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Patient Handout

NAME:

1/1
REQUESTING PHYSICIAN / INSTITUTION:

John Doe

ID:

n/a
Sample ID: DGT2D#6881 Date Received:

ABC Hospital/Dr. John Smith 1010 Main Street, Anytown, 60517 IL US 555-123-1234 04-03-2009
Date Reported:

Gender/DOB: Decode ID:

Male/10-10-1968

SA6881 -

Date Collected: 01-02-2009

04-29-2009

GENETIC TEST RESULTS - TYPE 2 DIABETES (T2D)

YOU

38%

LIFETIME RISK:
You are above average at 38%
It is estimated that 38 out of every 100 individuals with your genotype develop T2D in their lifetime, compared to 25 out of 100 in the general population of Caucasians (25% x 1.51 = 38%).

AVG
(AVERAGE)

25%

HAVE YOU BEEN DIAGNOSED WITH PREDIABETES?


Given you have prediabetes, your absolute risk of developing full blown diabetes in the next 3-4 years is:

RELATIVE RISK:
On a genetic risk scale you stand at 1.51
This means that you are at 51% increased risk relative to the average risk of white individuals to develop T2D. Without information on other possible risk factors your background risk is assumed to be the same as that of the general white population.

50% - 70%
based on your genotype results and the Diabetes Prevention Study. To learn more about prediabetes and screening recommendations, see below or ask your doctor.
(Florez, J.C., et al. TCF7L2 polymorphisms and progression to diabetes in the Diabetes Prevention Program. N Engl J Med, 2006. 355(3): p. 241-50.)

SCREENING AND DIAGNOSING


WHAT NEXT? deCODE T2 does not confirm or exclude T2D Other risk factors are involved do you know them? T2D can be prevented
Obesity is one of the major risk factors T2D: Overweight, age and family history are the most important risk factors. Elevated blood sugars or diabetes during pregnancy are an additional risk factor for women. Your results and the Diabetes Risk Test of the American Diabetes Association (ADA)
Question
Are you overweight? Are you under 65 years old and get no or little exercise in a typical day? Are you between 45 and 65 years old? Are you 65 years or older? Are you a woman who has had a baby weighing more than 9 pounds at birth? Do you have a sister or brother with diabetes? Do you have a parent with diabetes? Add your score x your genetic risk ( 1.51) = 10 or more points: High risk of diabetes 3 - 9 points: Probably low risk for now.

Pre-diabetes: Before people develop T2D, they almost always have "prediabetes" -- blood sugar levels that are higher than normal but not yet high enough to be diagnosed as diabetes. One third of pre-diabetics will develop T2D within 3 years without intervention. The ADA recommends yearly screening for pre-diabetes in patients with higher risk for T2D by a measurement of fasting blood glucose and a more aggressive strategy for prevention in obese pre-diabetics with other risk factors for conversion. An effective weight loss program works as well if not better for patients at highest genetic risk for conversion, reducing conversion to T2D by over 60%.

Yes

No

5 5 5 9 1 1 1

0 0 0 0 0 0 0

Lower your risk


- If you're overweight, lose excessive weight - Exercise regularly - Don't smoke - Eat healthy

ABOUT THE TEST


The deCODE T2 test measures only the relative genetic risk for T2D inferred by the 4 genetic factors tested, meaning that other risk factors such as your weight, age, family history or ethnicity have not been taken into account. Professional counseling is recommended for interpretation of the deCODE T2 risk results.

This test was developed and its performance characteristics determined by the deCODE genetics Diagnostic Laboratory. It has not been cleared or approved by the U. S. Food and Drug Administration (FDA) deCODE Diagnostic Laboratory Testing Site: Sturlugata 8, 101 Reykjavk, Iceland Customer Service: 2501 Davey Road, Woodridge IL, 60517 Phone: (877) 222-6510 Fax: (630) 783-4998 www.decodediagnostics.com This document contains private and confidential health information protected by state and federal law 2009 deCODE genetics Diagnostic Laboratory All rights reserved document version 1.0.9 W

PHYSICIAN REPORT
NAME:

1/5
REQUESTING PHYSICIAN / INSTITUTION:

John Doe

ID:

n/a
Sample ID: DGT2D#6881 Date Received:

ABC Hospital/Dr. John Smith 1010 Main Street, Anytown, 60517 IL US 555-123-1234 04-03-2009
Date Reported:

Gender/DOB: Decode ID:

Male/10-10-1968

SA6881 -

Date Collected: 01-02-2009

04-29-2009

GENETIC TEST RESULTS


YOUR PATIENT'S RELATIVE This means that the patient is at 51% increased risk relative GENETIC RISK to the average risk of the Caucasian population to develop type 2 diabetes (T2D). The picture shows the patient's risk relative to the range of the test, with the highest possible Equals 51% increased risk, risk result being 2.2 fold and the lowest 0.4 fold the average compared to general population population risk.

1.51

risk of 1.0

GENETIC RISK SCALE

LIFETIME RISK ESTIMATE

38%
POPULATION RISK DISTRIBUTION

It is estimated that 38 out of every 100 Caucasians with this 38% patients genotype develop T2D in their lifetime, compared to 25 out of 100 in the general population of Caucasians (25% x 1.51 = 38%). Important: The results only apply to Caucasians (people of European ancestry).

AVG 25%
(average)

Population risk distribution refers to the risk distribution in the population of Caucasians relative to the patients risk. The graph to the right depicts that 3% of the population have the same risk as the patient, where as 94% have About 94% of Caucasians have lower genetic risk than this patient lower risk and 3% have higher risk.

WHAT IS THE REMAINING LIFETIME RISK?


Refer to Table 2 on page 5 and multiply with 1.51

The genetic risk identified by the deCODE T2 test is largely independent of any other risk factors that the patient may have, such as family history or age and can therefore be multiplied by the effect of these known risk factors. For example the remaining lifetime risk (see table 2 on page 5) can be multiplied by 1.51 to obtain his/her specific residual lifetime risk. Remaining lifetime risk is the combined risk to develop T2D after a certain age, assuming the patient has not already been diagnosed with T2D. It is dependent on known risk factors, such as obesity, ethnicity, prediabetes, and age. However, not all genetic risk factors are known or measured by deCODE T2 .
TM

TM

PRE-DIABETES TO TYPE 2 DIABETES RISK


TCF7L2 genotype is:

TT

DRUG RESPONSE TO SULFONYLUREAS AND METFORMIN


TCF7L2 genotype is :

TT
TM

In overweight or obese Caucasian individuals with prediabetes (impaired fasting glucose and impaired glucose tolerance) a TT genotype at the TCF7L2 locus predicts a 1.8 to twofold increased risk to convert to T2D within the next 3 to 4 years (that is a 50 to 70% absolute risk to convert compared to a baseline conversion rate of 30 to 35% for overweight and obese prediabetics). Weight loss can reverse much or all of this increased genetic risk. Recent ADA guidelines state: In addition to lifestyle counseling, metformin may be considered in those who are at very high risk (combined IFG and IGT plus other risk factors) and who are obese and under 60 years of age (21). This genetic profile is one of the strongest risk factors for conversion from prediabetes to diabetes. These numbers are based on the prospective DPP and DPS studies outlined below (16-19). Caucasians who have T2D and are TT at the TCF7L2 are predicted to have a much lower response rate to sulfonylurea, half that of the general Caucasian diabetes population. At the same time it predicts that the patient is more likely to respond to metformin than sulfonylurea. See below for details. On the following pages is further information on the characteristics and the significance of the deCODE T2 test. deCODE provides consultation services to physicians ordering the test and professional counseling can be arranged for patients if needed. If you would like to discuss the results of this test to further your understanding or to discuss the needs and possibility of patient counseling, please contact our customer service department at diagnostics@decode.com or by phone at 1-877-222-6510 (office hours: 9am-5pm CST).
TM

MORE INFORMATION ABOUT THE deCODE T2 TEST

This test was developed and its performance characteristics determined by the deCODE genetics Diagnostic Laboratory. It has not been cleared or approved by the U. S. Food and Drug Administration (FDA) deCODE Diagnostic Laboratory Testing Site: Sturlugata 8, 101 Reykjavk, Iceland Customer Service: 2501 Davey Road, Woodridge IL, 60517 Phone: (877) 222-6510 Fax: (630) 783-4998 www.decodediagnostics.com This document contains private and confidential health information protected by state and federal law 2009 deCODE genetics Diagnostic Laboratory All rights reserved document version 1.0.11 W

NAME

DOB

GENDER

Patient ID

deCODE ID

2/5

John Doe

10-10-1968

Male

n/a

DGT2D#6881

ABOUT THE RESULTS What the test measures


Four genetic markers and their associated risk only

The test measures only the risks inferred by the 4 genetic factors tested. The relative genetic risk result is the product of the risks associated with each of the alleles detected for the 4 DNA markers (SNPs) multiplied together. This is based on finding no significant interaction between the markers in thousands of patients and controls. The genetic risk identified by the deCODE T2 test is largely independent of any other risk factors, such as family history or age and can therefore be multiplied by the effect of these known risk factors. For example if the remaining lifetime risk is known it can be multiplied by 1.51 to obtain this patient's specific residual lifetime risk. Remaining lifetime risk is the combined risk to develop T2D after a certain age, assuming the patient has not already been diagnosed with T2D. It is dependent on known risk factors, such as obesity, ethnicity, prediabetes, and age. However, not all genetic risk factors are known or measured by deCODE T2 .
TM TM

Use of results
May be used to multiply other identifiable risks

The lifetime risk estimate


Have other risk factors been accounted for?

Without information on other possible risk factors the lifetime risk is based on the presumption that the patients background or prior risk is the same as that of the general population of Caucasians (25%). This means that other risk factors known to influence the lifetime risk have not been taken into account and these may further increase or decrease this patients lifetime risk. A high risk result does not mean the patient is destined to develop T2D and a low risk result does not mean the patient is without risk for T2D. deCODE T2 is not a determinative diagnostic test or a conventional genetic test as is done for the diagnosis or carrier status detection of Mendelian diseases. It is a risk test, much like LDL-cholesterol and PSA are used to predict cardiovascular disease and prostate cancer respectively. The test results should be considered along with other medical information about the patient, including age, weight, fasting blood sugar values and family history. Professional counseling for the patient is recommended for better understanding.
TM

What this test is not


This is not a determinative diagnostic test for T2D

MORE ABOUT THE RESULTS


deCODE T2 - relevance for prediabetics and treatment options: According to two prospective clinical trials, the Diabetes Prevention Program (DPP) and the Diabetes Prevention Study (DPS) (2,3), overweight or obese white Caucasian patients who already have impaired fasting glucose and impaired glucose tolerance, a condition called prediabetes, have a 30 to 35% general risk for progressing to T2D over a 3 to 4 year period (2,3). TCF7L2 is one of the strongest risk factors known for conversion. For the 10% of white Caucasian prediabetic patients with two copies of the risk variants at TCF7L2 there was a 1.8 to 2.0-fold risk of converting to diabetes resulting in 50 to 70% absolute risk of converting to T2D within 3-4 years if no intervention was made by lifestyle management or metformin treatment (4,5). Genotyping of the DPP and DPS study cohorts (4,5) showed that for white Caucasians, lifestyle intervention or metformin therapy are equally effective if not more effective for patients with increased genetic risk of conversion. Lifestyle intervention or metformin use decreased in white Caucasians the conversion rate to T2D by 58% and 31%, respectively. Metformin is even more effective in white patients younger than 45 (43% decreased rate) (17). Not all prediabetics progress to diabetes and many develop normal fasting glucose spontaneously without intervention. Therefore, deCODE T2 may help target patients at highest risk for more aggressive prevention strategies which can compensate for most, if not all, of the genetic risk. Metformin is also recommended in the 2008 ADA (American Diabetes Association) guidelines as an option for obese prediabetics younger than 60 who have other risk factors and who fail to lose weight (1). TCF7L2 is the strongest known risk factor for conversion in overweight or obese prediabetics. Studies in two Caucasian populations show that T2D patients who are homozygous TT at TCF7L2 have much lower response to sulfonylurea compared to those who are not TT homozygous, with only 36% meeting HbA1C target of 7% or lower, versus 62% of those who were not TT homozygous (8,9). Metformin response on the other hand did not depend on the TCF7L2 genotype, meaning that patients who have the TT TCF7L2 genotype were likely to respond better to metformin than sulfonylureas.
TM TM

This test was developed and its performance characteristics determined by the deCODE genetics Diagnostic Laboratory. It has not been cleared or approved by the U. S. Food and Drug Administration (FDA) deCODE Diagnostic Laboratory Testing Site: Sturlugata 8, 101 Reykjavk, Iceland Customer Service: 2501 Davey Road, Woodridge IL, 60517 Phone: (877) 222-6510 Fax: (630) 783-4998 www.decodediagnostics.com This document contains private and confidential health information protected by state and federal law 2009 deCODE genetics Diagnostic Laboratory All rights reserved document version 1.0.11 W

NAME

DOB

GENDER

Patient ID

deCODE ID

3/5

John Doe

10-10-1968

Male

n/a

DGT2D#6881

MARKER SPECIFIC RESULTS AND TEST DESCRIPTION TABLE 1


Locus TCF7L2 CDKN2A/B CDKAL1 PPARG SNP rs7903146 rs10811661 rs7756992 rs1801282 Genotype Result TT CT AG CC 1.54 0.88 1.09 1.03 Relative Risk Population Frequency 8% 28% 38% 81% Cases/ Controls References

3,905 / 4,542 3,905 / 4,542 3,905 / 4,542 14,586 / 17,968

6,7,8,9 6,10,11,12 10,11,12,13 6,14

DNA from the patient was genotyped for 4 common SNP variants that have consistently shown to confer significant risk for T2D. Risk conferred by each gene compared to that of the general population was separately derived from the published results of thousands of Caucasian patients and controls genotyped in the same way (6,7,10-14).

Combined relative genetic risk The patients lifetime risk estimate General population lifetime risk

1.51 38% 25%

The variants are located in or near the following genes: TCF7L2, CDKN2A, CDKAL1, and PPARG (6,7,10 -14). These genes have each been widely replicated in at least 3 independent populations. The risks for all the markers were then simply multiplied together resulting in the combined genetic risk for this patient compared to the general population. This is justified based on these large studies which showed that each genetic marker is an independent risk factor for T2D. Note that this test does not measure other risk factors for T2D associated with obesity, prediabetes, age or family history or gestational diabetes each of which can be multiplied by the genetic risk identified by the test. All the associated risk with T2D of the genes tested has been validated in both East Asians and whites. Furthermore, the deCODE T2 test does not measure all possible gene variants contributing to T2D, many of which have not yet been discovered. deCODE T2 is a risk prediction test, meaning patients at higher risk based on their genetic profile are not destined to develop T2D and patients with relatively lower genetic risk may still develop T2D. These risks need to be put in the context of other clinical risk factors and vigorous attention to management of modifiable risk factors remains important.
TM TM

TEST DETAILS AND TERMINOLOGY (see table above)


DNA from this patient has been tested for the genetic variants at the DNA locations indicated in the table which have been associated with increased likelihood of developing T2D using the Centaurus method of genotyping (Nanogen, Inc). This reliable method has greater than 99.9% accuracy and is based on a DNA hybridization technology and the use of probe and primer sets that enable base-specific fluorescent detection of polymerase chain reaction (PCR) products.
TM

Locus: The name given to the genomic region where the SNP variant is located, usually in reference to the closest gene. SNP: Stands for single nucleotide polymorphism and is a single base (letter) change in the DNA sequence at that location. For example, the TCF7L2 SNP measured can have a T or a C at that location in the human genome. The SNP tested for is given as a standard reference number or rs number. Genotype Results: The actual SNP genotype of the patient tested with each of the two letters referring to the actual base (letter) present on one of the two chromosomes. For example, the TCF7L2 SNP can have three possible genotypes: TT, CT, or CC. Relative Risk: The relative risk associated with each genotype indicated as calculated from the frequency of that genotype in the number of cases (individuals with T2D) vs. controls (general population) using as a reference thousands of patients and population controls in several independent populations of European descent. A relative risk of 1 means the same risk as the general population average; numbers smaller than 1 (0.01 - 0.99) mean a risk lower than average and a number greater than 1 means a risk higher than the general population average. For example, a risk of 0.50 means half the average lifetime risk of the general population whereas risk of 2 means twofold the average risk of the general population. Population Frequency: The frequency with which the genotype of the patient occurs in the general population of white Europeans (the control group). Cases/ Controls: Number of cases/controls is the number of individuals with T2D and numbers of controls from the various populations used in the validation studies to derive the associated relative risk. Combined relative genetic risk: The product of the risks for each of the 4 variants multiplied together, assuming the relative risks are independent and have no significant interaction. This assumption is based on findings of no significant interaction between these markers in thousands of patients and controls. General population lifetime risk: The general population risk of Caucasians of developing T2D in a lifetime.

This test was developed and its performance characteristics determined by the deCODE genetics Diagnostic Laboratory. It has not been cleared or approved by the U. S. Food and Drug Administration (FDA) deCODE Diagnostic Laboratory Testing Site: Sturlugata 8, 101 Reykjavk, Iceland Customer Service: 2501 Davey Road, Woodridge IL, 60517 Phone: (877) 222-6510 Fax: (630) 783-4998 www.decodediagnostics.com This document contains private and confidential health information protected by state and federal law 2009 deCODE genetics Diagnostic Laboratory All rights reserved document version 1.0.11 W

NAME

DOB

GENDER

Patient ID

deCODE ID

4/5

John Doe

10-10-1968

Male

n/a

DGT2D#6881

GENETIC RISK DISTRIBUTION BY deCODE T2 GENOTYPE RESULTS


Based on the justified assumption that the markers tested are independent, and the individual risk can therefore be multiplied, genotype combinations have associated relative risks in the range of 0.4 fold (non carriers for any of the risk markers) to almost 2.2 fold (homozygous for all of the 4 risk variants) compared to the risk of the Caucasian population in general. Combined, the 4 variants appear to account for about 57% of the cases of T2D (sometimes termed population attributable risk). About 40% of the population has a genotype combination of the tested markers that have an increased relative risk (>1) over the general population, about 5% of the population have 1.5 to 2.2 relative risk. The results are only valid for the assessment of the specified risk factors for T2D tested and provide only the fold decrease/increase in lifetime risk over the general population based on the Caucasian study populations described above. This test does not measure all of the genetic factors contributing to the risk of developing T2D, many of which are unknown. The intersection of this patients relative genetic risk with the x-axis, gives the proportion of the population that has greater or lower risk than the patient. Other known risk factors, such as age, obesity, prediabetes, ethnicity other than White or family history are not any less relevant than they would be in the absence of the test result. Patients who have significantly increased genetic risk have all the more reason to begin or comply with preventive measures against T2D. The conventional prevention and treatment guidelines of eating healthy foods, exercising and keeping the weight under control have been shown to overcome some or all of the added genetic risk associated with risk factors, including genetic risks. This is simply a risk test, not a determinative Mendelian genetic test; therefore, a high risk result would not mean that the individual will for certain develop T2D while a low risk result would not mean that the patient has no risk of developing T2D. The diagnosis or confirmation of diabetes is based on measuring fasting blood glucose and glucose tolerance tests and not from this test.

TM

This test was developed and its performance characteristics determined by the deCODE genetics Diagnostic Laboratory. It has not been cleared or approved by the U. S. Food and Drug Administration (FDA) deCODE Diagnostic Laboratory Testing Site: Sturlugata 8, 101 Reykjavk, Iceland Customer Service: 2501 Davey Road, Woodridge IL, 60517 Phone: (877) 222-6510 Fax: (630) 783-4998 www.decodediagnostics.com This document contains private and confidential health information protected by state and federal law 2009 deCODE genetics Diagnostic Laboratory All rights reserved document version 1.0.11 W

NAME

DOB

GENDER

Patient ID

deCODE ID

5/5

John Doe

10-10-1968

Male

n/a

DGT2D#6881

REMAINING LIFETIME RISK TABLE 2 Remaining lifetime risk (%)


Age BMI(kg/m2)
Male 18 years < 18.50 18.50 24.99 25.00 29.99 30.00 34.99 > 35.00 45 years < 18.50 18.50 24.99 25.00 29.99 30.00 34.99 > 35.00 65 years < 18.50 18.50 24.99 25.00 29.99 30.00 34.99 > 35.00 6.2 16.9 25.5 51.8 66.1 6 15.9 23.7 47.5 59.4 2.1 10.2 13.8 28.3 33.2

White
Female 9.8 14.5 30.7 48.8 69.3 9.1 13.2 27.5 42.2 58.4 3.5 9 17.3 26.3 34.9 Male 9.0 21.4 33.1 61.3 72.9 9.2 20.7 31.7 59.2 71 2.5 10.3 14.4 29.8 35.2

Black
Female 14.9 18.4 39.3 60.1 79.8 14.1 16.7 35.6 53.4 71.2 4.2 8.7 17.5 26.9 35.7

Hispanic
Male 9.7 25 36.9 68.1 81.1 9.3 23.3 33.8 62.9 75.6 3 14 18.6 37.2 43.6 Female 15.5 21.5 43.4 66 86 14 18.9 38 56.4 74.5 4.9 11.9 22.5 33.8 44.3

(Modified from Naryan et al., 15,16)

REFERENCES:
1) Standards of medical care in diabetes--2008. Diabetes Care, 2008. 31 Suppl 1: S12-54. 2) Tuomilehto, J., et al., Prevention of type 2 diabetes mellitus by changes in lifestyle among patients with impaired glucose tolerance. N Engl J Med, 2001. 344: 1343-50. 3) The Diabetes Prevention Program (DPP): description of lifestyle intervention. Diabetes Care, 2002. 25: 2165-71. 4) Florez, J.C., et al., TCF7L2 polymorphisms and progression to diabetes in the Diabetes Prevention Program. N Engl J Med, 2006. 355(3): p. 241-50. 5) Wang, J., et al., Variants of transcription factor 7-like 2 (TCF7L2) gene predict conversion to type 2 diabetes in the Finnish Diabetes Prevention Study and are associated with impaired glucose regulation and impaired insulin secretion. Diabetologia, 2007; 50(6):1192-1200. 6) Weedon, M.N. et. al. The importance of TCF7L2. Diabet Med. 2007;24:1062-1066. 7) Grant, S.F., et al., Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nat Genet, 2006. 38(3): p. 320-3. 8) Pearson, E.R., et al., Variation in TCF7L2 influences therapeutic response to sulfonylureas: a GoDARTs study. Diabetes, 2007. 56(8): p. 2178-82. 9) Pearson ER, D.L., Doney A, , Variation in TCF7L2 influences glycemic response to sulfonylureas. American Diabetes Association 67th Scientific Sessions, 2007.1. 10) Zeggini, E., et al., Replication of Genome-Wide Association Signals in U.K. Samples Reveals Risk Loci for Type 2 Diabetes. Science, 2007; 316(5829):1336-1341. 11) Saxena, R., et al., Genome-Wide Association Analysis Identifies Loci for Type 2 Diabetes and Triglyceride Levels. Science, 2007; 316(5829):1331-1336. 12) Scott, L.J., et al., A Genome-Wide Association Study of Type 2 Diabetes in Finns Detects Multiple Susceptibility Variants. Science, 2007;316(5829):1341-1345. 13) Steinthorsdottir, V., et al., A variant in CDKAL1 influences insulin response and risk of type 2 diabetes. Nat Genet, 2007. 39: p. 770-776. 14) Altshuler, D., et al., The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat Genet, 2000. 26(1): p. 76-80. 15) Narayan KM et al., Lifetime risk for diabetes mellitus in the United States. JAMA. 2003 Oct 8;290(14):1884-90. 16) Narayan, K.M., et al., Effect of BMI on lifetime risk for diabetes in the U.S. Diabetes Care, 2007. 30(6): p. 1562-6. 17) Crandall, J., et al., The influence of age on the effects of lifestyle modification and metformin in prevention of diabetes. J Gerontol A Biol Sci Med Sci, 2006. 61(10): p. 1075-81.

This test was developed and its performance characteristics determined by the deCODE genetics Diagnostic Laboratory. It has not been cleared or approved by the U. S. Food and Drug Administration (FDA) deCODE Diagnostic Laboratory Testing Site: Sturlugata 8, 101 Reykjavk, Iceland Customer Service: 2501 Davey Road, Woodridge IL, 60517 Phone: (877) 222-6510 Fax: (630) 783-4998 www.decodediagnostics.com This document contains private and confidential health information protected by state and federal law 2009 deCODE genetics Diagnostic Laboratory All rights reserved document version 1.0.11 W