Chapter 062. Principles of Human Genetics (Part 25)

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Complex Genetic Disorders The expression of many common diseases such as cardiovascular disease, hypertension, diabetes, asthma, psychiatric disorders, and certain cancers is determined by a combination of genetic background, environmental factors, and lifestyle. A trait is called polygenic if multiple genes contribute to the phenotype or multifactorial if multiple genes are assumed to interact with environmental factors. Genetic models for these complex traits need to account for genetic heterogeneity and interactions with other genes and the environment. Complex genetic traits may be influenced by modifying genes that are not linked to the main gene involved in the pathogenesis of the...

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Chapter 062. Principles of Human Genetics (Part 25) Complex Genetic Disorders The expression of many common diseases such as cardiovascular disease, hypertension, diabetes, asthma, psychiatric disorders, and certain cancers is determined by a combination of genetic background, environmental factors, and lifestyle. A trait is called polygenic if multiple genes contribute to the phenotype or multifactorial if multiple genes are assumed to interact with environmental factors. Genetic models for these complex traits need to account for genetic heterogeneity and interactions with other genes and the environment. Complex genetic traits may be influenced by modifying genes that are not linked to the main gene involved in the pathogenesis of the trait. This type of gene-gene interaction, or epistasis, plays an important role in polygenic traits that require the
simultaneous presence of variations in multiple genes to result in a pathologic phenotype. Type 2 diabetes mellitus provides a paradigm for considering a multifactorial disorder, as genetic, nutritional, and lifestyle factors are intimately interrelated in disease pathogenesis (Table 62-7) (Chap. 338). The identification of genetic variations and environmental factors that either predispose to or protect against disease is essential for predicting disease risk, designing preventive strategies, and developing novel therapeutic approaches. The study of rare monogenic diseases may provide insight into some of genetic and molecular mechanisms important in the pathogenesis of complex diseases. For example, the identification of the hepatocyte nuclear factor α (HNFα) in maturity-onset of diabetes type 4 defined it as a candidate gene in the pathogenesis of diabetes mellitus type 2 (Tables 62-2 and 62-8). Genome scans have identified various loci that may be associated with susceptibility to development of diabetes mellitus in certain populations. Efforts to identify susceptibility genes require very large sample sizes, and positive results may depend on ethnicity, ascertainment criteria, and statistical analysis. Association studies analyzing the potential influence of (biologically functional) SNPs and SNP haplotypes on a particular phenotype are a promising approach for the detection of involved genes. Table 62-7 Genes and Loci Involved in Mono- and Polygenic Forms of Diabetes
Disorder Genes or Susceptibility Chromoso Othe Locus mal Location r Factors Monogen ic forms of diabetes MODY HNF4α (hepatocyte 20q12-q13.1 AD 1 nuclear factor 4α) inheritance MODY GCK (glucokinase) 7p15-p13 1 MODY HNF1α (hepatocyte 12q24.2 1 nuclear factor 1α) MODY IPF1 (insulin receptor 13q12.1 1 substrate) MODY HNF1β (hepatocyte 17cen-q21.3 5 (renal cysts,
diabetes) nuclear factor 1β) MODY NeuroD1 (neurogenic 2q32 6 differention factor 1) Diabetes Genes and loci identified mellitus type 2; by linkage/association studies loci and genes linked and/or associated with susceptibility for diabetes mellitus type 2 CPN10 (Calpain-10) 2q37.3 Diet HNF4α (hepatocyte 20q12-q13.1 Energ nuclear factor 4α) y expenditure PTPN1 (protein- 20q13.1- Obesi
tyrosine phosphatase) q13.2 ty PKLR (liver pyruvate 1q21 kinase) CASQ1 (calsequestrin 1q21 1) APM1 (adiponectin) 3q27 TCF7L2 (transcription 10q25.3 factor 7-like 2) 1q21-23 1q21-23 2q 2q 3q22-27 3q22-27 8p21-23 8p21-23
11q 11q 12q24 12q24 15 15 18p11 18p11 20q 20q 20p 20p Selected candidate genes with possible contribution PPARγ (Peroxisome 3p25 proliferator receptor γ) KCNJ11(ATP-sensitive 11p15.1 K channel Kir6.2)
ABCC8 (ATP-binding 11p15.1 cassette, subfamily c, member 8) Insulin VNTR 11p15 IRS-1 (insulin receptor 2q36 substrate) PGC1α (PPAR 4p15.1 γcoactivatory α) ENPP1 (ectonucleotide 6q22-23 pyrophosphatase/phosphodieste rase 1)