1. Genetics & Genomics in Primary Care: ? progress Nadeem Qureshi Clinical Professor in Primary Care University of Nottingham

2. Where are we now? Advances in past 2 years? – Genetic screening – Exploiting family history – Genomic potential

3. Where are we now? Advances in past 2 years? – Genetic screening continuing – Exploiting family history some extent – Genomic potential still opportunities Level of Evidence – Tier ONE – Tier TWO Khoury et al, CDC Public Health Genomics

4. Strength of Evidence for Implementation of Genetics & Genomics in Primary Care Tier 1 FDA label requires use of test to inform choice or dose of a drug Clinical practice guidelines based on systematic review supports testing Tier 2 FDA label mentions biomarkers Clinical practice guideline, not based on systematic review, supports use of test Clinical practice guideline finds insufficient evidence but does not discourage use of test Systematic review, without clinical practice guideline, supports use of test Systematic review finds insufficient evidence but does not discourage use of test Clinical practice guideline recommends dosage adjustment, but does not address testing

5. Khoury et al. Genet Med, 2007 Only ~2% publications T2+ Lack of evidence base

6. Pre-genomic era Screening Genetics in antenatal screening [Tier 1] Transferable skills

8. © 2006 University of Nottingham (on behalf of PEGASUS) Autosomal Recessive  A baby can be affected only if both parents are carriers  Carriers are more common in certain population groups but are found in any population  The risk of both parents carrying the same recessive condition is increased in consanguinous families, where the parents share one or more common ancestors – cystic fibrosis – sickle cell disorders – phenylketonuria AishaMarcus Sara Jade Wayne P

9. Pre-genomic era Family history Traditional history taking skills Integral to primary care Elicit monogenic inheritance Elicit genetic predisposition

12. Bethea et al, 2008

13. Utility of family history in Primary Care Health policy/guideline-driven risk stratification & referral criteria – Coronary Heart Disease [Tier 1 & lower] – Cancer

14. Familial hypercholesterolaemia Implementing NICE guidance 2008 NICE clinical guideline 71

15. © 2006 University of Nottingham (on behalf of PEGASUS)  Pattern –Affected people in each generation –Males and females affected in approx. equal numbers –All forms of transmission seen, including male to male transmission  Dominant: Needs only one copy of a gene pair to be altered to cause the disease Dominant inheritance

16. Simon-Broome criteria Apply to the general population and not to relatives 1 : In Adults, total cholesterol above 7.5mmol/l and LDL-C above 4.9 mmol/l. For children (< 16 years of age) 6.7 mmol/l together with an LDL-C above 4.0 mmol/l. Plus for a diagnosis of Definite FH Tendon xanthomas in patient or 1 st or 2 nd degree relative or DNA-based evidence of FH. Plus for a diagnosis of Possible FH Family history of myocardial infarction below age 50 in 2 nd degree relative, below age 60 in 1 st degree relative, or a Family history of raised cholesterol levels.

21. Shift in CHD risk resulting from intervention (systematic FHQ) Family history intervention groupEnhanced CHD risk category (including CHD FHx information) Average riskModerate riskHigh risk Standard CHD risk category Average risk217180 Moderate risk08620 High risk0049 FH practices: 18% (69) High CVD risk compared to 13% 40% increase in High CVD risk patients Qureshi et al, 2012

22. Utility of family history in Primary Care Specific: guideline-driven risk stratification & referral criteria – Coronary Heart Disease – Cancer [Tier 1 & lower]

23. Referral Guidelines for Suspected Cancer (“2 week wait”) Upper Gastrointestinal Dyspepsia combined with at least one of the following known risk factors: - Family history of Upper GI cancer in more than 2 first degree relatives - Barrett’s oesophagus - Pernicious anaemia -……..

27. Demand PULL

30. INTERVENTIONS based on family history in General Practice Familial Breast Cancer – Surveillance – Chemoprevention Familial Hypercholesterolaeamia – Lipid lowering therapy – Cascade screening

31. INTERVENTIONS based on family history in General Practice

32. Dr informed respondent of familial DM risk: Behaviour of respondents Qureshi & Kai, 2008

33. Family histories & FH instruments in General Practice Positive family histories are common Systematic FH Instruments: useful method of initial primary care genetic enquiry Lack of evidence for interventions for many positive family histories discovered…coping with uncertainty

34. 38 69 Arrythmia 68 64 Thalassemia carrier Hysterectomy 40 Committed suicide 25 40 endometriosis Heart attack 60 Old age 80 Old age 70 Cancer 60 Cancer 70 88 Arrythmia 85 old age 80 Committed suicide 20 Committed suicide 20

35. 38 Thalassemia carrier 69 Arrythmia 68 64 Thalassemia carrier Hysterectomy 40 Committed suicide 25 40 endometriosis Heart attack 60 Old age 80 Old age 70 Cancer 60 Cancer 70 88 Arrythmia 85 old age 80 Committed suicide 20 Committed suicide 20

36. 38 Thalassemia carrier 69 Arrythmia 68 64 Thalassemia carrier Hysterectomy 40 Committed suicide 25 40 endometriosis Heart attack 60 Old age 80 Old age 70 Cancer 60 Cancer 70 88 Arrythmia 85 old age 80 Committed suicide 20 Committed suicide 20

37. Genomics & Primary Care Emerging impact Family history meets genotyping Revisit monogenic disease Emerging variants Direct-to-Consumer marketing Pharmacogenomics [Tier 2]

38. Genomics & Primary Care The vision

39. Addiction paper: ROC

40. Family history meets the Genomic era Qualitative interviews: demand pull again “The reason I was interested in getting involved in it in the first place was because my dad died in 1989 … I believe it was the cardiovascular but I don’t know. He was 62, it’s young isn’t it? “ Middlemass et al, BJGP 2014

41. Family history &/or Genotyping Qualitative interviews: appreciate strength of evidence (CVD genotype –ve) “There will be a load of other genes that you don’t know about yet. … I haven’t interpreted to mean that I haven’t got any genes that are involved that might increase my cardiovascular risk you know. … I think there are probably other genes that will affect ones cholesterol metabolism and one’s blood pressure or whatever that you perhaps haven’t mapped yet? “

42. Genomics & Primary Care Emerging impact Family history meets genotyping Revisit monogenic disease Emerging variants Direct-to-Consumer marketing Pharmacogenomics [Tier 2]

45. Genomics & Primary Care Emerging impact Family history meets genotyping Revisit monogenic disease Emerging variants Direct-to-Consumer marketing Pharmacogenomics [Tier 2]

48. Genomics & Primary Care Emerging impact Family history meets genotyping Revisit monogenic disease Emerging variants Direct-to-Consumer marketing Pharmacogenomics [Tier 2]

50. Genomics & Primary Care Emerging impact Family history meets genotyping Revisit monogenic disease Emerging variants Direct-to-Consumer marketing Pharmacogenomics [Tier 2]

52. The FUTURE: the Genomic era Impact of 100,000 Genome England project Cancer: ongoing support & keep family history up- to-date Rare diseases: supporting consanguineous marriages Infectious disease: ?? therapeutics

53. The FUTURE: the Genomic era Make sure not increase inequality: Role for Public Health

54. Thank you

55. Birmingham Hospital Haematology Department SurnameForenameSexDOB Registration No KhanClaireF01.01.82 1000000000 LocationConsultant Lab No/Spec No Haematology deptConsultant not known H,05.0033730.B WBC7.1 x 109/1(4.0-15.0) Hb13.3g/dl(10.0-16.0) MCV*65.0fl(79.0-98.0) MCH*22.0 pg(27.0-33.0)

56. Birmingham Hospital Haematology Department SurnameForenameSexDOB Registration No KhanClaireF01.01.82 1000000000 LocationConsultant Lab No/Spec No Haematology deptConsultant not known H,05.0033730.B WBC7.1 x 109/1(4.0-15.0) Hb13.3g/dl(10.0-16.0) MCV*65.0fl(79.0-98.0) MCH*22.0 pg(27.0-33.0)

57. Birmingham Hospital Haematology Department SurnameForenameSexDOB Registration No KhanClaireF01.01.82 1000000000 LocationConsultant Lab No/Spec No Haematology deptConsultant not known H,05.0033730.B WBC7.1 x 109/1(4.0-15.0) Hb13.3g/dl(10.0-16.0) MCV*65.0fl(79.0-98.0) MCH*22.0 pg(27.0-33.0) Ferritin = (normal value) SICKLE CELL AND THALASSAEMIA SCREEN HPLC HbA PEAK82.1 % Hb A2*5.85 %(2.0-3.5) HPLC: BETA THALASSAMETA CARRIER. NO EVIDENCE OF COMMON Hb-VARIANTS, S,C,D,E,O OR Lepore.