of Multifactorial Traits for Which Specific Genetic and Environmental Factors are Known

Figure 8-7 Pedigree of a family with retinitis pigmentosa due to digenic inheritance. Dark blue symbols are affected individuals. Each individual’s genotypes at the peripherin locus (first line) and ROM1 locus (second line) are written below each symbol. The normal allele is 1; the mutant allele is mut. Light blue symbols are unaffected, despite carrying a mutation in one or the other gene. See Sources & Acknowledgments.

A multigenic model has also been observed in a few families with Bardet-Biedl syndrome, a rare birth defect characterized by obesity, variable degrees of intellectual disability, retinal degeneration, polydactyly, and genitourinary malformations. Fourteen different genes have been found in which mutations cause the syndrome. Although inheritance is clearly autosomal recessive in most families, a few families appear to demonstrate digenic inheritance, in which the disease occurs only when an individual is homozygous for mutations at one of these 14 loci and is heterozygous for a mutation at another of the loci.

Gene-Environment Interactions in Venous Thrombosis

One such disorder is idiopathic cerebral vein thrombosis, a disease in which clots form in the venous system of the brain, causing catastrophic occlusion of cerebral veins in the absence of an inciting event such as infection or tumor. It affects young adults, and although quite rare (<1 per 100,000 in the population), it carries a high mortality rate (5% to 30%). Three relatively common factors—two genetic and one environmental—that lead to abnormal coagulability of the clotting system are each known to individually increase the risk for cerebral vein thrombosis (Fig. 8-8):

A missense variant in the gene for the clotting factor, factor V

A variant in the 3′ untranslated region (UTR) of the gene for the clotting factor prothrombin

The use of oral contraceptives


Figure 8-8 The clotting cascade relevant to factor V Leiden and prothrombin variants. Once factor X is activated, through either the intrinsic or extrinsic pathway, activated factor V promotes the production of the coagulant protein thrombin from prothrombin, which in turn cleaves fibrinogen to generate fibrin required for clot formation. Oral contraceptives (OC) increase blood levels of prothrombin and factor X as well as a number of other coagulation factors. The hypercoagulable state can be explained as a synergistic interaction of genetic and environmental factors that increase the levels of factor V, prothrombin, factor X and others to promote clotting. Activated forms of coagulation proteins are indicated by the letter a. Solid arrows are pathways; dashed arrows are stimulators.

A polymorphic allele of factor V, factor V Leiden (FVL), in which arginine is replaced by glutamine at position 506 (Arg506Gln), has a frequency of approximately 2.5% in white populations but is rarer in other population groups. This alteration affects a cleavage site used to degrade factor V, thereby making the protein more stable and able to exert its procoagulant effect for a longer duration. Heterozygous carriers of FVL, approximately 5% of the white population, have a risk for cerebral vein thrombosis that, although still quite low, is sevenfold higher than that in the general population; homozygotes have a risk that is eightyfold higher.

The second genetic risk factor, a mutation in the prothrombin gene, changes a G to an A at position 20210 in the 3′ UTR of the gene (prothrombin g.20210G>A). Approximately 2.4% of white individuals are heterozygotes, but it is rare in other ethnic groups. This change appears to increase the level of prothrombin mRNA, resulting in increased translation and elevated levels of the protein. Being heterozygous for the prothrombin 20210G>A allele raises the risk for cerebral vein thrombosis three to sixfold.

Finally, the use of oral contraceptives containing synthetic estrogen increases the risk for thrombosis fourteen- to twentytwofold, independent of genotype at the factor V and prothrombin loci, probably by increasing the levels of many clotting factors in the blood. Although using oral contraceptives and being heterozygous for FVL cause only a modest increase in risk compared with either factor alone, oral contraceptive use in a heterozygote for prothrombin 20210G>A raises the relative risk for cerebral vein thrombosis 30- to 150-fold!

There is also interest in the role of FVL and prothrombin 20210G>A alleles in deep venous thrombosis (DVT) of the lower extremities, a condition that occurs in approximately 1 in 1000 individuals per year, far more common than idiopathic cerebral venous thrombosis. Mortality due to DVT (primarily due to pulmonary embolus) can be up to 10%, depending on age and the presence of other medical conditions. Many environmental factors are known to increase the risk for DVT and include trauma, surgery (particularly orthopedic surgery), malignant disease, prolonged periods of immobility, oral contraceptive use, and advanced age.

The FVL allele increases the relative risk for a first episode of DVT sevenfold in heterozygotes; heterozygotes who use oral contraceptives see their risk increased thirtyfold compared with controls. Heterozygotes for prothrombin 20210G>A also have an increase in their relative risk for DVT of twofold to threefold. Notably, double heterozygotes for FVL and prothrombin 20210G>A have a relative increased risk of twentyfold—a risk approaching a few percent of the population.

Thus each of these three factors, two genetic and one environmental, on its own increases the risk for an abnormal hypercoagulable state; having two or all three of these factors at the same time raises the risk even more, to the point that thrombophilia screening programs for selected populations of patients may be indicated in the future.

Multiple Coding and Noncoding Elements in Hirschsprung Disease

Familial HSCR-L is often characterized by patterns of inheritance that suggest dominant or recessive inheritance, but consistently with reduced penetrance. HSCR-L is most commonly caused by loss-of-function missense or nonsense mutations in the RET gene, which encodes RET, a receptor tyrosine kinase. A small minority of families have mutations in genes encoding ligands that bind to RET, but with even lower penetrance than those families with RET mutations.

HSCR-S is the more common type of HSCR and has many of the characteristics of a disorder with complex genetics. The relative risk ratio for sibs, λs, is very high (approximately 200), but MZ twins do not show perfect concordance and families do not show any obvious mendelian inheritance pattern for the disorder. When pairs of siblings concordant for HSCR-S were analyzed genome-wide to see which loci and which sets of alleles at these loci each sib had in common with an affected brother or sister, alleles at three loci (including RET) were found to be significantly shared, suggesting gene-gene interactions and/or multigenic inheritance; indeed, most of the concordant sibpairs were found to share alleles at all three loci. Although the non-RET loci have yet to be identified, Figure 8-9 illustrates the range of interactions necessary to account for much of the penetrance of HSCR in even this small cohort of patients.


Figure 8-9 Patterns of allele sharing among sibpairs concordant for Hirschsprung disease, divided according to the number of loci for which the sibs show allele sharing. The three loci are located at 10q11.2 (the RET locus), 3p21, and 19q12. See Sources & Acknowledgments.

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Nov 27, 2016 | Posted by in GENERAL & FAMILY MEDICINE | Comments Off on of Multifactorial Traits for Which Specific Genetic and Environmental Factors are Known

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