Craniofacial anomalies

Julian LittleCanada Research Chair in Human Genome EpidemiologyDepartment of Epidemiology & Community MedicineUniversity of Ottawa

HuGENet NETWORK OF NETWORKS WORKSHOP

October 2005

Origins

• WHO Human Genetics Programme, 2000

• Financial support from NIDCR (US)

• Five-year project designed to take forward international strategy on craniofacial anomalies

Objectives of WHO project

• to develop an international network for consensus building, planning and development for international collaborative biomedical, epidemiological and behavioural studies in the core areas of craniofacial anomalies research

• to create a directory of research resources in craniofacial anomalies.

• to create the International Database on Craniofacial Anomalies (CFA)

Core areas

• genetic basis of CFA

• gene-environment interactions involved in CFA

• prevention of CFA

• optimal treatment of CFA

Consensus meetings

• Nov 2000 – concurrent workshops on (1) genetic basis (2) g-e interaction (3) treatment

• May 2001 – prevention

• Dec 2001 – global registry

20032002

Consensus meetings

• Nov 2000 – concurrent workshops on (1) genetic basis (2) g-e interaction (3) treatment

• May 2001 – prevention

• Dec 2001 – global registry

• Dec 2004 – progress and future strategies________

Reported investigations on gene-environment interaction in aetiology of oral clefts

Maternal exposure Smoking Vitamin Alcohol Occup

exp Medication

Variants of

Supps A Folate/FA

TGFα 8 2 1 2 TGFβ3 4 2 MSX1 3 2 BCL3 1 CYP1A1 1 EPHX1 1 GSTM1 1 1 GSTT1 1 1 NAT1 1 1 1 NAT2 2 1 1 RARA 1 1 MTHFR 2 2 RFC 1

Gene-environment interaction and oral clefts: data and sample collections

Area, period (ref)

Design Genotyping of

CL(P) n≤

CP n≤

Variants reported

Maternal exposures reported

Denmark, 1991-4 (Christensen et al., 1999; Mitchell et al., 2001, 2003)

Case- control

Infant 233 83 TGFα TGFβ3 MSX1 RARA

Smoking Alcohol Vitamins Liver

Netherlands, 1997-2000 (van Rooij et al., 2001, 2002, 2003)

Case- control

Infant & maternal

146 n.s. CYP1A1 GSTT1 NAT2 MTHFR

Smoking Medications FA Folate

Norway, 1996-8 (Jugessur et al., 2003a,b)

Case- parent trio

Infant, maternal, paternal

173 88 TGFα MTHFR

Smoking Alcohol Vitamins FA

USA, California, 1987-9 (Shaw et al., 1996, 1998a,b, 1999, 2003a, b; Lammer et al., 2004a,b ; Hartsfield et al., 2001)

Case- control

Infant 447 215 TGFα EPHX1 GSTM1 GSTT1 NAT1/2 MHFR RFC

Smoking (& P) Vitamins 13 occupational Chemical groups

USA, Iowa, 1987-94 (Romitti et al., 1999)

Case- control

Infant 154 60 TGFα TGFβ3 MSX1

Smoking Alcohol

USA, Maryland, 1984-92 (Hwang et al., 1995; Beaty et al., 1997, 2002; Maestri et al., 1997)

Case- control & trio

Infant, maternal, paternal

186 83 TGFα TGFβ3 MSX1 BCL1

Smoking

Identifying teams

• List developed from WHO reports and literature searches• Asked those who attended WHO meetings (1) about concept (2) to review list

and extend if possible• Contact additional teams identified

Teams1.with established data and sample collections

2.with ongoing data and sample collections

3.planning to establish data and sample collections

WHO region Established Ongoing Planned

Multicountry in >1 region

2 (trios and other familial)

3 (trios and other familial)

-

AFR - - 1

AMR 8 (cc & trio) 1 multicountry; 1 multistate; 1

2

EMR - - 1

EUR 1 multicountry (trio);

9 (cc & trio)

1 cohort

SEAR 4 (cc & trio) - 3

Numbers of teams

WHO region

Established Ongoing Planned

>1 ? + > 2000 trios 3 (trios and other familial)

-

AFR - - (1)

AMR 1343 cc (5); 324 trios (3); >7000 samples (1)

1 multicountry; 1 multistate 2100cc but

bio samp from 600 only;

(2)

EMR - - (1)

EUR multicountry 1169 trios; 1227 cc (9); 651 trios (4)

1 cohort

SEAR 259 cc (3) & 213 trios (2) - (3)

N of cases from cc studies; trios; samples; (studies)………

Co-ordination

• Ottawa• Dundee (Peter Mossey)• Iowa (Jeff Murray)

Funding

Other issues

• Different designs• Samples

– Governance– Further analyses possible?

• Outside country?

• Elsewhere within country?

• Only in own centre?