Drew Myers
Bio 303 Dr. Ely
Term Paper
November 1, 2012
Is there a genetic predisposition for kidney diseases?
According to the American Diabetes Association, type 1 diabetes is a disease in which
the body does not produce insulin, which is a hormone that affects the metabolism of glucose in
the body. As of 2011, 8.3% of the population had diabetes (ADA). Type 1 diabetes can be
controlled with insulin treatment. For 30% of patients with diabetes, their diabetes will lead to
further kidney diseases, including diabetic nephropathy and end stage renal disease (ADA).
Because people with diabetes will have increased blood sugar levels, their kidneys are filtering
more blood than normal and this added stress causes the kidneys to leak excess protein, known
as proteinuria. Diabetes was the cause of kidney failure in 44% of cases in 2008 (ADA). Diabetic
nephropathy is a disease of the kidney in which there is a decrease in kidney function and an
increase in proteinuria. Unlike many other kidney diseases, DN is diagnosed by clinical criteria,
as opposed to a biopsy or other histology (Böger et al. 2012). There is no cure for diabetic
nephropathy and the only available treatment is a treatment to decrease the amount of
proteinuria. Diabetic nephropathy, also known as DN, is the leading cause of end stage renal
disease (ADA). Commonly known as ESRD, end stage renal disease is when the kidney function
has decreased to such low levels that the patient can no longer continue without a kidney
transplant or constant dialysis. Currently, there is no cure for ESRD and it is not reversible. In
2009, ESRD treatment accounted for 40% of the total $43 billion that was spent for dialysis
treatment (Böger et al. 2012). Because DN can lead to other kidney diseases, including ESRD,
and has limited treatments, it is of great interest to determine if there are genetic factors that
influence DN so that better treatment can be developed.
In 2004, a Finnish team lead by Valma Harjutsalo set out to determine if there was a
genetic link in the development of diabetic nephropathy among family members who had type 1
diabetes. First, in 1998, the team identified 537 families in which at least two siblings had type 1
diabetes. The researchers identified the first sibling that they studied in each family as the
“proband.” These 537 families were studied until the end of 2001 to see if any of the siblings
would be diagnosed with DN. In 323 of the families, at least one sibling developed DN. In
families where the proband was diagnosed with DN, the other sibling with type 1 diabetes had a
38% chance of developing DN. However, in families where the proband did not develop DN, the
other sibling only had a 17% chance of developing DN. It was concluded that diabetic siblings of
patients with DN had a 2.3-fold higher chance of developing DN, as opposed to diabetic siblings
of patients whose diabetes did not develop into DN. The idea that the development of DN is
linked among siblings leads to the belief that there is either a large genetic factor in the
progression of type 1 diabetes to diabetic nephropathy, or that the progression is the result of an
environmental factor because siblings lead similar lifestyles. This would lead to further research
into the genetics of kidney diseases.
In 2010, Jeffrey Barrett and a group of 17 other researchers set out to do a genome-wide
association of type 1 diabetes patients, in an effort to locate different loci that increased
susceptibility to type 1 diabetes. They also did a meta-analysis to combine their findings with
two previous studies, in order to ensure that their results were statistically significant. They
genotyped 7,514 people with type 1 diabetes and 9,045 people without diabetes, who would
serve as the controls. Once genotyped, the researchers located 41 places on the genome that
showed an association to type 1 diabetes. However, they did not look into a link between these
41 loci and the development of DN or ESRD. The link between the identified 41 loci and the
development of kidney diseases would soon be tested.
In September of 2012, an experiment was conducted by a team under Niina Sandholm to
determine if there is a link between specific loci and diabetic nephropathy and end stage renal
disease. Using the genotyping of patients from previous studies, including the study conducted
by Barrett et al. (2010), Sandholm began the largest genome wide association and meta-analysis
of DN and ESRD. They wanted to find specific genetic markers in the form of single nucleotide
polymorphisms (SNP’s), which are single base pair changes in the DNA sequence that result in a
different allele. Because they were looking specifically for which SNP’s showed an association
with DN or ESRD in diabetes patients, they used patients that had been diagnosed for at least
fifteen years with type 1 diabetes and had never developed DN or ESRD as their control. After
doing a genome-wide association on 2.4 million SNP’s, the top 41 SNP’s that showed a link to
DN and ESRD were further genotyped to compare the frequency of the SNP’s among all
individuals.
The Sandholm et al. (2012) study found three alleles to be most associated with DN and
ESRD. An allele of rs7583877, located in the AFF3 gene was associated with a 29% increase in
the chances of developing ESRD. Specifically, this allele had the strongest association with the
early stages of ESRD. The AFF3 protein is a transcriptional activator and is involved in renal
fibrosis. Renal fibrosis is an excess production of fibrous connective tissue in the kidney that
leaves the kidney covered in scars. It is also one of the leading causes of lowered kidney function
and ultimately the need for dialysis. Also, an allele of rs12437854 located between the RGMA
and MCTP2 genes was associated with an increased chance of ESRD by 80%.
In an effort to find alleles that affected the chances of developing DN, the study by
Sandholm et al. (2012) identified an allele of rs7588550 located on the ERBB4 gene. The
ERBB4 protein has been shown to play a role in renal development and tubulogenesis, which is
the formation of tubules in epithelial and endothelial cells. This allele, as opposed to the others
identified in the study, showed protective effects and was associated with a 33% decreased
chance of developing DN from type 1 diabetes. The researchers found that this allele of
rs7588550 was typically downregulated in DN patients. However, it did not prove to be
significant in the genome-wide meta-analysis.
One of the major drawbacks in doing a study on the genetic factors that influence type 1
diabetes, diabetic nephropathy, and end stage renal disease is that these diseases have such a
large environmental factor. A person’s diet, glycemic control, and the way in which someone
with diabetes controls their sugar levels, are huge factors that play into the progression of all of
these diseases. If a person’s diabetes is controlled very well, they are less likely to develop DN
or ESRD, so it limits the effects of the genetic factors. Therefore, it is difficult to pinpoint a
specific allele as the main driving force behind these diseases because so many other things play
a part.
Additional studies of patients with type 1 diabetes, DN, and ESRD need to be performed
to determine which environmental factors and which genetic factors have more of an impact.
Once a specific allele is found to be a contributor to a disease, specific gene therapy and other
treatments can be developed to try to alleviate the effects of the allele or eliminate the allele all
together. Also, in the case of the allele that decreased the chances of developing DN from type 1
diabetes, this allele can become a target for treatment. Researchers could work to upregulate the
expression of a specific allele in DN patients or in type 1 diabetes patients to see if it alleviated
symptom or stopped the progression of the disease. The overall findings of these studies call for
much more research and data. Because the findings of these studies were very preliminary, the
development of treatment for patients is far off.
Literature Cited
1. “Diabetes Statistics” American Diabetes Association 2012.
2. Barrett J, Clayton D, Concannon P, Akolkar B, Cooper J, Erlick H, et al. 2010. “Genomewide association study and meta-analysis finds over 40 loci affect risk of type 1
diabetes” National Genetics 41:703-707.
3. Böger C, Sedor J 2012. “GWAS of Diabetic Nephropathy: Is the GENIE out of the
Bottle?” PLoS Genetics 8.
4. Harjutsalo V, Katoh S, Sarti C, Tajima N, Tuomilehto J. 2004. “Population-Based
Assessment of Familial Clustering of Diabetic Nephropathy in Type 1 Diabetes”
Diabetes 53:2449-2454.
5. Sandholm N, Salem RM, McKnight AJ, Brennan EP, Forsblom C, Isakova T, et al. 2012.
“New Susceptibility Loci Associated with Kidney Disease in Type 1 Diabetes”
PLoS Genetics 8(9). .