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V ITAMIN B12 STATUS IN PREGNANCY AND CHILD S IQ AT AGE 8: A M ENDELIAN RANDOMIZATION STUDY IN ALSPAC EUCCONET International Workshop Bristol, October 18-19,

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Presentation on theme: "V ITAMIN B12 STATUS IN PREGNANCY AND CHILD S IQ AT AGE 8: A M ENDELIAN RANDOMIZATION STUDY IN ALSPAC EUCCONET International Workshop Bristol, October 18-19,"— Presentation transcript:

1 V ITAMIN B12 STATUS IN PREGNANCY AND CHILD S IQ AT AGE 8: A M ENDELIAN RANDOMIZATION STUDY IN ALSPAC EUCCONET International Workshop Bristol, October 18-19, 2011 Carolina Bonilla School of Social and Community Medicine

2 V ITAMIN B12 FACTS Only synthesised by microorganisms Main sources: fish, shellfish, eggs, meat, dairy products Recommended Daily Amount: 2-3 ug/day Dietary deficiency rare (vegans at risk) B12 deficiency: <150 pmol/l Main functions: red blood cell formation, DNA synthesis, maintenance of healthy nervous system Transport: 80% bound to transcobalamin I (HC) 20% bound to transcobalamin II (holoTC). holoTC delivers B12 to cells. Stored in the liver

3 indicators of B12 deficiency modified from Nexo and Hoffmann-Lucke (2011) Birth defects Spontaneous abortion Pre-eclampsia Prematurity Low birth weight Cardiovascular disease Cognitive deficit Dementia

4 V ITAMIN B12 STATUS DURING PREGNANCY AND COGNITION IN CHILDREN Lower cognition tests scores among offspring of mothers with deficient intake of B12 (Mexico; del Rio Garcia et al., 2009) Children of mothers with low B12 levels performed worse in sustained-attention and working memory tests (India; Bhate et al., 2008) No association of maternal B12 levels with cognitive performance in children. Although verbal ability scores were higher in children of mothers with low B12 (India; Veena et al., 2010) Problem: residual confounding?

5 M ENDELIAN R ANDOMIZATION Mendelian Randomization uses genetic variants to make causal inferences about (modifiable) environmental risk factors for disease related outcomes

6 M ENDELIAN R ANDOMIZATION Assumptions genotype associated with exposure of interest genotype not associated with confounders no direct effect of the genotype on outcome, only through exposure Advantages not affected by confounding not affected by reverse causation Bochud and Roussod (2010)

7 I NSTRUMENTAL VARIABLES rs (A68A) FUT2 GWAS Hazra et al. (2008) Tanaka et al. (2009) rs (P259R) rs (I23V) TCN2 candidate gene studie s

8 P ROJECT FRAMEWORK

9 ALSPAC (A VON L ONGITUDINAL S TUDY OF P ARENTS AND C HILDREN ) Population-based prospective study conducted in Bristol, England, to evaluate factors that affect health and development of children ~ 14,000 pregnant women enrolled between April 1991 and December 1992 Information on mother and child collected at regular intervals and ongoing DNA samples available for mothers and children (~10000 each, ~7000 duos) IQ scores available for 6259 children aged 8 y.o. Maternal dietary intake: FFQ Cord blood vitamin B12 levels available for 331 children

10 Main outcome: full scale IQ at age 8 years: WISC-III (Wechsler, Golombok and Rust, 1992), age-adjusted mean (SD): (16.4) Exposures: maternal dietary intake during pregnancy (ug/day) cord blood vitamin B12 levels (pmol/l)

11 P OTENTIAL CONFOUNDERS / MEDIATORS Age Education Social class Parity Any infection during pregnancy Ever smoked Alcohol consumption (before and during pregnancy) Folate supplementation in pregnancy Sex Age Gestation Birth weight Breastfeeding duration Mother Child

12 A SSOCIATION WITH COVARIABLES IQ: associated with 12/14 covariables (p<0.01), except for gestation and sex Maternal dietary intake: associated with 10/14 covariables (p<0.01), except for having an infection in pregnancy, smoking, gestation and sex Maternal FUT2 genotype: associated with having an infection in pregnancy (p=0.03) Maternal TCN2 rs genotype: no associations Maternal TCN2 rs genotype: associated with parity (p=0.01) Offspring FUT2 genotype: associated with parity (p=0.01), alcohol intake before (p=0.02) and during pregnancy (p=0.03) Offspring TCN2 genotypes: no associations

13 O BSERVATIONAL S TUDY Model 1: Adjusted for offspring sex and age at time of IQ assessment, and maternal energy intake. Model 2: Model 1 + maternal education, social class, age at delivery, parity, any infection in pregnancy, ever smoked, alcohol consumption before and during pregnancy, folate supplementation. Model 3: Model 2 + gestational length and birth weight. N = 5004 mean difference in child IQ per doubling of maternal vitamin B12 intake 95% CIp-value Model , 2.76< Model , Model ,

14 M ATERNAL SNP S VS DIETARY INTAKE AND CORD BLOOD B12 SNPgenotypeN median (IQR) of maternal vitamin B12 dietary intake ( μ g/day) N median (IQR) of vitamin B12 cord blood (pmol/L) FUT2 rs TT (3.0, 6.1)62291 (183, 397) TC (3.1, 6.1) (196, 424) CC (3.0, 6.2)50294 (214, 534) ratio of geometric means per C allele (95% CI) (0.98, 1.02) (0.97, 1.19) p-value TCN2 rs GG (3.0, 5.9)41276 (173, 369) CG (3.1, 6.2) (196, 479) CC (3.1, 6.1)68318 (226, 436) ratio of geometric means per C allele (95% CI) (0.99, 1.02) ( ) p-value TCN2 rs AA (3.2, 6.2) (205, 397) AG (3.1, 6.1)58298 (206, 484) GG (3.0, 6.2)2238 (82, 394) ratio of geometric means per G allele (95% CI) (0.97, 1.01) (0.89, 1.18) p-value

15 M ATERNAL SNP S VS OFFSPRING IQ SNPgenotypeN IQ mean (SD) FUT2 rs TT (16.8) TC (16.1) CC (16.7) mean difference in child IQ per C allele (95% CI) (0.14, 1.58) p-value0.02 TCN2 rs GG (16.6) CG (16.0) CC (17.0) mean difference in child IQ per C allele (95% CI) (-0.38, 1.08) p-value0.35 TCN2 rs AA (16.0) AG (17.0) GG (14.5) mean difference in child IQ per G allele (95% CI) (-0.39, 1.58) p-value0.24

16 M ATERNAL SNP S VS OFFSPRING IQ - ADJUSTED SNPunadjusted adjusted for childs genotype adjusted for childs genotype and AIMs FUT2 rs mean difference in child IQ per C allele (95% CI) 0.77 (-0.14, 1.68) 1.04 (-0.02, 2.09) 1.04 (-0.02, 2.09) p-value TCN2 rs mean difference in child IQ per C allele (95% CI) 0.52 (-0.42, 1.45) 0.36 (-0.72, 1.45) 0.34 (-0.74, 1.43) p-value TCN2 rs mean difference in child IQ per G allele (95% CI) 0.69 (-0.71, 2.09) 1.09 (-0.52, 2.71) 1.08 (-0.53, 2.69) p-value

17 M ATERNAL SNP S VS OFFSPRING IQ BY RDA SNPgenotypeN< RDAN RDA p-value for interaction mean IQ (SD) FUT2 rs TT (17.2) (16.7)0.12 TC (15.1) (16.1) CC (17.9) (16.3) mean difference in child IQ per C allele (95% CI) (-0.93, 3.04) (0.15, 1.72) p-value TCN2 rs GG (17.2) (16.5)0.52 CG (15.9) (15.9) CC (17.2) (16.8) mean difference in child IQ per C allele (95% CI) (-2.46, 1.57) (-0.24, 1.37) p-value TCN2 rs AA (16.5) (15.9)0.69 AG (16.9) (17.0) GG (9.2) (15.3) mean difference in child IQ per G allele (95% CI) (-2.02, 3.45) (-0.47, 1.68) p-value

18 L IMITATIONS Dietary intake measurements do not account for bioavailability No maternal B12 levels available Small group of children with measured B12 concentration SNPs explain a small proportion of trait variance (<5%) Replication in an Australian birth cohort did not confirm these results (awaiting meta-analysis)

19 C ONCLUSIONS Observational association of maternal B12 dietary intake and offspring IQ attenuated markedly with adjustment for confounding factors There was some evidence of association between maternal genotypes and cord blood B12 levels (although power is low) Maternal FUT2 genotype was associated with offspring IQ No statistical evidence of association found between maternal TCN2 SNPs and offspring IQ B12 levels during pregnancy may not have an important causal effect on offsprings cognitive ability However, larger Mendelian randomization studies are needed to further explore this issue.

20 A CKNOWLEDGEMENTS BristolOxford Sarah LewisDavid Smith Debbie LawlorHelga Refsum Andy Ness Yoav Ben-Shlomo Australia David GunnellMarie-Jo Brion George Davey SmithCraig Pennell Amy Taylor Raine team and participants Pauline Emmett Nic Timpson Beate St. Pourcain Kate Northstone Phil Lobb & Sue Ring ALSPAC team and participants

21 O FFSPRING SNP S VS CORD BLOOD VITAMIN B 12 SNPgenotypeN median (IQR) of vitamin B12 cord blood (pmol/L) FUT2 rs TT64224 (168, 318) TC (207, 399) CC79368 (239, 503) ratio of geometric means per C allele (95% CI) (1.13, 1.35) p-value1.79x10 -6 TCN2 rs GG53284 (197, 423) CG (193, 417) CC91287 (207, 393) ratio of geometric means per C allele (95% CI) ( ) p-value0.96 TCN2 rs AA (204, 420) AG59273 (196, 394) GG6223 (108, 227) ratio of geometric means per G allele (95% CI) (0.78, 1.01) p-value0.06


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