Lead genetic factors

Poretz RD Rutgers University Biochemistry Microbiology, New Brunswick, NJ To define a possible genetic factor which may cause certain individuals to be hypersusceptible to lead-incuded neurobehavioral abnormality U. S. Department of Agriculture, Cooperative State Res... 

Familial amyotrophic lateral sclerosis. Familial amyotrophic lateral sclerosis (FALS) is observed in =10% of all cases, but substantially more ALS cases are suspected to be influenced to some degree by genetic factors [75], Mutations in two genes (SOD1 and ALS2 Table 39-3) have been shown to cause FALS, apart from mutations in tau (MAPT) leading to FTD with parkinsonism and... 

All these genetic factors may interact in still-unknown genetic networks, leading to a cascade of pathogenic events characterized by abnormal protein processing and misfolding with snbseqnent accnmnlation of abnormal proteins (conformational changes), nbiqnitin-proteasome system dysfunction, excitotoxic reactions, oxidative... 

The cause of Alzheimer s disease is unknown, but genetic factors clearly play a role. One clue supporting this view is provided by the observation that individuals with Down syndrome, a common cause of mental retardation, frequently develop a dementia similar to Alzheimer s disease during early adulthood. Vascular dementia, which is also called multi-infarct dementia, results from the accumulation of tiny strokes. Individually, these strokes or infarcts are too small to cause any noticeable problem, but as they accumulate, they produce deficits similar to Alzheimer s disease. Other neurological diseases such as Parkinson s disease, Pick s disease, and Huntington s disease cause slow deterioration of the brain that ultimately leads to a degenerative dementia. 

It therefore appears that neurons in the substantia nigra might ultimately be destroyed because genetic factors lead to neuronal protein accumulation and free radical-induced oxidative stress that causes the degeneration and death of these neurons. As indicated earlier, however, the influence of environmental factors should be considered.49,64 It has been theorized, for example, that environmental toxins (e.g., herbicides, insecticides, fungicides) accelerate the neuronal destruction in people with Parkinson disease.14 Much of this evidence is based on the finding that a compound known as l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) appears to be selectively toxic to these neurons and can invoke parkinsonism in primates.84... 

The cline shown by D. melanogaster males in the ratio of 7-T 7-P, mentioned above, leads to asymmetric male-male courtship between these strains. 7-P-rich males are strongly courted by 7-T-rich males but the inverse does not occur, indicating that 7-P-rich males are not stimulated by 7-T. The variation in courtship response is linked to genetic factors that are independent of those involved in the variation of the 7-T 7-P ratio (Sureau and Ferveur, 1999). 

Most diabetics are in this category. Genetic factors rather than viruses or autoimmune antibodies are apparently causal. The metabolic alterations observed are milder than those described for IDDM (for example, NIDDM patients typically are not ketotic), but the long-term clinical consequences can be just as devastating (for example, vascular complications and subsequent infection can lead to amputation of the lower limbs). 

Typically, metabolic processes leading to detoxication of the parent compound are favored and activation pathways are minor however, some conditions cause a shift toward bioactivation events becoming predominant. When an organism is exposed to a large quantity of a xenobiotic, it may saturate or activate certain enzymes, thereby altering the resultant detoxication pathway. A number of physiological and genetic factors, as well as metabolic and chemical interactions, may also favor the activation of a parent compound as opposed to its detoxication. 

Figure 1 Risk factors that contribute to cardiometabolic risk. A model proposed by the ADA, where environmental and genetic factors lead to metabolic disorders that contribute to T2D and CVD. From Reference 1, with permission.

---