Chapter 062. Principles of Human Genetics (Part 25)

Complex Genetic DisordersThe 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) 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 isdetermined by a combination of genetic background, environmental factors, andlifestyle. A trait is called polygenic if multiple genes contribute to the phenotypeor multifactorial if multiple genes are assumed to interact with environmentalfactors. Genetic models for these complex traits need to account for geneticheterogeneity and interactions with other genes and the environment. Complexgenetic traits may be influenced by modifying genes that are not linked to the maingene involved in the pathogenesis of the trait. This type of gene-gene interaction,or epistasis, plays an important role in polygenic traits that require thesimultaneous presence of variations in multiple genes to result in a pathologicphenotype. Type 2 diabetes mellitus provides a paradigm for considering amultifactorial disorder, as genetic, nutritional, and lifestyle factors are intimatelyinterrelated in disease pathogenesis (Table 62-7) (Chap. 338). The identification ofgenetic variations and environmental factors that either predispose to or protectagainst disease is essential for predicting disease risk, designing preventivestrategies, and developing novel therapeutic approaches. The study of raremonogenic diseases may provide insight into some of genetic and molecularmechanisms important in the pathogenesis of complex diseases. For example, theidentification of the hepatocyte nuclear factor α (HNFα) in maturity-onset ofdiabetes type 4 defined it as a candidate gene in the pathogenesis of diabetesmellitus type 2 (Tables 62-2 and 62-8). Genome scans have identified various locithat may be associated with susceptibility to development of diabetes mellitus incertain populations. Efforts to identify susceptibility genes require very largesample 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 apromising approach for the detection of involved genes. Table 62-7 Genes and Loci Involved in Mono- and Polygenic Forms ofDiabetes Disorder Genes or Susceptibility Chromoso Othe Locus mal Location r Factors Monogenic forms ofdiabetes MODY HNF4α (hepatocyte 20q12-q13.1 AD1 nuclear factor 4α) inheritance MODY GCK (glucokinase) 7p15-p131 MODY HNF1α (hepatocyte 12q24.21 nuclear factor 1α) MODY IPF1 (insulin receptor 13q12.11 substrate) MODY HNF1β (hepatocyte 17cen-q21.35 (renal cysts,diabetes) nuclear factor 1β) MODY NeuroD1 (neurogenic 2q326 differention factor 1) Diabetes Genes and loci identifiedmellitus type 2; by linkage/association studiesloci and geneslinked and/orassociated withsusceptibilityfor diabetesmellitus type 2 CPN10 (Calpain-10) 2q37.3 Diet HNF4α (hepatocyte 20q12-q13.1 Energ nuclear factor 4α) y expenditure PTPN1 (protein- 20q13.1- Obesityrosine phosphatase) q13.2 ty PKLR (liver pyruvate 1q21kinase) CASQ1 (calsequestrin 1q211) APM1 (adiponectin) 3q27 TCF7L2 (transcription 10q25.3factor 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 geneswith possible contribution PPARγ (Peroxisome 3p25proliferator r ...