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Migrant Studies

Migrant Studies. Migrant Studies: vary environment, keep genetics constant: Evaluate incidence of disorder among ethnically-similar individuals living in native environment.

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Migrant Studies

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  1. Migrant Studies • Migrant Studies:vary environment, keep genetics constant: • Evaluate incidence of disorder among ethnically-similar individuals living in native environment. • Evaluate incidence of disorder among comparable group of ethnically-similar individuals who have migrated to a new environment that has much higher or lower rates of the disorder. • As the rates of disorder among migrants approach those observed in the new environment, evidence for environmental influence increases.

  2. Migrant Studies Examples of Findings from Migrant Studies: With exception of stomach cancer, Japan historically has had much lower rates of cancer than the U.S. BUT, after just 2 generations, Japanese migrants to the U.S. have nearly assumed the same rates of cancer (including lower rates of stomach cancer). European immigrants (high latitude) who migrate to Israel (low latitude) at a young age experience a low incidence of multiple sclerosis. However, if the migration occurs after age 14, the “relevant” environmental exposure may have already occurred.

  3. Migrant Studies Limitations of Migrant Studies: --- Migrants are highly selected. --- Age at migration varies – prior causal exposure in the native environment may have already occurred. --- The extent to which migrants retain cultural and lifestyle elements of their original environment can make it difficult to evaluate environmental influences of the new environment.

  4. Genetic Marker Studies • Genetic Marker Studies:vary environment, keep genetics constant: • 1) Examine links between genetic markers and specific disorders or traits. • 2) Genetic markers are a measurable human trait controlled by a single gene with known chromosomal location. Must be polymorphic with at least two alleles having a gene frequency of at least 1 percent.

  5. Genetic Marker Studies • Markers Used to Study Allele/Disease Associations • 1) Analysis of gene products or phenotypic expression: • --- Blood groups • --- Human leukocyte antigens (HLAs) – extensive investigations have been/being conducted • --- Protein polymorphisms • 2) Analysis of DNA polymorphisms • --- Allelic variants of genes • --- Restriction fragment length polymorphisms • --- Variable tandem repeats • Note: The “marker” may or may not be causally involved in development of the disease.

  6. Genetic Marker Studies • Genetic Marker Studies:vary environment, keep genetics constant • 3) The fact that alleles at different loci, but very close in proximity, tend to be transmitted together beyond that expected by chance alone is known as “linkage disequilibrium.” • 4) Two types of genetic marker studies: • a) Association studies • b) Linkage studies

  7. Genetic Marker Studies a) Association studies: Select disease cases and controls using case-control design. Compare the frequency of the genetic marker of interest (e.g. specific allele) between cases and controls. Unrelated individuals from different families in the general population should be selected for both cases and controls. Ethnicity is strong potential confounder – controls should be selected from same ethnicity as cases.

  8. Genetic Marker Studies a) Association studies

  9. Genetic Marker Studies b) Linkage studies: Assess the association of general markers and disease within families. --- Linkage is defined as the tendency of genes to be inherited together as a result of their location on the same chromosome.

  10. Genetic Marker Studies Linkage (background): --- Genes co-exist on chromosomes. 22 pairs of non-sex chromosomes (autosomes) 1 pair of sex chromosomes (XX:F, XY:M) --- In meiosis, 2 pairs of chromosomes segregate; one chromosome of each pair is transmitted to gamete --- Chromosomes segregate independently. --- However, chromosomes do not always stay intact; crossing over (recombination) occurs. --- Frequency of crossover between 2 loci on same chromosome depends on their distance apart.

  11. Genetic Marker Studies Recombination: No recombination Recombination Chromosome A Loci 1 2 Break 3 Linkage

  12. Genetic Marker Studies Lod Score Method: Requires knowledge of the mode of inheritance. Based on estimation of the “recombination fraction” – the proportion of all gametes that are recombined between two loci of interest – the lower the probability, the greater the likelihood of linkage. A likelihood ratio test is an odds ratio comparing the probability that linkage is present versus not present (null probability value of 0.5).

  13. Genetic Marker Studies • Lod Score Method --- Assumptions: • 2 traits of interest are inherited as simple, single locus Mendelian traits. • Relations between genotype and phenotype are known (e.g. dominance and penetrance). • Gene frequencies of various alleles are known. • For a family to be informative for linkage, one parent must be heterozygous for both traits of interest (e.g. Aa, Bb).

  14. Genetic Marker Studies The Lod Score is the log of the odds ratio. For monogenetic diseases that have Mendelian patterns of inheritance: > 3 evidence of linkage < -2 evidence against linkage > -2 to < 3 inconclusive However, Lod Scores required to confirm or reject linkage for complex disorders (e.g. psychiatric disorders) need to be of greater magnitude due to complex patterns of inheritance.

  15. Gene-Environment Interaction • Gene-Environment Interactions: • Statistical: Coefficient of the product term of 2 or more risk factors (e.g. extent to which the coefficient departs from a multiplicative model). • Biological: Co-participation between 2 factors in the same causal mechanism to disease development (e.g. extent to which coefficient departs from an additive model).

  16. Gene-Environment Interaction Genetic-Environment Interactions: * Two types of genetic markers used in gene- environment interaction studies: a) Markers based on gene products such as specific blood groups, HLA antigens, serum proteins, and enzyme systems b) Markers based on direct analysis of DNA.

  17. Gene-Environment Interaction • Study Designs: • Traditional (e.g. case-control, cohort) --- these have many of the same concerns as non-genetic-based studies (e.g. selection of external control subjects). • Using an Internal Control Group • Case-only study • Case-parental control study • Twin studies

  18. Gene-Environment Interaction Example: Traditional Cohort Study: Compare product of RR’s for 1 factor present versus both present (null value = 1.0) H0: RGE / (RG x RE) = 1.0 H1: RGE / (RG x RE) = 1.0

  19. Gene-Environment Interaction Hypothetical Example: (Exposure): Epstein-Barr virus (Genotype): HLA-DR4 (Outcome): Rheumatoid arthritis In the above example, is there evidence of gene-environment interaction on the development of rheumatoid arthritis?

  20. Gene-Environment Interaction Hypothetical Example: (Exposure): Epstein-Barr virus (Genotype): HLA-DR4 (Outcome): Rheumatoid arthritis H0: RGE / (RG x RE) = 1.0 3.38 / (1.45 x 1.31) = 3.38 / 1.90 = 1.78 Since 1.78 = 1.0, then there is evidence of G-E interaction.

  21. Gene-Environment Interaction • Case-Only Study (internal controls): • Primary goal: assess gene-environment interaction. • Valid under assumption of independence between distribution of exposure and genotype in the population (see below). • Cannot assess effects of exposure or genotype alone. • ORCA = RGE / (RE * RG) * ORCO • ORCA = RGE / (RE * RG) • H0: ORCA = 1 • H1: ORCA > 1 (mult.); ORCA < 1 (additive)

  22. Example of Case-Control Study: Example of Case-Only Study: ORCA = AD / BC = (36 * 13) / (7 * 13) = 468 / 91 = 5.1

  23. Gene-Environment Interaction • Case-Parental Control Study (internal controls): • Primary goal: assess gene-environment interaction. • Cannot assess independent effect of exposure. • Permits assessment of effect of genotype with and without exposure. • Parents of case subjects are used as controls – must have genotype information on the parents. • Genotype of case is compared to genotype of a fictitious control formed by the non-transmitted allele from each parent.

  24. Gene-Environment Interaction Case-Parental Control Study: Can compare the two odds ratios to assess presence of interaction

  25. Gene-Environment Interaction • Twin Studies: • Involves 2 measures of relative risk (RR) • RRE = Relative risk for disease among exposed vs. unexposed co-twins, stratified by zygosity: If effect of exposure is constant, no interaction with genotype

  26. Gene-Environment Interaction Twin Studies: • In the above example: • Is exposure related to risk of disease? • Does genotype interact with exposure on risk of disease?

  27. Gene-Environment Interaction Twin Studies: • Since exposed persons are at overall higher risk of disease than unexposed persons, the exposure is related to risk of disease? • Since the effect of exposure on risk of disease is similar by zygosity (RR of 2.7 vs. 2.6), genotype does not interact with the exposure.

  28. Gene-Environment Interaction Twin Studies: RRz = Relative risk for disease among MZ vs. DZ co-twins, stratified by exposure status: If effect of genotype is constant, no interaction with exposure

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