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Oral Clefts, Environmental Exposures, and Genetic Variation of Candidate Genes

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Oral Clefts, Environmental Exposures, and. Genetic Variation of Candidate Genes ... Xenobiotic metabolizing enzymes. phase 1 : CYP2D6, NAT1, NAT2, EPHX1 ... – PowerPoint PPT presentation

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Title: Oral Clefts, Environmental Exposures, and Genetic Variation of Candidate Genes


1
Oral Clefts, Environmental Exposures, and
Genetic Variation of Candidate Genes
Edward Lammer, MD Eric
Lloyd David Iovannisci, PhD
Poulina Uddin
Shira Kupperman

Dorian Ramirez Gary Shaw, DrPH CA Birth
Defects Monitoring Pgm. Richard Finnell, PhD
IBT, Texas AM Univ.
2
Oral Clefts, Environmental Exposures, and
Genetic Variation of Candidate Genes
  • Multivitamins with folate
  • folate-related metabolism and transport
  • MTHFR, CBS, FR-alpha, RFC1
  • Xenobiotic metabolizing enzymes
  • phase 1 CYP2D6, NAT1, NAT2, EPHX1
  • phase 2 GSTT1, GSTM1, GSTP1, NAT1

3
Isolated cleft lip ? cleft palateMaternal
smoking CA 87-89
  • Maternal smoking from
  • conception - 3 months Odds ratio 95
    CI
  • Any smoking 1.6 1.1-2.4
  • ? 20 cigs/day 2.4 1.2-5.1
  • 1-19 cigs/day 1.5 1.0-2.2

4
Isolated cleft palateMaternal smoking CA
87-89
  • Maternal smoking from
  • conception - 3 months Odds ratio 95 CI
  • Any smoking 1.6 1.0-2.6
  • ? 20 cigs/day 2.7 1.1-6.3
  • 1-19 cigs/day 1.3 0.78-2.3

5
(No Transcript)
6
GSTM1/GSTT1/Albumin Analysis
7
Frequencies and risks of Glutathione-S-transferase
genotypes CA 87-89
  • GSTM1 Isolated Cleft Lip
  • Genotypes Cleft Palate Cleft Palate
    Controls
  • GSTM1 149 70 146
  • Null 149 55 148 50
  • OR 0.99 0.71-1.4 OR
    0.78 0.50-1.2
  • GSTT1 Isolated Cleft Lip
  • Genotypes Cleft Palate Cleft Palate
    Controls
  • GSTT1 250 106 250
  • Null 48 19 44 15
  • OR 1.1 0.68-1.7 OR 1.0 0.54-1.9

8
Any Maternal Smoking, GSTT1 Genotype, and Cleft
Lip Risk
  • Isolated Cleft Lip Cleft Palate
  • Genotypes Any Smoking
    Nonsmokers

9
Any Maternal Smoking, GSTT1 Genotype, and Cleft
Palate Risk
  • Isolated Cleft Palate
  • Genotypes Any Smoking
    Nonsmokers

10
Any Maternal Smoking, GSTM1 Genotype, and Cleft
Lip Risk
  • Isolated Cleft Lip Cleft Palate
  • Genotypes Any Smoking
    Nonsmokers

11
Any Maternal Smoking, GSTM1 Genotype, and Cleft
Palate Risk
  • Isolated Cleft Palate
  • Genotypes Any Smoking
    Nonsmokers

12
Summary
  • Maternal smoking during pregnancy is associated
    (OR 1.6) with isolated cleft lip ? CP and
    isolated cleft palate
  • Neither GSTM1 nor GSTT1 null polymorphisms are
    independently associated with either isolated
    cleft lip ? CP or isolated cleft palate
  • For isolated cleft lip ? CP, we found a
    gene-environment interaction between any amount
    of maternal smoking during pregnancy and GSTT1
    null genotype, with the at risk genotype doubling
    the risk associated with smoking (OR2.9)
  • No Similar interactions were observed for
    isolated cleft palate

13
NAT1 1088 1095 polymorphisms among controls
  • T1088 C1095
  • Allele frequency 0.71 0.67
  • 1088A/1088A 1095A/1095A
  • Genotype freq 9.4 11
  • D value for T1088AC1095A (pairwise LD estimate
    in controls) 0.833 plt10-4

14
NAT1 1088 1095 haplotypes
  • NAT1 1088-1095 Isolated Cleft Lip/-
  • Haplotypes Controls Cleft palate Isolated Cleft
    Palate
  • T-C 362 (64.2) 330 (58.5) 153 (67.1)
  • A-A 145 (25.7) 177 (31.4) 48 (21.1)
  • T-A 39 (6.9) 38 (6.7) 22
    (9.6)
  • A-C 18 (3.2) 19 (3.4) 5
    (2.2)
  • Haplotype frequencies estimated using
    Expectation-Maximization (EM) algorithm in the
    PyPop software

15
NAT1 1088 genotypes CA 87-89
  • 1088 Isolated
    Cleft Lip
  • Genotypes Cleft Palate Cleft Palate
    Controls
  • A/A 9 36 28 9.4
  • A/T 40 132 119
  • T/T 74 130 151
  • A/A vs. T/T OR1.5 OR0.66
  • A/A vs. A/TT/T OR1.3 OR0.76

16
NAT1 1095 genotypes CA 87-89
  • 1095 Isolated
    Cleft Lip
  • Genotypes Cleft Palate Cleft Palate
    Controls
  • A/A 11 46 31 11
  • A/C 48 123 122
  • C/C 56 114 129
  • A/A vs. C/C OR1.7 OR0.82
  • A/A vs. A/CC/C OR1.6 OR0.85

17
Any Maternal Smoking, NAT1 1088 Genotypes, and
Cleft Lip Risk
  • Isolated Cleft Lip Cleft Palate
  • Genotypes Any Smoking Nonsmokers

18
Maternal Smoking ?20 Cigs/day, NAT1 1088
Genotypes, and Cleft Lip Risk
  • Isolated Cleft Lip Cleft Palate
  • Smoking
  • Genotypes ?20 Cigs/day Nonsmokers

19
Maternal Smoking 1-19 Cigs/day, NAT1 1088
Genotypes, and Cleft Lip Risk
  • Isolated Cleft Lip Cleft Palate
  • Smoking
  • Genotypes lt20 Cigs/day Nonsmokers

20
Any maternal smoking, NAT1 1095 genotype and
cleft lip risk
  • Isolated Cleft Lip Cleft Palate
  • Genotypes Any Smoking Nonsmokers

21
Maternal Smoking ?20 Cigs/day, NAT1 1095
Genotypes, and Cleft Lip Risk
  • Isolated Cleft Lip Cleft Palate
  • Smoking
  • Genotypes ?20 Cigs/day Nonsmokers

22
Maternal Smoking 1-19 Cigs/day, NAT1 1095
Genotypes, and Cleft Lip Risk
  • Isolated Cleft Lip Cleft Palate
  • Smoking
  • Genotypes lt20 Cigs/day Nonsmokers

23
Any Maternal Smoking, NAT1 1095 Genotypes, and
Cleft Palate Risk
  • Isolated Cleft Palate
  • Genotypes Any Smoking Nonsmokers

24
NAT2 acetylator phenotypes and orofacial clefts
  • NAT2 Isolated Isolated
  • phenotype cleft lip CP cleft palate
    Controls
  • slow 136 (46) 55 (45) 149
    (52)
  • rapid 161 68 139
  • OR1.3 .90-1.8 OR1.3 .85-2.1

25
Any Maternal Smoking, Infant NAT2 Acetylator
Phenotypes, and Isolated Cleft Lip ? Cleft Palate
Risk
  • Isolated Cleft Lip ? Cleft Palate
  • Acetylator
  • Phenotypes Any Smoking Nonsmokers

26
Any Maternal Smoking, Infant NAT2 Acetylator
Phenotypes, and Cleft Palate Risk
  • Isolated Cleft Palate
  • Acetylator
  • Phenotypes Any Smoking Nonsmokers

27
Summary
  • Maternal smoking during pregnancy is associated
    (OR 1.6) with isolated cleft lip ? CP and
    isolated cleft palate
  • These risks are primarily driven by smokers
    of ? 20 cigs/day (OR 2.5)
  • Neither NAT1 1088 nor NAT1 1095 polymorphisms are
    independently associated with either isolated
    cleft lip ? CP or isolated cleft palate
  • For isolated cleft lip ? CP, we found a
    gene-environment interaction between any amount
    of maternal smoking and homozygosity for the
    uncommon variants of either NAT1 1088 or NAT1
    1095 (ORs 4)
  • No similar interaction was observed for isolated
    cleft palate

28
Summary
  • NAT2 acetylator status was not associated with
    either isolated cleft lip ? CP or isolated cleft
    palate
  • No gene-environment interaction was observed
    between maternal smoking during pregnancy and
    infant NAT2 acetylator status upon risk for
    either isolated cleft lip ? CP or isolated cleft
    palate
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