Genetics of Common Medical

Diseases

Prof. Dr. Mohamed Ali, M.Sc.. M.Phil., B.Ed., M.S (Sing)., Ph.D (Sing)
Department of Clinical Biochemistry
Faculty of Medicine
University of Tabuk
 Objectives/Rational

Genetics: study of heredity; transmission of physical, biochemical, and

physiologic traits from biological parents to their children

 Hereditary or genetic disease: resulting from a chromosome abnormality

or a defective gene

 The effects of genetic diseases have life-long consequences.

 Although some genetic and developmental disorders may first emerge at

birth, these disorders may appear at any age.
Human Disease Inheritance Patterns
 Common diseases

 Congenital malformations

Cleft lip/palate, Congenital hip dislocation Congenital heart defects

Neural tube defects, Pyloric stenosis, Talipes

 Multifactorial
 • Examples include some cases of cleft lip and palate; neural tube
defects;diabetes and hypertension

 • Caused by a combination of genetic predisposition and

environmental
 Influences

 • Pattern – more affected people in family than expected from

incidence
 in population but doesn’t fit dominant, recessive or X-linked
 inheritance patterns.
  Do genes cause disease?

 It all depends…on who…how you ask

Gene

a. genetic material instructing proteins that confer relative advantage or

disadvantage (inherited polymorphisms): “normal”.

b. germ-line mutations: instructing proteins that confer relative advantage or

disadvantage (sporadic/random polymorphisms) in germ cells – inheritable.

c. somatic mutation: instructing proteins that confer relative advantage or

disadvantage (sporadic or random) limited to one cell.
 Background-re-visit

Chromosomes: composed of double coils of DNA

Genes: segments of DNA chains

Genome: sum total of all genes contained in a cell’s

chromosomes; the same in all cells

In human beings, normal chromosome component:

22 pairs of autosomes

1 pair of sex chromosomes (XX in females and XY in males)

Karyotype: a representation of a person’s set of chromosomes

 In somatic cells: chromosomes exist in pairs, one member of each
pair is derived from male parent and other from female parent

 With 22 pairs called autosomes

 Except for the sex chromosomes, members of the pair are similar in
size, shape, and appearance (homologous chromosomes)

 Mitosis: cell division of somatic cells

 Each of two new cells or daughter cells receives the same

chromosomes as the parent cell
 Mitosis

 All cells of normal mature individual have 46 chromosomes.

 These cells duplicate themselves and divide to form daughter

cells, each with 46 chromosomes

 Process is called mitosis and can occur with most cells in the
body
 Meiosis

 Germ cells that develop into sperm and ova undergo a different type
of cell division called meiosis.

 One chromosome from each pair is passed on to each gamete (sperm

or ovum).

 Each gamete has only 23 chromosomes.

 When an ovum is fertilized with a sperm, the newly formed individual

will have a combined total of the normal forty-six chromosomes one
half (23), from each parent.
Meiosis involves two complete divisional operations forming four potential sex cells.
 Comparing Mitosis & Meiosis
Chromosome number-

Mitosis- identical daughter cells

Meiosis- daughter cells form haploids (4 cells)

Chromosome behavior-

Mitosis- act independently

Meiosis- pair together until anaphase

Genetic Identity-
Mitosis- identical daughter cells
Meiosis- daughter cells have new assortment of parental chromosomes
-chromatids (either of the two daughter strands of a replicated
chromosome that are joined by a single centromere and separate during cell
division to become individual chromosomes) are not identical (cross over)
 Autosomal and Sex Chromosomes

 a. 44 of the 46 chromosomes determine body function - these are

referred to as autosomes

 b. the remaining 2 chromosomes determine sex of individual

 XX chromosomes = female
 XY chromosomes = male
 It is the male sperm that determines sex of fetus

 c. the sex chromosomes are in every cell of body and are responsible
for directing activity of cell specifically for a female or for a male
 Visualizing Chromosomes

 a. Karyotyping – process to visualize chromosomes which involves:

taking picture of cell during mitosis

 arranging chromosome pairs in order from largest to smallest

numbering chromosome pairs one through 23

 b. Sex chromosomes can be evaluated by a buccal smear - test is

performed by obtaining epithelial cells from buccal cavity of mouth,
staining the cell, and microscopically observing for X chromosomes
(referred to as Barr bodies)
 Visualizing Chromosomes

 c. Barr bodies – visualized when two X chromosomes are present

(female)

 X chromosomes are much larger than Y chromosomes and carry

more genetic information.

 The X chromosome carries genes for female characteristics and

other genes essential to life (blood formation, metabolism activities,
immunization)

 The Y chromosome is smaller and only carries genes related to

masculinity.
 Genotypes are the genetic pattern of an individual.

 each gene in an allele (matched pair) of genes may be dominate or

recessive.

 Dominate genotypes expressed with capital letter (example: brown

eyes = B

 Recessive genotypes are expressed with smaller (example: blue

eyes = b)

 if alleles in a pair match (BB or bb), they are said to be homozygous

 if alleles do not match (Bb) they are said to be heterozygous (will

only express the phenotype of dominant gene)
 Not all genes are expressed in all cells and not all genes active all
the time

 Meiosis: cell division that occurs during development of egg and

sperm
 Number of chromosomes is reduced

 Daughter cells receive only half of chromosomes possessed by

the parent cell

 DNA ultimately controls formation of essential substances

throughout the life of every cell in the body through the genetic
code (precise sequence of AT and CG pairs on the DNA
molecule)
Genes control

Hereditary traits, cell reproduction, and daily functions of all cells

Cell function, through structures and chemicals made within the cell

RNA formation that controls formation of specific proteins; most are

enzymes that assist in chemical reactions in cells
 Trait Predominance
 Each parent contributes 1 set of chromosomes (or a set of genes)
so that every child has two genes for every locus on the autosomal
chromosomes

 Some characteristics or traits of the child are determined by 1 gene

that may have many variants (e.g. eye color)

 Polygenic traits require interaction of ≥ 1 genes

 Environmental factors may affect how genes are expressed

 Alleles: variations in a particular gene

 Homozygous: has identical alleles on each chromosome

 Heterozygous: alleles are different

 Children will express a dominant allele when one or both
chromosomes in a pair carry it.

 A recessive allele is expressed only if both chromosomes carry the

recessive alleles.

 For example, a child may receive a gene for brown eyes from one
parent and a gene for blue eyes from the other parent.

 Gene for brown eyes is dominant.

 Gene for blue eyes is recessive

 The dominant gene is more likely to be expressed and child is more

likely to have brown eyes
 Abnormalities

 may be due to chromosomal, genetic, or environmental factors, or

combination of these major chromosomal abnormalities usually lead to
spontaneous abortion of fetus

 chromosomal disorders are usually related to number or placement of

chromosomes

 chromosomes may fail to separate properly during cell division causing

daughter cell to have an extra chromosome while other daughter cell
has no chromosomes.

 Abnormal number or structure of autosomal chromosomes is usually

incompatible with life because these chromosomes carry a large
number of essential genes
 Genetically Determined Diseases

 Result from abnormalities of individual genes on the

chromosomes

 Chromosomes appear normal.

 Some defects arise spontaneously.

 Others may be caused by environmental teratogens (agents or

influences that cause physical defects in the developing
embryo)

 Mutation: permanent change in genetic material that may occur

spontaneously or after exposure of a cell to radiation, certain
chemicals, or viruses
 Understanding basic heredity
 Genotypes are the genetic pattern of an individual.

 a. each gene in an allele (matched pair) of genes may be dominate or

recessive.

 Dominate genotypes expressed with capital letter (example: brown

eyes = B

 Recessive genotypes are expressed with smaller (example: blue

eyes = b)

 if alleles in a pair match (BB or bb), they are said to be homozygous

 if alleles do not match (Bb) they are said to be heterozygous (will

only express the phenotype of dominant gene)
 Understanding basic heredity

b. expression of a trait (blue eyes, brown hair, etc.) is called phenotype.

c. Homozygous pairs (dominant or recessive) will always express that

trait (BB = brown eyes, bb = blue eyes, etc.)

d. Heterozygous alleles will express the phenotype (trait) of dominate

gene only. (Bb = brown eyes)

e. Heterozygous pairs are said to be carriers of recessive disorders -

recessive traits will not be expressed unless paired with another
recessive gene
 Two ways that people acquire an abnormal gene

A. mutation of gene during meiosis

B. passing abnormal gene from parents (heredity)

a. genetic disorders are passed to offspring in four different ways: autosomal

dominant, autosomal recessive, sex-linked dominant, and sex-linked
recessive.

1. Autosomal dominant
 Easily recognized because presence of disorders identifies individuals with
dominant gene
 Line of inheritance is easily followed from one generation to another
 Dominant genes will always be expressed
 whether homozygous or hetrozygous
 Example of autosomal dominant disorder:
 polydactyly (excessive number of finger or toes)
 2. Autosomal recessive

 Only seen when two recessive genes are paired

 Each parent may be phenotypically normal or without sign of disorder but is a
heterozygous carrier of the disorder

 a. When each parent is heterozygous, chance of offspring having disorder is one

in four

 b. If one parent has the disorder, chances increase to one in two


 c. If one parent is homozygous dominant, none of offspring will be affected

 d. These disorders may skip generations before it is paired with another

recessive gene and is expressed
Autosomal Recessive
3. sex-linked dominant - these are more rare than recessive disorders and are
easily recognized

4. sex-linked recessive

these disorders are typically carried by females and passed to males

reason for this: recessive gene disorders on the X chromosome of female are
overridden by dominance of normal gene on other X chromosome

in males, the X disorder is expressed because there is no corresponding gene on

the Y chromosome.

X-linked disorders usually appear every other generation since they are passed
mother to son (mother to son; son to daughters (who become carriers) -
affected male is unable to pass this disorder to sons because male gives a Y
chromosome to sons, not an X.

example of sex-linked recessive disorder: hemophilia

 Congenital anomalies

A. Approximately two percent of all newborns have congenital

anomalies (birth defects).

a. 65% of congenital anomalies are idiopathic (unknown cause)

b. 20% are genetic

c. 5% are chromosomal

d. 10% are environmental (maternal radiation, infection, drugs, alcohol,

medications
 Congenital Diseases
 Appear at birth or shortly after, but they are not caused by
genetic or chromosomal abnormalities.

 Congenital defects usually result from some failure in

development during the embryonic stage, or in the first 2
months of pregnancy.

 Therefore, congenital diseases cannot be transmitted to

offspring.
 Ex: spina bifida, cleft lip and cleft palate, and pyloric stenosis
 Four factors in congenital malformations

1. Chromosomal abnormalities
2. Abnormalities of individual genes
3. Intrauterine injury to embryo or fetus
4. Environmental factors
 Causes of Congenital Malformations

2-3% of all newborn infants have congenital defects

Additional 2-3% defects: NOT recognized at birth; developmental

defects demonstrated later as infants grow older

25% to 50% spontaneously aborted embryos, fetuses, and stillborn

infants have major malformations
Molecular Basis of Genetic Diseases

a). Determinants of phenotypic expression

i). Nature of the mutation
ii). Genetic background
iii). Environmental influences

b). Types of mutations affecting genes

i). Regulatory mutations factor IX promoter mutations, etc.
ii). Mutations affecting the protein product b-globin mutations
iii). Large-scale gene mutations b-globin deletions
dystrophin deletions iv). Trinucleotide repeat expansion mutations
neuropsychiatric disorders
 Determinants of phenotypic expression
Nature of the mutation
different mutations in the same gene can lead to more- or less-
severe phenotypes depending on the effects of the mutations on the
expression of the gene or on the function of the protein product

Genetic background
two individuals within a family may have the same mutated gene,
however, they will certainly (unless they are identical twins) have a
lot of genes that are not similar – the expression of these
background genes may influence the disease phenotype

Environmental influences
factors such as lifestyle, diet, and exposure to environmental
toxins may affect the disease phenotype
Nature of the mutation

regulatory mutations

point mutations in the Factor IX promoter

mutations affecting the protein product point mutations in the b-

globin gene

large-scale gene mutations deletion mutations of the globin genes

deletion mutations in the dystrophin gene

trinucleotide repeat expansion mutations neuropsychiatric

disorders
 Diabetes mellitus

Type II diabetes mellitus (T2DM)

Definition / Diagnosis
Risk factors for T2DM
Race/ethnicity, culture, and other
demographic characteristics
Behavior
Environment
Genetics
Influences on Diabetes Risk, Prevalence, and Outcomes

Race /
Ethnicity

Culture Genetics

Diabetes
Risk
Prevalence
Outcomes

Lifestyle Health Care

Environment
Diabetes is a group of metabolic disorders characterized by hyperglycemia
resulting from insulin resistance and/or impaired insulin secretion

Complications include neuropathy, nephropathy, vascular disease, and

retinopathy

Classic Symptoms
“Polys” – Polyuria, Polydipsia, Polyphagia
Unexplained weight loss
Risk Factors for T2DM
Age >45 years
BMI >25 kg/m2
First-degree relative with diabetes
Sedentary lifestyle
Race / Ethnicity
Impaired fasting glucose (fasting glucose 100-126 mg/dL)
Impaired glucose tolerance (2-h OGTT 140-200 mg/dL)
H/o gestational DM or delivery of a baby weighing >9 lbs
Hypertension (BP>140/90)
Dyslipidemia – HDL-c <35 mg/dL OR TG >250 mg/dL
Polycystic ovary syndrome
History of vascular disease
Genetic predisposition – but genetics “complex …and not
clearly defined”)
 Importance of Family History

If a single first degree relative has diabetes, the

prevalence of diabetes increases to about 15%,
i.e. an odds ratio of about 5
Clinicians should ask about whether other family
members have:
Diabetes
Obesity
Hypertension
Chronic Kidney Disease (CKD)
Coronary Heart Disease
Stroke
Racial/Ethnic Disparities in DM

In the U.S., higher relative risk of diabetes among minority

populations

Up to 50% of increased relative risk among minorities due to

modifiable factors

Physical activity
Smoking
Alcohol
Dietary energy intake
BMI
Waist-to-hip ratio

In addition to disparities in prevalence, there also are disparities in

access to care and quality of care between whites and minorities.
Genetics and DM

Both twin and population-based studies suggest that T2DM has a strong
genetic component

Complex interactions between a multitude of genes.

Genes seem to be strongly influenced by environmental and behavioral

factors.

Are there specific genes that have been identified?

With advances in genomic technology, large number of specific genetic

polymorphisms are being associated with T2DM, but genetics of diabetes are
complex and each polymorphism carries only a modest increase in relative
risk.
The environment may affect diabetes risk directly or through behaviors
Lifestyle modification can prevent diabetes or delay its incidence in those
with biologic risk
 Insulin Dependent Diabetes

This disease is characterized by insufficient production of insulin due to

an autoimmune destruction of the beta cells of the pancreas

Peak onset is b/w 10 and 14 years of age

Disease may be attributed to genetic and environmental conditions

About 95% of white diabetics carry the HLA-DR3 or DR4 genes

It appears that true susceptibility genes for IDDM may occur in the HLA-
DQ region
Viral infections have been linked with diabetes

Mumps virus, rubella virus, CMV, and Coxsakie B4 virus have all
been inconclusively linked to diabetes

Congenital rubella infection is the only one for which a link has
been definitively identified

There appears to be similarity between coxsakie viral protein P2-C

and the enzyme glutamic acid decarboxylase.

Antibodies are formed against glutamic acid decarboxylase in IDDM

Molecular mimicry could initiate Ab production against self Ag

 “Obesogenic” and “Diabetogenic”
Environments
South LA has the highest
concentration of fast food
restaurants in the city

Getty Images – Los Angeles July 24th 2008

A high the ratio of fast-food and convenient stores to grocery

and produce stores is associated with higher prevalence of
both diabetes and obesity, even after controlling for
race/ethnicity, income, age, gender, and physical activity.

Auchincloss, Epidemiology. 2008.

California Center for Public Health Advocacy, April 2008, http://www.publichealthadvocacy.org/designedfordisease.html, last
accessed March 22, 2009
Autoimmune diseases are the result of damage to the body by the
presence of autoantibodies or autoreactive cells

About 2% of the population are affected by such diseases

There is a breakdown of self tolerance in these individuals

Self tolerance is brought about by such mechanisms as clonal

deletion of relevant effector cells, active regulation by TS cells and
regulation through idiotypic networks

Majority of T cells that are processed through the thymus do not

survive. Self reactive T cells are destroyed

Loss of TS cells may encourage the production of autoAbs

MHC molecules influence Ag recognition or nonrecognition by
determining peptide that can be presented to T cells

The expression of class II molecules on host cells may result in

presentation of self
Ags for which there is no tolerance

In several diseases, there are host cells that exhibit class II

molecules on their surfaces after inflammatory response

Such cells may function as Ag presenting cells for their own

cellular proteins
 Systemic Lupus Erythematosus

It is a chronic systemic inflammatory disease marked by alternating

exacerbation and remissions

Approximately 1 in every 2000 individuals are affected

Age of onset is usually b/w 20 and 40 yrs of age

Women are much more likely than men to be stricken by a margin of

13 to 1

Etiology is unknown but may be due to genetic and environmental

factors

In whites, it is strongly associated to with HLA-DR3 or DR2 and

DQB1
Rheumatoid arthritis is a systemic autoimmune disorder

It involves the synovial membrane of multiple joints

Women are more likely to be affected than men and usually strikes
between the ages of 20 and 40

Spontaneous remission may be experienced by some patients

otherwise the disease may progress and result in deformity and
disability

RA has been associated with certain of the HLA class II molecules.

HLA-DR1 and DR4 occur in 70% of patients with RA

 Hashimoto’s Thyroiditis

Hashimoto’s thyroiditis and Graves’ disease are organ specific

autoimmune diseases

Both diseases interfere with the thyroid gland function

The thyroid gland located in the anterior region of the neck consist
of units called follicles

Follicles are lined with cuboidal epithelial cells and filled with colloid

The primary constituent of colloid is thyroglobulin which is made up

of triiodothyronine (T3) thyroxine (T4)

TRH acts on the pituitary gland to induce the release of TSH

TSH binds to receptors on the cell membrane of the thyroid gland
causing break down of thyroglobulin into T3 and T4

AutoAbs may interfere with this process and cause under or

overactivity of the thyroid

Hashimoto’s thyroditis is most often seen in women between the

ages of 30 and 40 years

Patients develop a combination of goiter or enlarged thyroid,

hypothyroidism and thyroid autoantibodies

An association with HLA antigens DR4 and DR5 has been noted.
DQA1 and DQB1 genes seem to confer resistance
 Graves’ disease

Graves’ disease is another autoimmune disease that affects the

thyroid gland

Graves’ disease produces hyperthyroidism

It the most common cause of hyperthyroidism and affects about

0.5% of the population

Women are more susceptible than men by a margin of 7:1 and

usually present between the ages of 30 and 40.

In whites, the disease is associated with the HLA antigen DR3

while in Asians HLA Bw35 and Bw36 occur more frequently
HLA DQB1 appears to confer resistance to the disease

Clinical Signs:
Disease is presented as thyrotoxicosis with a diffusely enlarged
goiter that is soft instead of rubbery

Signs include nervousness, insomnia, depression, weight loss, heat

intolerance, sweating, rapid heart beat

Other signs include fatigue, cardiac dysrhythmias, restlessness, and

exopthalmus
 Multiple Sclerosis

Destruction of the myelin sheath results in the formation of lesions

known as plaques in the white matter of the brain and spinal cord

Genetic and environmental factors predispose one to this disease

MS is associated with the inheritance of HLA antigen DRw15 and

DRw6

An inflammatory response to bacteria or virus may trigger the

autoimmune process

Disease is most often seen in those b/w the ages of 20 & 50 and is
more common in women
 Myasthenia Gravis

Symptoms of disease include facial weakness, difficulty in

chewing, and swallowing, difficulty breathing

Others include inability to maintain support of the trunk, the

neck or the head

Antibody mediated damage to the acetylcholine receptors in

the skeletal muscle leads to muscle weakness

May be associated with the presence of other autoimmune

diseases such as SLE

Appears to be linked with either HLA-B8 or DRw3 antigens

 Goodpasture’s Syndrome
Goodpasture’s syndrome is a glomerulonephritis
due to Abs reacting specifically with Ags in the
kidney

Necrosis of the glomerulus is triggered by an Ab that

reacts with glycoprotein present in the basement
membrane of the glomerulus

Results in immune complex deposit and

complement fixation which causes the damage to
the kidney
This may eventually produce renal failure
Thank You