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Genomics' prez 1

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Consanguinity >>> susceptibility to infectious diseases

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Genomics' prez 1

  1. 1. ConsanguinityAdvanced Topics in Genomics 6-10-2011Prof. Moein Kanaan Amer Wazwaz
  2. 2. Consanguinity is a term, derived from two Latin words con " meanscommon , orof the same and "sanguineus " meansblood"Hence, referring to a relationship between two people who share acommon ancestor or blood In genetics,a consanguineous marriage means union between coupleswho are related as second cousins or closer Alwan A, Modell BEndogamy is the marriage within a specific group or class with in the[same population [isolated populations, small towns, villages or tribes
  3. 3. IntroductionLittle quantitative information on consanguinity is available fromregions of high predisposition to consanguineous marriagesDifferent religious and cultural opinions and subsequentlylegislatives, most of them prohibit or even ban consanguineousmarriages; especially first-cousin marriagesof the global population are related as second cousins or 10.4% closerMortality in first-cousin progeny is ~3.5% higher than that innon-consanguineous offspringAlthough the overall prevalence of consanguineous marriageseems to be declining, in some countries the present rates ofconsanguinity exceed those of the preceding generations likeQatar, Yemen, and UAE Tadmouri G.O et al
  4. 4. The Current Global Prevalence of Consanguineous Marriage Consanguinity rates vary from one population to another depending on religion, culture and geographyGlobal distribution of marriages between couples related as second cousins or closer
  5. 5. Consanguinity Rates in Arab Populations 1C< Double first-cousin marriage 1C First-cousin marriageSource: Tadmouri G.O et al, Reproductive Health .2009
  6. 6. Consanguinity Extent and Complexity Influences and outcomes of consanguineous marriages
  7. 7. Contrasting biological and social outcomesof consanguineous marriage in traditional rural and modern urban settings Consanguineous marriages are generally thought to be more stable than marriages between non-relatives Societies with high consanguinity rates have to understand and prevent the deleterious impact of .consanguinity on health Guidelines for health care providers to assist them in counseling for consanguinity
  8. 8. Population StratificationPopulation stratification has critical importance in studyingconsanguinity-associated morbidity and mortalityGreater importance in larger populations with more diversegenetic originsPopulation substructure often results in variant marker allele frequencies in different subpopulationsIn most populations theclan or its hereditary equivalentmay be the most logical unit for genetic screening
  9. 9. Influence of Consanguinity on Complex DiseasesConsanguinity expected to exert a greater influence on the complex diseases ifrare autosomal recessive alleleswere causally implicated, Whether in commondisease/common variant or common disease /rarevariantWhile if the involved disease alleles are common in thegene pool, then intra-familial marriage would have arelatively lesser effectDifferent impacts on adulthood complex diseases &congenital defects For example:+ve for Schizophrenia and Alzheimer for Breast Cancer and Hypertensionve-
  10. 10. Dalmatian islands study indicated a positive associationbetween inbreeding and a wide range of adulthood disordersUbiquitous involvement of rare autosomal recessive genes inadult-onset complex diseases. As an increasing in thegenomewide heterozygosity after a decline in consanguineousmarriage, lead to a widespread reduction in the burden ofcomplex diseases Pakistani community in the United Kingdom studyexaminedthe influence of first-cousin marriage on autosomal recessive single-gene disordersA 7/1,000 increase in autosomal recessive disorders per 0.01.increase in the mean coefficient of inbreedingIn the Pakistan national population, where 50% of marriageswere between first cousins. Some 22/1,000 extra single-genedisorders would be expected
  11. 11. Comparative mortality in first cousin versus non- consanguineous progeny in 69 study populations mean excess mortality at first-cousin level of 3.5%1C first cousin NC non-consanguineous
  12. 12. Consanguinity and Susceptibility to Infectious Diseases in Humans At least in Animal Populations Low genetic heterozygosity is a risk factor for infection by a diverse range of pathogens In This Study Microsatellite genome screen data fortuberculosis ,hepatitis and leprosy, used to test the hypothesis that inbreeding depression increases risk of infection
  13. 13. IntroductionStudies link between genetic diversity and diseasesusceptibility are increasingTwo mechanisms may be responsible for maintenance ofpathogens in a population inbreeding depression andbalancing selectionIt remains unclear if these animal studies have anyrelevance to human Consanguinity has been implicated in susceptibility to a number of human diseases includingheart disease,multiple sclerosis ,depression andasthma
  14. 14. In This First Study of its Kind in HumansThey used microsatellite genome screen linkage data for three infectious diseases in contrasting populations ,tuberculosis inGambia hepatitis B both inGambia andItaly and leprosy inIndiaTo determine the extent of genomewide heterozygosity asan important predictor of susceptibility to some diseases Particularly in populations where inbreeding is common
  15. 15. ResultsStrong association between consanguinity and humansusceptibility to both TB and hepatitis B in West AfricansNo significant association for hepatitis B in the Italians,probably due to the low levels of consanguinityNo significant association in the leprosy dataset in Indians,where the heterozygosity–heterozygosity correlationsindicate similar levels of inbreeding in both cases andcontrols
  16. 16. ResultsIn two of three examples where a population has highlevels of consanguineous marriages, affected individualsreveal significant evidence of inbreeding compared withunaffected controlsLeprosy in India is an exception, as it thought to bestrongly associated with two major effect loci/oligogenicityTherefore, may be that persistent, strong inbreeding inthe Indian populations has led to genetic purging
  17. 17. Correlations in heterozygosity among markers for affected and unaffected individuals A the entire dataset R affected family stronger impact of consanguinity on hepatitis than on TB unaffected individuals yielded a higher correlation than for affected individuals,** p>0.0009of consanguinity in each population is in brackets, * p>0.05 %
  18. 18. Relationship between the strength of the heterozygosity and the proportion of inbred individuals second cousins first cousins equal mixture of the two first-cousin marriages appear necessary in order to account for the values observed in Gambia
  19. 19. ConclusionConsanguinity ManagementSocial awareness of consanguinity risks Populations genetic screening Counseling the youth Warning who at risk

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