Association of a nicotine receptor polymorphism with reduced ability to quit smoking in pregnancy

Transcription

1 Research Symposium, MRC CAiTE & Department of Social Medicine, University of Bristol, 3 rd March Association of a nicotine receptor polymorphism with reduced ability to quit smoking in pregnancy Rachel Freathy (rachel.freathy@pms.ac.uk)

2 Cnattingius (2004) Nicotine Tob Res; Bolling et al. (2007) The Information Centre Despite a strong public health message, many women continue to smoke in pregnancy Year 2000 prevalence: 12% (USA), 13% (Sweden), 20% (UK)

3 Genes may be important in determining which women quit Between 20% and 40% of female smokers quit during pregnancy Probability of quitting may be influenced by: Age SEP Partner smoking Parity Genes Cnattingius (2004) Nicotine Tob Res Up to 70% of the variance in nicotine dependence is due to genetic factors High concordance between the smoking behaviour of adoptees and their biological full siblings Lerman & Berrettini (2003) Am J Med Genet B Neuropsychiatr Genet; Osler et al. (2001) Genet Epidemiol

4 A genome-wide association study identified a common variant that predisposes smokers to smoke more N = Icelandic smokers SNP in nicotinic acetylcholine receptor gene, CHRNA3. Nearby genes: CHRNA5, CHRNB4 Thorgeirsson et al Nature

5 Thorgeirsson et al Nature A genome-wide association study identified a common variant that predisposes smokers to smoke more Frequency of the CHRNA3 risk allele P=5x10-7 P=5x10-16 P = 4x10-6 P = 2x10-8 P = 7x10-6 P = 0.04 TT AT % AA Never smoked 1-10 cigs per day cigs per day cigs per day cigs per day

6 Thorgeirsson et al Nature The genetic variant is not associated with smoking initiation Frequency of the CHRNA3 risk allele % P=0.60 P = 4x10-6 P = 2x10-8 P = 7x10-6 P = 0.04 TT AT AA Never smoked All smokers

7 Hypothesis: Some people will find it harder to give up smoking than others because of their genetics Genetic variant Heavier smoking Harder to quit Pregnancy is a time of high pressure to quit We aimed to test the hypothesis that: CHRNA3 risk allele less likely to quit smoking in pregnancy

8 Methods: study subjects were pregnant mothers from the South-West ALSPAC: N= women EFSOCH: N= women smoked regularly just before pregnancy First trimester 28% had stopped smoking 72% still smoked regularly Third trimester 43% had stopped smoking 57% still smoked regularly

9 Results: The risk allele was associated with higher odds of continued smoking in pregnancy Percentage of women who continued to smoke in the first trimester 80 P = % R = risk allele N = non-risk allele 50 NN NR RR Freathy et al. submitted

10 Results: The risk allele was associated with higher odds of continued smoking in pregnancy Percentage of women who continued to smoke in the third trimester 80 P = % R = risk allele N = non-risk allele 50 NN NR RR Freathy et al. submitted

11 Results: The risk allele was associated with heavier smoking before pregnancy and in the first trimester Frequency of the risk allele P = 1x10-5 P = P = % Cigs per day: Pre-pregnancy First trimester N=2379 N=1741 No difference between smokers and non-smokers: OR = 1.02 [95%CI: ]; P=0.57 Third trimester N=1361 Freathy et al. submitted

12 Results: Adjustment for pre-pregnancy smoking weakened, but did not remove the association Odds ratio for continued smoking vs quitting Unadjusted OR (95%CI) P value 1.27 (1.11, 1.45) (1.12, 1.44) Freathy et al. submitted

13 Results: Adjustment for pre-pregnancy smoking weakened, but did not remove the association Odds ratio for continued smoking vs quitting Unadjusted Adjusted for pre-pregnancy smoking quantity OR (95%CI) P value OR (95%CI) P value 1.27 (1.11, 1.45) (1.03, 1.39) (1.12, 1.44) (1.05, 1.39) Smoking quantity Genetic variant Smoking cessation Freathy et al. submitted

14 Results: The risk allele was not associated with environmental factors that may influence smoking cessation in pregnancy Potential confounder Association with continuing to smoke Odds ratio (95%CI) P value Age 0.98 (0.96, 1.00) Occupation 1.38 (1.08, 1.76) Education level 0.73 (0.68, 0.79) Age started smoking 0.66 (0.59, 0.75) Partner smoking 1.80 (1.49, 2.18) Freathy et al. submitted

15 Results: The risk allele was not associated with environmental factors that may influence smoking cessation in pregnancy Potential confounder Association with continuing to smoke Odds ratio (95%CI) P value P value for association with genetic variant Age 0.98 (0.96, 1.00) Occupation 1.38 (1.08, 1.76) Education level 0.73 (0.68, 0.79) Age started smoking 0.66 (0.59, 0.75) Partner smoking 1.80 (1.49, 2.18) Freathy et al. submitted

16 Birth weight adjusted for sex and gestation We hypothesized that the risk allele would be associated with reduced birth weight in smoking mums 48g lower birth weight per 10 extra cigarettes/day in 1 st trimester Smoking quantity Birth weight CHRNA3 allele = 0.8 cigs/day CHRNA3 variant? Expected effect of CHRNA3 variant on birth weight = 4g (95%CI: 1-6g) lower per allele

17 Birth weight adjusted for sex and gestation Results: There was a trend to reduced birth weight for smoking mums with the risk allele, as expected 48g lower birth weight per 10 extra cigarettes/day in 1 st trimester Smoking quantity Birth weight CHRNA3 allele = 0.8 cigs/day CHRNA3 variant? Observed effect of CHRNA3 variant on birth weight = 28g (95%CI: 2-59g) lower per allele N=1829 mums; P=0.07 P = 0.86 in non-smoking mums

18 Results: Larger numbers of mothers and babies will be needed to confirm association with birth weight Instrumental variables analysis: F=9.46 Ordinary regression: 48g lower BW per 10 extra cigarettes smoked in 1 st trimester Using CHRNA3 as IV: 318g lower BW (95%CI: -118 to 753g) per 10 cigs in 1 st trimester

19 Summary Each copy of the CHRNA3 risk allele is associated with higher odds of continued smoking in pregnancy OR = 1.27 (95%CI: ) We replicated the association with smoking quantity pre-pregnancy and in the first trimester Adjustment for pre-pregnancy smoking weakened, but did not remove the association with quitting Birth weight association consistent with expected, but bigger numbers required for secondary outcomes

20 Could genotype inform intervention strategy? Application to other situations: after diagnosis of CHD, Crohn s etc

21 Acknowledgements Exeter Team: Bev Shields Bea Knight Michael Weedon Tim Frayling Andrew Hattersley Bristol Team: Sue Ring Bruna Galobardes George Davey Smith Avon Longitudinal Study of Parents and Children (ALSPAC) Exeter Family Study of Childhood Health (EFSOCH) All study subjects and healthcare professionals who contributed to the studies

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23 ALSPAC mums: smoking SNP-BMI association by ever-smoking status (N=6161) 23.5 BMI NN NR Genotype N=non-risk allele R=risk allele L-R test P value for deviation from additive model = RR S2 S1 Ever-smoker Numbers in each group NN NR RR Yes No