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Genetics of Caries Update

Genetics of Caries Update. COHRA Symposium November 2, 2006. Genes. Chromosomes consist of molecules of DNA strung together Nucleotides, base pairs (A, T, C, G) Humans have 23 pairs of chromosomes (22 autosomes, plus XX or XY

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Genetics of Caries Update

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  1. Genetics of Caries Update COHRA Symposium November 2, 2006

  2. Genes • Chromosomes consist of molecules of DNA strung together • Nucleotides, base pairs (A, T, C, G) • Humans have 23 pairs of chromosomes (22 autosomes, plus XX or XY • Chromosomes include genes which encode proteins, regulatory regions, etc. • “Markers” are pieces of DNA whose chromosomal location is known, may or may not be inside a gene

  3. Genes and Markers • Genes and markers have pairs of “alleles”, one from mother and one from father • Genes and markers may have one, two or a large number of possible alleles • Consider ABO blood group: A, B, O alleles • AO, BO, AB, OO possible genotypes (combinations of pairs of alleles) • If more than one possible allele, then “Polymorphic”

  4. SNP Markers • One very common class of DNA marker is “Single Nucleotide Polymorphisms” or SNP’s • SNP’s are variants at one base pair (e.g. A, T, C, G) so all SNP’s are two-allele markers • Fast and easy to type • Outweighs their disadvantage of being somewhat less informative than other types of markers

  5. Genetic Mapping Studies • Discover where on chromosome genes for disease are likely to be • Linkage---exploits recombination between paired chromosomes during meiosis • Look for a genetic marker that is either linked or associated with your disease of interest • COHRA: caries

  6. Marker alleles co-segregate with disease alleles in families Usually no population level allelic association Linkage equilibrium Marker allele associated with disease allele in population Same allele across families Linkage disequilibrium Linkage vs. Association

  7. Association • Case control studies • Population-based: possible bias • Family-based controls • Siblings • AFBAC • TDT

  8. TDT • Allelic association method • Transmission Disequilibrium Test • Overcome potential bias in population-based case-control studies • Family-based controls: non-transmitted alleles as controls • Minimal family structure (triads—mother, father, child) • Dichotomous and continuous traits

  9. TDT • Transmission disequilibrium tests • Rely on linkage disequilibrium • Distortion of transmission from parent to child • Informative triads—at least one parent must be heterozygous • E.g. if a SNP has alleles A and G, possible genotypes are AA, AG, GG • AG is heterozygous, AA and GG are homozygotes

  10. Transmission Disequilibrium

  11. TDT--interpretation • Allelic Association (population level) • Positive results imply close linkage? • Simulation studies show that can be positive even if association and loose linkage present

  12. TDT-extensions • Quantitative-TDT • Sib-TDT • Logistic regression (covariates) • Variance components methods (covariates, interactions) • FBAT—family based association test • Nuclear families, extended kindreds

  13. Markers with Caries • SNPs in the following candidate genes • Enamelin (ENAM1), 4q21 • Tuftelin (TUFT1), 1q21-q31 • Ameloblastin (AMBN), 4q21 • Tuftelin interacting protein (TFIP11), 22q12.1

  14. Definitions • Severe caries • Age < 6: > 20% of existing teeth d or f • 6-8: > 1 d or f • 8-12: > 3 • > 12: > 4 • Low caries (> 14: < 2 d or f; <14: < 1) • ECC (ages 1-6 only, 20%)

  15. COHRA Families • 332 families (n=3-12), 1432 individuals • 110 with 1 genotyped severe caries affected • 88 with 2 genotyped severe affected • 15 with > 3 affected • 220 with > 1 severe child • 67 with both parents genotyped • 142 with one parent • 123 with no parents (need to check)

  16. FBAT, Caries

  17. Tuftelin • Involved in enamel development/mineralization • Secreted into the enamel matrix, detected at dentin-enamel junction • Over-expression of TUFT led to imperfections in enamel prisms and crystallite structure (mouse model)

  18. Tuftelin • Located 1q21-q31 • Genome scan in Philippines families—no linkage seen • Candidates in Guatemala---no association • Slayton case-control study • Slayton, Cooper, Marazita JDR 84:711-714, 2005 • ECC • No main effect for TUFT • TUFT was associated when S. mutans levels included as a covariate and interaction

  19. TO DO • Include S. mutans levels in model • Get other COHRA families done • Do more SNPs in TUFT • Check SNP allele vs. Slayton et al • Other definitions of “affected” • Other candidates • Sweet preference • Behavior • WGA—new grant: 500,000 SNP’s

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