complex genetic diseases Flashcards
diabetes: explain how genome-wide SNP association studies are designed and their contribution to our understanding of diabetes risk; explain how increased risk of polygenic disorders may be mediated e.g. single nucleotide polymorphisms, copy number variants; distinguish between monogenic and polygenic diabetes, explain the implications of genetics for clinical management of diabetes
define monogenic (MODY as example)
single gene defect; born and always going to get it
MODY clinical features
autosomal dominant disorder; young onset; affects genes for B-cell glucose sensing and insulin secretion; generational as B-cells apoptose with age so eventually insulin needed to treat (if also type 2, insulin resistant so no effect)
causes of monogenic forms of obesity
poor appetite and medication regulation
HNF-1a (gene responible for MODY): mutation
within B-cell; TF stimulates insulin production so acts as a glucose sensor; if 1 mutated copy, insufficient insulin
HNF-1a (gene responible for MODY): treatment
treated with sulphonylureas (sensitive so avoid hypoglycaemia); close K+ channels without ATP causing insulin secretion
effect of glucokinase in B cell
within B-cell; glucose sensor; glucose→glucose-6-phosphate (glycolysis→ATP→insulin production)
mutated glucokinase
increases insulin secretion set point; leads to stable, mild hyperglycaemia with no retinopathy complications; as physiology intact can come off all treatments
purpose of GWAS
identify candidate risk factors of common obesity: “common disease = common variant”; determines if disease is statistically associated with single nucleotide polymorphism (SNPs; common change at 1 nucleotide - missense mutation)
define polygenic (type 1 and 2 as examples)
compilation of genetic changes increases predisposition, but requires 2nd hit from environment or lifestyle; risk increases from both low→low genetic and high environment risks→high genetic and low environment risks→both high
type 2 diabetes as GWAS example
90 loci associated with increased risk; small observed effect on B-cell function; most likely affected by environment and lifestyle, not heritability; genomic structural variants possibly responsible
permanent neonatal diabetes (PND; monogenic)
mutations in 1st 6 months; treated with sulphonylureas
mitochondrial diabetes (monogenic) and affect of heteroplasmy
maternally inherited but as mitochondrial, heteroplasmy involved (multiple organelles so mutation shunted down different pathways so different proportions of mitochondria affected in daughter cells)
mediating increased risk of polygenic diabetes (type 1 and 2) using SNPs and CNVs
SNPs: mutation occuring in >1% population increases risk of polygenic disease; copy number variants (CNVs): repetitions of deletions, duplications or insertions in genome increases risk of polygenic disease
environmental vs genetic aspects of diabetes (polygenic and monogenic)
polygenic: greater impact from environment (very common mean allele frequency; small effect size); monogenic (single gene dominant→single gene recessive): greater impact from genes (rare mean allele frequency; large effect size)
