assistance in making decisions if results are positive.

    Direct-to-Consumer Genetic Testing?

    The American College of Medical Genetics (ACMG) believes that appropriately qualified health care professionals should be involved in the ordering and interpretation of genetic tests and the counseling of individuals and families about the meaning and implications of test results. Failure to follow this policy will likely result in misused tests, misinterpreted results and misguided responses. In some cases, appropriate information is available from other simpler tests and genetic testing is not the best approach.
    Here is the statement issued by their Board of Directors on 29 June 2003:

    Genetic tests of individuals or families for the presence of or susceptitibility to disease are medical tests. At the present time, genetic testing should be provided to the public only through the services of an appropriately qualified health care professional. The health care professional should be responsible for both ordering and interpreting the genetic results, as well as for pretest and posttest counseling of individuals and families regarding the medical signficiance of test results and the need, if any, for follow-up. Due to the complexities of genetic testing and counseling, the self-ordering of genetic tests by patients over the telephone or the Internet, and their use of genetic “home testing” kits, is potentially harmful. Potential harms include inappropriate test utilization, misinterpretation of test results, lack of necessary follow-up, and other adverse consequences.

    Trying to cover the entire field of genetic condition is an intimidating prospect, so we’ve selected some conditions to show what’s been found so far and possibly give you a glimpse of what the near future might hold. Some of these subjects are extremely common and might be nesting on one of the branches of your family tree. We’ve also added some suggested references for each subject, but didn’t try to swamp you with them, because you can always find many more.

    GENETIC STUDIES ON SPECIFIC CONDITIONS

    Common Genetic Disorders
    Asthma
    Cataracts
    Color Blindness
    Cystic Fibrosis
    Diabetes Mellitus
    Gout
    Lactase Persistence
    Psoriasis

    ASTHMA

    Asthma and allergic diseases have genetic predispositions without classic Mendelian inheritance and it is apparent that approporiate environmental triggers are needed. Genes have been reported that cause pulmonary inflammation and associated allergic reactions plus providing a susceptibility to asthma.

    An estimated 15 million Americans suffer from asthma and the incidence of the disease has increased steadily in industrialized countries during recent years. Investigators at Stanford University have used mice to find a group of genes called Tim, with which the mice could be stimulated into developing asthma.

    CATARACTS

    Has anyone in your family had cataracts? There is a good possibility, because cataracts are by far the most common eye disease, causing blindness in 15 million people and increasing in frequency as the population ages. Age-related cataracts are strongly influenced by environmental factors, especially the effects of ultraviolet light. Some attempts have been made to link sunlight to cortical cataracts or capsular thickening and smoking to nuclear lens cataracts. Corticosteroid drugs also increase the risk. Mining the genealogical data base of Iceland may lead to future cataract prevention by combine genetic means with protection against the environmental hazards.

    Inherited lens opacities known as cataracts are usually found at birth or early in infancy. The prevalence is from 1-6 cases per 10,000 live births. Most of these seem to be transmitted via autosomal dominance, meaning that children of an affected parent will have a 50% chance of having congenital cataracts. Two genes seem to be involved with many of the congenital cases. These mutant genes are associated with lens connexin, tiny protein units which interconnect cells in the lens. The opacities have similarities to those in cataracts developed in adults and possibly the same genes are taking part in both conditions.

    Other studies have implicated at least 12 genes can be implicated in autosomal dominant cataracts. Myotonic dystrophy, an autosomal dominant disease affecting skeletal muscle and the heart, also includes cataracts.

    COLOR BLINDNESS

    Much the high-powered genetic research seems to focus on exotic, complicated diseases. Maybe researchers find them more challenging, or more likely it’s because each disease has now attracted a few charitable foundations and numerous web sites. Some common conditions seem to be overlooked. Color blind victims of the world, unite! Insist that more scientists focus on hue! Between 5-8% of the men and 0.5 percent of the women of the world are color blind. One of 12 men and one of 200 women is a huge number of people! One shudders at how many with red/green color blindness memorize charts to obtain driver’s licenses.

    Because the condition is so clearly defined, at least to those who aren’t color blind, the basic genetic principles have long been recognized. Color blindness was recognized to involve X-chromosome defects almost 100 years ago, and since women have two X chromosomes and men have but one, color blindness is much more common in males. A female with the color blindness defect in one of her X-chromosomes is an asymptomatic carrier, but her male chldren are just as likely to be color blind as though fathered by a color blind male. The molecular genetics are very detailed and involve atypicalities of photopigment genes, with shifting of sensitivity among the L-cones and M-cones, which recognize color. One of 100 males has red-weakness, called protanomaly, and 5 out of 100 males are green-weak, known as deuteranomaly. The dichromatic folks, who lack one of the three normal cone types, have troubles with red, orange, yellow and green. Then, as if it weren’t already too complicated, there’s protanopia, deuteranopia and achromatopsia with blue cone monochromacy. We’d like to report all kinds of useful molecular biology research, but if it’s under way, it’s hard to focus on it. Isn’t it time for researchers to start studying the “Three Blind Mice”?

    Researchers from Johns Hopkins went to Micronesia for color vision research, but they had a good excuse to put on the sunblock and the shades, as some islanders there have a rare variety of total color blindness. It’s said that a storm on Pingellap Atoll in 1775 left but 20 survivors, one of whom carried a gene for achromatopsia, which also inflicts severe light sensitivity and poor vision. Today there are 3,000 Pingelapese and 5% of them have achromatopsia. The researchers found a gene on chromosome 8, which appears to cause the disease. They probably are now continuing their research by breeding color blind mice who don’t mind living in Baltimore.

    CYSTIC FIBROSIS
    A common heritable disorder is cystic fibrosis (CF), occurring in one of every 3,200 Caucasian infants and in lesser degrees in other ethnic groups. (Ref. Table 3) The well-recognized heterogenicity of these groups makes such estimates very general, especially when population admixture in the US is increasing so rapidly. A mutated gene controling chloride balance was recognized in 1989 and over 1,000 CFTR mutations have now been reported. When the American College of Medical Genetics and the American College Obstetricians and Gynecologists recommended population CF carrier screening in 2001, they must not have envisioned the complexity of such an undertaking, especially when it came to selecting “ethnic-specific” mutation panels. Premarital and prenatal CF screening has been studied in the Ashkenazi Jewish population, which constitutes a less diverse group for study of recessive diseases because of the founder effect and/or selection.

    Screening for CF was once simple and inexpensive. Observations that CF babies sweat excessively and tolerate heat poorly first led to the recognition of an imbalance involving sodium and chloride. For years “gold standard” tests for CF were based on analysis of sweat, starting with using silver nitrate-impregnated filter paper and progressing to iontophoresis and other elaborate apparatus designed to increase test sensitivity. The complexity and cost of CF screening took a quantum leap when the CFTR mutation panels increased to include dozens of specific mutations. Fortunately the use of Bayesian analysis for CF risks in prenatal and carrier screening can reduce the CFTR panel size to 25 but does include ultrasound and other pertinent evaluations.

    It became obvious that the original name of “cystic fibrosis of the pancreas” ignored much of the pathology of the disease, especially in the lungs, so pathologists began calling it “mucoviscidosis.” This name didn’t stick, so now it’s just “CF”. Patients produce abundant thick mucus which clogs pancreatic ducts and impaires breathing by plugging the bronchial tree.
    Classic CF includes the following:

    * Chronic sinusitis
    * Severe chronic bacterial infection of airways
    * Pancreatic digestive insufficiency
    * Bowel malfunctions (meconium ileus) at birth in 15-20%
    * Male reproductive tract ostruction; infertility

    Nonclassic CF, with a better survival rate:

    * Chronic sinusitis
    * Chronic bacterial infection of airways
    * Usually adequate pancreatic digestive function
    * Pancreatitis, in 5-20%
    * Moderately elevated sweat chloride levels
    * Male reproductive tract obstruction

    Why perform genetic testing, and when is it indicated? A “Consensus” Statement on this subject was issued by the NIH Consensus Development Program, but you should be aware that these are the opinions of so-called “experts” and do not represent official NIH or Federal Government policy. The reader can decide what best represents what is in his or her own best interests. The panel decided that genetic testing for CF should be offered to:

    * adults with a positive family history of CF
    * partners of people with CF
    * couples currently planning a pregnancy
    * couples seeking prenatal care

    It did not recommend offering CF genetic testing to:

    * the general population
    * newborn infants

    Obviously these pronouncements failed to address some major issues and deliberately omitted others to avoid religious or ethical controversy. When should affected individuals, already diagnosed by other means, be offered genetic testing? A strong case can be made for checking adults planning to have children, if only to document the genetic aberrations for future reference, e.g., if specific genetic therapy became available for them or their offspring. Even if both parents are positive, there is just once chance in four that their child will have CF. Largely ignored was that diagnosis of CF in the fetus is possible by performing a chorionic villus biopsy around the 11th week of pregnancy and also by means of amniocentesis genetic analysis done about the 16th week of pregnancy. Since CF is currently incurable, probably some couples will consider termination of pregnancy. Neither of these procedures is without risk (see discussion of Down syndrome) and genetic counseling is recommended.
    ______________________________________________________________________________
    Table 3.
    Cystic Fibrosis Carriers in Ethnic Groups
    Ethnic Group Carrier Rate

    __________________________________________________

    Caucasian 1:3,200
    Hispanic 1:9,200
    African American 1:15,000

    ______________________________________________________________________________

    There are factors other than gene mutations which can cause changes which can’t be distinguished from the non-classic CF. The diagnosis of CF currently requires ruling out other diseases showing similar clinical features, using radiographic and biochemical methods to supplement molecular analysis. Much more work is needed to understand this complicated disease!

    DIABETES MELLITUS

    In diabetes mellitus you have too much sugar in your blood because something is amiss with your glucose metabolism. There are four types:

    *Type 1, juvenile onset diabetes
    * Type 2, adult onset diabetes
    * Maturity-Onset diabetes of the young (MODY)
    * Gestational diabetes

    In type 1, the pancreas doesn’t produce enough insulin. The body has developed antibodies and auto-immunity to the insulin-producing beta cells scattered in little islets throughout the pancreas. Genetic factors can predispose for developing the disease, but viruses may also be involved. Most, but not all cases of type 1 diabetes begin in childhood, and insulin therapy is required.
    Type 2 diabetes accounts for between 55 to 75% of cases. These patients are sometimes called “non-insulin dependent,” because the pancreas is producing significant amounts of insulin but the body can’t use it, or is insulin-resistant. Risk factors include obesity and a high-carbohydrate diet, but there’s also extensive genetic involvement. Onset is usually around age 40. Early symptoms are mild and often this type can be controlled by diet.
    Type 2 diabetes can run in families. Brothers and sisters of a type 2 diabetic have around a 40% risk of developing type 2 diabetes or of glucose intolerance. Children of a type 2 diabetic have a 33% chance of having type 2 diabetes or glucose intolerance, and in identical twins the odds are about 80%. Native Americans and Hispanics have genetic susceptibility to diabetes type 2, while Caucasians, Melanesians and Eskimos are at low risk. On the Pacific island of Nauru, 34% have type 2 diabetes and in Arizona, the Pima Native Americans have a 40% rate.
    Maturity-onset diabetes of the young (MODY) is an autosomal dominant condition appearing usually before age 25 and frequently in childhood or adolescence. Pancreatic beta cells are defective, as in type 1 diabetes. Usually the disease has a mild onset, and it involves non-obese children who have a prominent history of diabetes, often in successive generations. The glucose tolerance test may fluctuate for several years before becoming definitely impaired. MODY accounts for 1-5% of all diabetes cases in the United States.

    Gestational Diabetes

    Diabetes during pregnancy is called “gestational diabetes mellitus” and affects about 180,000 women each year in the U.S., approximately 2-5% of pregnant women. It usually disappears after birth. There is usually a faulty interaction between mother and fetus. Like type 2 diabetes, 90% of the cases are because the mother can’t use the insulin she produces, perhaps because of a placetental hormone.. The fetus doesn’t have diabetes, but its high blood sugar stimulates it to produce insulin to move this sugar into its cells. As a result, the fetus may gain weight and be unusually large.

    Children born to women with gestational diabetes seem to be at increased risk of having chromosomal defects compared to children of women with normal pregnancies, according to Dr. Lynn Moore et al. at Boston U. School of Medicine. They found the rate of chromosomal abnormalities twice as high among the offspring of 231 women with gestational diabetes (43.3/1,000 vs. 21.0/1,000), The anomalies were mostly numeric sex chromosome defects.

    Factors predisposing to gestational diabetes include a family history of diabetes, obesity, diabetes during previous pregnancy, age over 25 years, and a history of sugar in the urine. About 40% of women who have gestational diabetes will develop type 2 diabetes later in life. More immediate concerns are a risk of hypertension, preeclampsia and urinary tract infections. If not controlled, the baby may be born with respiratory distress and develop a low blood sugar right after birth.
    Table 5 shows the usual levels for interpreting results of a standard glucose tolerance test.
    _____________________________________________________________________________

    Table 5. Interpreting a Glucose Tolerance Test

    Blood Glucose (g/dL)
    fasting 30-90 min. 120 min.
    normal <115 <200 <140
    diabetic >140 >200 >200
    impaired glucose tolerance <140 >200 140-199
    ______________________________________________________________________________

    The molecular pathology of type 1 diabetes is not entirely known, but there is malfunction of the body’s immune system which destroys the islets. The concordance for twins in type 1 is small, so the inheritance factor is not great. Researchers are working on the development of gene therapy for type 1 diabetes. One possible treatment for the condition would be to transplant normal islet cells into the patient to replace those destroyed by the autoimmune reaction. Of course, sources for islet cells are limited. And the patient’s immune system will also reject and destroy the islet cells unless the recipient’s immune response is suppressed. Suppressing the immune system in a diabetic patient carries risks. Also the atypical antibodies which caused the type 1 diabetes will attack the new cells. The challenge is to find ways to protect transplanted cells against these two immunologic barriers. This could be done by transferring protective genes into the new islets so they will resist the immunologic reactions, or perhaps to create new islet cells from stem cells. It may also be possible, in early cases, to genetically protect the body’s healthy beta cells.
    In type 2 diabetes, the genetic picture is quite different. If inherited genes completely controlled the occurrence of diabetes, both identical twins and half of the non-identical twins would always have the disease. The figures are 80 percent and 40 percent instead of 100 percent and 50 percent. This means there are small but definite environmental components, such as obesity, alcohol, pancreatitis, and others.
    ______________________________________________________________________________
    Table 6
    Type 2 Concordance of Diabetes in Twins

    Type of twins Number of twins Diabetic pairs

    Identical 46 37

    Non-identical 10 4
    ______________________________________________________________________________

    The maturity-onset diabetes of the young (MODY) genes were reported by S. S. Fajans et al. in September, 2001. They described an autosomal dominant mode of inheritance and a primary defect in the function of the beta cells in the pancreas. MODY can result from mutations in any one of at least six different genes expressed in the beta cells. Mutation of any of them results in beta cell dysfunction and diabetes mellitus.
    Medical Genealogy
    The identification of these MODY genes makes it possible to identify members of pedigrees who have inherited specific mutations within their families, even before abnormal glucose tolerance tests occur. If a child doesn’t have the mutation, the authors feel no further clinical testing is necessary. Genetic screening may be important for treatment and prediction of the outcome. They recommended genetic counseling for MODY patients and also for those patients having type 1 diabetes plus a strong family history of diabetes.
    The following web sites have information on diabetes:

    National Institute of Diabetes and Digestive and Kidney Diseases
    http://www.niddk.nih.gov/health/diabetes/diabetes.htm
    The MedlinePlus web site for Diabetes
    http://www.nim.nih.gov/medlineplus/diabetes.html
    The Centers for Disease Control
    http://www.cdc.gov/diabetes/faqs.htm
    The Joslin Diabetes Center
    http://www.joslin.harvard.edu/


    ______________________________________________________________________________

    Table 7. Distinguishing MODY from Type 2 Diabetes Mellitus
    CharacteristicMODY Type 2 Diabetes Inheritance mode Autosomal dominant Gene+gene and gene+
    environmental effects
    Age at onset Childhood to age 25 Age 40-60 yrs*
    Pedigree Multigenerational common Rarely multigenerational
    Penetrance 80-95 percent Varies, 10-40 percent
    Body shape Non-obese Usually obese
    Syndrome: diabetes, Absent Usually present
    insulin-resistance,
    hypertension, high
    blood cholesterol
    * Type 2 diabetes occasionally appears in adolescence if a person is obese.

    GOUT
    Gout prefers to develop in people who are overweight, even more so if they drink lots of alcohol. To practically guarantee that you’ll get gout (or gout will get you), eat food high in purines, such as sweetbreads, liver, veal, turkey, dried peas and beans. If you prefer sea foods, stick to anchovies, shrimp, mackerel and scallops. There are also diseases which predispose to gout, particularly if they interfere with uric acid excretion. Among these are hypertension, hyperlipidemia (high levels of fat in your blood), diabetes, kidney disease and arteriosclerosis, just to mention a few.
    Gout occurs in about 275 out of every 100,000 people; it’s more common in males between the ages of 40 and 50. They tend to develop the condition earlier than women, who usually don’t become afflicted prior to menopause. The pain from gout comes from crystalline deposits of uric acid in your joints, causing pain, swelling and inflammation. Its favorite habitat is the great toe, accounting for about 75 percent of cases, but many other joints can be affected.
    Since 6 to 18 percent of people with gout have a family history of the disease (everybody quotes the same figures), it is assumed that genetics may play a role. It’s a particularly hard statistic to evaluate, because families tend to have similar diets, even to favorite brands of beer. As gout often occurs along with high blood pressure, heart disease and obesity, any genetic predispositions for those conditions could predispose to the onset of gout.
    A rare disease having an undisputed genetic role for gout is the Lesch-Nyhan syndrome, with neurological and behavioral symptoms appearing by 3 to 6 months of age. Lesch-Nyhan is inherited by sons only from the mother in an X-linked recessive manner (the chance of transmission is 25 percent); 25 percent of daughters become carriers. Molecular genetic testing is available and rapid detection of heterozygotes is possible using hair follicles. Males under 10 years show uric acid overproduction on urinalysis.

    LACTASE PERSISTENCE
    My dictionary defines “normal” as conforming to the standard or the common type. Since 75% of the world’s population, including at least 25% of inhabitants the United States, lose their lactase enzymes after weaning and can’t digest milk, they truly represent the genetic norm. Although called “lactose intolerant,” it’s the norm for most people in the world. (See our summary of Ethnic Predisposition for Heritable Disorders)
    This concept is bitterly opposed in the United States, but for economic rather than scientific reasons. Cows have superb public relations and lots of influence in Congress. There’s even a computer that looks like a cow. Not surprisingly, even the medical community gets misled. In 1960 the SS HOPE, a hospital ship sponsored by the People-to-People Health Foundation, sailed across the Pacific to help Indonesians with health care delivery. They proudly demonstrated their “mechanical cow,” a machine that combined powdered milk with reconstituted sea water and spewed out little cartons of milk embellished with photos of the beautiful white hospital ship. Teams of nurses and hosptial aides visited the villages to distribute these cartons to the children, all carefully recorded on film. They proudly reported they had offloaded 80,000 pounds of milk. What they didn’t report was all the nausea, cramps, bloating, gas and diarrhea that developed after they had moved on to the next village. The gesture, although well-intentioned, overlooked the fact that nearly all of the children were lactose intolerant.
    Investigators from UCLA and Finland found the mutated gene that decides whether or not you can produce the lactase-phlorizin enzyme and be able to digest lactose. They concluded that the original form of the gene is the one that prevails around the world, in which adults no longer can metabolize lactose in milk and milk products. At some time in the past, a mutation occurred, probably in northern Europe, which enabled adults to tolerate milk sugar. Meanwhile, the vast majority of the world’s population seem to have fared quite well. Why? Milk is promoted as a source of calcium to slow osteoporosis, but osteoporosis is affected much more by other factors. Otherwise, why would the age-adjusted prevalence of osteoporosis be 21 percent in American Caucasian women age 50 or over, but only 16 percent in Hispanic Americans and 10 percent in African-Americans?
    Calcium intake isn’t as important as the balance between calcium intake and calcium loss. Bone changes are greatly affected by genetics, diet and lifestyle. Long-term smokers have a greatly increased risk of bone fracture. What the cows don’t tell you is that green leafy vegetables, beans and calcium-fortified soy milk or juices are good sources of calcium without the accompanying baggage of fat, cholesterol and animal proteins. Bring on those black-eyed peas and turnip greens!

    PSORIASIS
    Psoriasis affects 5.8 to 7.5 million people in the U.S., so it deserves more than a passing mention, especially because about 1 million of these also have arthritis.
    Many past studies of psoriasis have shown a genetic predisposition to the skin disease. There is a higher than average incidence of psoriasis in their relatives and an increased incidence of psoriasis in children when one or both parents have the condition. And psoriasis appears more often in both identical twins than it does in nonidentical twins. There are, however, many people with psoriasis who have no family history of the disease, so other factors appear to be involved.
    Before DNA became so useful for identifying individuals and their close relatives, human leukocyte antigens (HLAs) were the best means of checking that there were close family ties. HLA antigens are increased on cells of psoriasis patients and their close relatives, supporting the heritability of psoriasis and suggesting the genetic keys to psoriasis might be closely located. HLA testing is a fairly simple serological procedure, as compared to DNA analysis. HLA research has proved fruitful in the study of psoriasis and so far has provided much of the specific data of value in understanding the mechanisms of the disease. There are numerous HLA-associated conditions associated with heritable diseases, and in most of them there is not simple Mendelian inheritance. This is also true of psoriasis. Although it is definitely HLA-related, we don’t know exactly how. There is increasing evidence of a genetic relationship among psoriasis, rheumatoid arthritis and systemic lupus erytematosis.
    In November, 2003 researchers reported finding a DNA binding site which appears associated with susceptibility to psoriasis. This is but a small part of world-wide molecular research on psoriasis. As with all of the other diseases we have mentioned, there are dedicated web sites which are excellent sources for the most recent information on psoriasis. One of these is sponsored by the National Psoriasis Foundation, and another by the National Institute of Arthritis and Musculoskeletal and Skin Diseases.



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