Chapter 062. Principles of Human Genetics (Part 25) docx

Principles of Human Genetics Part 25 Complex Genetic Disorders The expression of many common diseases such as cardiovascular disease, hypertension, diabetes, asthma, psychiatric disor

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

Disorder Genes or Susceptibility

Locus

Chromoso mal Location

Othe

r Factors

Monogen

ic forms of

diabetes

MODY

1

HNF4α (hepatocyte nuclear factor 4α)

20q12-q13.1 AD

inheritance

MODY

1

GCK (glucokinase) 7p15-p13

MODY

1

HNF1α (hepatocyte nuclear factor 1α)

12q24.2

MODY

1

IPF1 (insulin receptor substrate)

13q12.1

MODY

5 (renal cysts,

HNF1β (hepatocyte 17cen-q21.3

diabetes) nuclear factor 1β)

MODY

6

NeuroD1 (neurogenic differention factor 1)

2q32

Diabetes

mellitus type 2;

loci and genes

linked and/or

associated with

susceptibility

for diabetes

mellitus type 2

Genes and loci identified

by linkage/association studies

CPN10 (Calpain-10) 2q37.3 Diet

HNF4α (hepatocyte nuclear factor 4α)

20q12-q13.1 Energ

y expenditure

tyrosine phosphatase) q13.2 ty

PKLR (liver pyruvate kinase)

1q21

CASQ1 (calsequestrin 1)

1q21

APM1 (adiponectin) 3q27

TCF7L2 (transcription factor 7-like 2)

10q25.3

1q21-23 1q21-23

3q22-27 3q22-27 8p21-23 8p21-23

11q 11q 12q24 12q24

18p11 18p11 20q 20q 20p 20p

Selected candidate genes with possible contribution

PPARγ (Peroxisome proliferator receptor γ)

3p25

KCNJ11(ATP-sensitive

K channel Kir6.2)

11p15.1

ABCC8 (ATP-binding cassette, subfamily c, member 8)

11p15.1

Insulin VNTR 11p15

IRS-1 (insulin receptor substrate)

2q36

PGC1α (PPAR γcoactivatory α)

4p15.1

ENPP1 (ectonucleotide pyrophosphatase/phosphodieste rase 1)

6q22-23