33881 - Genetics of Diabetes Jan Dorman, PhD University of...

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Genetics of Diabetes Jan Dorman, PhD University of Pittsburgh School of Nursing jsd@pitt.edu
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Type 1 Diabetes (T1D)
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Type 1 Diabetes Caused by the destruction of  the pancreatic beta cells Insulin is no longer produced Leads to hyperglycemia, ketoacidosis and potentially death if  not treated with insulin  Treatment goals for T1D Maintaining near normal levels of blood glucose Avoidance of long-term complications
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Type 1 Diabetes 2 nd  most common chronic childhood disease Peak age at onset is around puberty But T1D can occur at any age Incidence is increasing worldwide by ~3% per year Related to increase in T2D?
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T1D Incidence Worldwide
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Importance of Environmental Risk  Factors in T1D Seasonality at diagnosis Migrants assume risk of host country Risk factors from case-control studies Infant/childhood diet Viruses – exposures as early as in utero Hormones Stress Improved hygiene Vitamin D
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Importance of Genetic Risk Factors in  T1D Concordance in identical twins greater in MZ versus DZ  twins 15-fold increased risk for 1 st  degree relatives Risk is ~6% through age 30 years Risk increases in presence of susceptibility genes
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MHC Region – Chromosome 6p21
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Predisposition to T1D is Better  Determined by Haplotypes DRB1-DQB1 haplotypes more accurately determine T1D  risk Testing for both genes is more expensive Most screening is based only on DQA1-DQB1 High risk T1D haplotypes DQA1*0501-DQB1*0201 DQA1*0301-DQB1*0302
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Relative Increase in T1D Risk by Number  of High Risk Haplotypes Number of High Risk DQA1- DQB1 haplotypes Ethnicity  Two One Caucasians 16 4 African Americans 45 7 Asians 11 4
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Absolute T1D Risk (to age 30) by Number  of High Risk Haplotypes Number of High Risk  DQA1-DQB1 Haplotypes Ethnicity Two One Zero Caucasians 2.6% 0.7% 0.2% African Americans 3.1% 0.5% 0.1% Asians 0.2% 0.1% 0.02%
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Absolute T1D Risk for Siblings of  Affected Individuals  Number of High Risk DQA1- DQB1 Haplotypes Two One Zero Risk of developing  T1D 25% 8.3% 1%
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Genome Screens for T1D IDDM1 6p21 IDDM13 2q34-q35 IDDM2 11p15 IDDM15 6q21 IDDM3 15q26 IDDM17 10q25 IDDM4 11q13 IDDM18 5q31-q33 IDDM5 6q25-q27 PTPN22 1p13 IDDM6 18q21 8q24 IDDM7 2q31 VDR, INF γ 12q12-qter IDDM8 6q27-qter 16p11-p13 IDDM9 3q21-q25 16q22-q24 IDDM10 10p11-q11 17q24-qter IDDM11 14q24-q31 TGF β 1 19p13-q13 IDDM12 2q33 Xp11
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Insulin (INS) gene Chromosome 11p15, OMIM: 176730 Variable number of tandem repeats (VNTR) Class I:  26-63 repeats Class II:  ~80 repeats Class III:  141-209 repeats Relative increase in risk ~2-fold with two class I alleles (compared to  0 class I alleles) Class I is associated with lower mRNA in the thymus – may  reduce tolerance to insulin and its precursors
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This note was uploaded on 03/08/2012 for the course PHARM 300 taught by Professor Staff during the Fall '11 term at Rutgers.

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33881 - Genetics of Diabetes Jan Dorman, PhD University of...

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