疾病的多基因遺傳

1、06疾病的多基因遺傳,Polygenic Inheritance,疾病的多基因遺傳,前言數(shù)量性狀的多基因遺傳多基因病的遺傳,前言,微效基因（minor gene） 人類的一些遺傳性狀或某些遺傳病的遺傳基礎(chǔ)不是一對主基因，而是幾對基因，每一對基因?qū)z傳性狀或遺傳病形成的作用是微小的。,,多基因遺傳（polygenic inheritance） 性狀

2、或疾病的遺傳方式取決于兩個以上微效基因的累加作用，還受環(huán)境因子的影響，因此這類性狀也稱為復(fù)雜性狀或復(fù)雜疾?。╟omplex disease）。,The multifactorial model is (1) Several, but not an unlimited number, loci are involved in the expression of the trait. (2) There is no dominanc

3、e or recessivity at each of these loci. (3) The loci act in concert in an additive fashion, each adding or detracting a small amount from the phenotype. (4) The environment interacts with the genotype to produce the

4、final phenotype.,,多基因遺傳受環(huán)境因子的影響,,,常見的多基因疾病近視高血壓糖尿病精神分裂癥哮喘,數(shù)量性狀的多基因遺傳,質(zhì)量性狀（qualitative character）,,數(shù)量性狀（quantitative character）,,,數(shù)量性狀的遺傳規(guī)規(guī)律,,數(shù)量性狀的遺傳規(guī)律,多基因病的遺傳,易患性（liability） 在多基因遺傳病發(fā)生中，遺傳因素和環(huán)境因素共

5、同作用決定一個個體患某種遺傳病的可能性稱為易患性。,,易感性（susceptibility） 易感性特指由遺傳因素決定的患病風(fēng)險，僅代表個體所含有的遺傳因素；但在一定的環(huán)境條件下，易感性高低可代表易患性高低。,,發(fā)病閾值 （threshold） 當(dāng)一個個體易患性高到一定限度就可能發(fā)病。這種由易患性所導(dǎo)致的多基因遺傳病發(fā)病最低限度稱為發(fā)病閾值。,,群體易患性變異分布圖,,正態(tài)分布曲線中?與?關(guān)系

6、,,,,易患性的平均值和閾值距離與患病率關(guān)系,遺傳度及其估算,遺傳度（heritability） 多基因累加效應(yīng)對疾病易患性變異的貢獻大小。遺傳度愈大，表明遺傳因素對病因的貢獻愈大。,,疾病 遺傳度精神分裂癥 80%哮喘 80%唇裂±腭裂

7、 76%,,,唇裂 遺傳度76%,,,精神分裂癥遺傳度 80%,遺傳度的估算,Falconer公式,,,Xg－一般群體易患性平均值與閾值之間的標(biāo)準(zhǔn)差數(shù)Xc－對照組親屬中的易患性平均值與閾值之間的標(biāo)準(zhǔn)差數(shù)Xr－先證者親屬易患性平均值與閾值之間的標(biāo)準(zhǔn)差數(shù)ag－一般群體易患性平均值與一般群體中患者易患性平均值之間的標(biāo)準(zhǔn)差數(shù)r－－親屬系數(shù)ar－先證者親屬易患性平均值與先證者親屬中患者易患性平均值之間的標(biāo)

8、準(zhǔn)差數(shù)qg－一般群體發(fā)病率qc－對照親屬發(fā)病率，Pc－1- qcqr－先證者親屬發(fā)病率,例題1,先天性房間隔缺損在一般群體中的患病率為0.1％，在100個先證者的家系中調(diào)查，先證者的一級親屬共有 669人(雙親200人，同胞279人，子女190人)，其中有22人發(fā)病。,,先證者一級親屬的患病率22／669×100％＝3.3％查Falconer表，按群體患病率查得Xg和ag，再根據(jù)親屬患病率查得Xr，然后代入公式求出b值

9、。q%=0.1 X=3.090 a=3.367 q%=3.3% X=1.838 b=( 3.090-1.838)/3.367=0.37 r=0.5 ＝0.37/0.5=74%,例題2,江蘇啟東調(diào)查結(jié)果：肝癌一級親屬6591人，359人發(fā)病，q=5.45%，對照組5227名一級親屬，54人發(fā)病，q=1.03%。,,q=5.45%， X=1.603 q=1.03%，X=2.315 a=

10、2.655P=1-q=1－0.0103=0.987 b=0.2654 h2=b/r=0.2654/0.5=0.53=53%,Holzinger公式,Holzinger公式CMZ－一卵雙生子的同病率CDZ－二卵雙生子的同病率,,例題,對躁狂抑郁性精神病的調(diào)查表明，在15對單卵雙生子中，共同患病的有10對；在40對雙卵雙生子中，共同患病的有2對。依此來計算單卵雙生子的同病率為67％，雙卵雙

11、生子的同病率為5％。代入上式：,,,影響多基因遺傳病再發(fā)風(fēng)險估計的因素,患病率與親屬級別有關(guān),,例如：無腦畸形和脊柱裂的患病率為0.38％，在圖中橫軸上查出0.38之點，作一垂直線與縱軸平，已知此病的遺傳度為60％，從圖中找出遺傳度60％的斜線，把它和0.38的垂直線相交點作一橫線在縱軸上的一點近于4，即表明該病的一級親屬患病率接近4％。,影響多基因遺傳病再發(fā)風(fēng)險估計的因素,患者親屬再發(fā)風(fēng)險與親屬中受累人數(shù)有關(guān) 患者親屬再發(fā)風(fēng)險與患

12、者畸形或疾病嚴(yán)重程度關(guān),影響多基因遺傳病再發(fā)風(fēng)險估計的因素,多基因遺傳病的群體患病率存在性別差異時，親屬再發(fā)風(fēng)險與性別有關(guān),,群體患病率較低即閾值較高的那種性別罹患，則患者親屬的發(fā)病風(fēng)險較高。 例如人群中男性先天性幽門狹窄的患病率高于女性，男性患病率為0.5％，女性患病率為0.1％，男性的患病率比女性高5倍，即男性發(fā)病閾值低于女性。男性患者的兒子患病率是5.5％，女兒的患病率2.4％。如為女性患者，其兒子的患病率達到19.4％

13、，女兒的患病率達到7.3％。表明女性患者比男性患者帶有更多的致病基因。,(1) Recurrence risk increases with the number of affected children in a family. (2) Recurrence risk increases with severity of the defect. A more severely affected parent is more lik

14、ely to produce an affected child. (3) Consanguinity slightly increases the risk for an affected child. (4) If the two sexes have a different probability of being affected, the least likely sex, if affected, is the m

15、ost likely sex to produce an affected offspring.,Risk,1. schizophrenia , SP,Schizophrenia is a humorous brain disorder characterized by delusional thinking and unique but unpopular perceptions. Schizophrenia affect

16、s 1% of the world population.,Netherlandish painter: van gogh,,German musician :Robert Alexander Schumann,,,Mental health professionals normally diagnose this illness if, during any one-month period of a person’s life, t

17、hat person has suffered two or more of the following: Delusions Hallucinations Disorganized speech Grossly disorganized or catatonic behavior Negative symptoms,,Negative sympto

18、ms are the most insidious behavioral effects of schizophrenia. They can include low levels of: Interest Motivation Emotional arousal Mental activity Social drive

19、 Speech,,Schizophrenia is equally represented in women and men. The onset of the illness generally occurs at a later age in women than in men (between ages 23 and 35 in women versus 18 to 25 for men). Not only do women

20、generally present with schizophrenia at later ages, but the phenomenon of late onset schizophrenia (40+ years) is almost entirely a female one.,,Subtypes of SchizophreniaDisorganized Type Catatonic Type Paranoid Type

21、 Undifferentiated Type Residual Type ( waiting for psychiatry),,Causes of schizophrenia The cause of schizophrenia is unknown. Many mental health professionals believe there are factors which increase an ind

22、ividual’s risk of having schizophrenia.,,For example, first-degree biological relatives of persons with schizophrenia have a ten times greater risk of developing the illness than members of the general population.,,Becau

23、se there is no cure for schizophrenia, the goal of treatment is to eliminate or reduce symptoms, minimize side effects, prevent relapse, and socially and occupationally rehabilitate the patient.,,mental health profession

24、als generally begin advising their patients of the schizophrenic likelihood of suicide.,Related genes——DRD genes,DRD3 gene dopamine receptor D3, located on 3q13.3normal function of the DRD3 gene The DRD3 gene p

25、rovides instructions for making a protein called dopamine receptor D3, which is found in the brain. This protein responds to the chemical messenger (neurotransmitter) dopamine to trigger signals within the nervous system

26、, including signals involved in producing physical movement.,,excitatory neurotransmitterDRD3 expressed in endbrain、hippocampi（Emotional arousal Mental activity ）antagonist of DRD3 receptor,,DRD2 gene (11q22.

27、1-11.3) 141c missing DRD4 gene (11q15.5),,5-HTR2A（13q14）5-HTR：inhibitory transmitter agonist,,KCNN3 gene (1q21.3) K+ channel of cell membrane,,MTHFR\RGS4\CH13L1\DISC1\ERBB4\SYN2\PMX2B\EPNR\DTNBP\NOTCH4\TRAR4\NRG1

28、\GRIN1\BDNF\FYXD6\DAO\NOS1\G72\AKT1\CHRNA7\SLC6A4\SLC6A4\GNAL\C3\APOE\COMT\ZDHHC8\PRODH\RTN4R,2. diabetes mellitus,The term diabetes mellitus describes a metabolic disorder of multiple aetiology characterized by chronic

29、hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action, or both.,,,Symptoms： such as thirst, polyuria, blurring of vision, and weight loss

30、. In its most severe forms: ketoacidosis ,state may develop and lead to stupor, coma and, in absence of effective treatment, complication， death.,,risk： potential blindnessfoot ulcers, features of autonomic dy

31、sfunction, including sexual dysfunction. cardiovascular, peripheral vascular and cerebrovascular disease.,Aetiological Classification of Disorders of Glycaemia Type 1 : (beta-cell destruction, usually leading to absolu

32、te insulin deficiency) Type 2 : (may range from predominantly insulin resistance with relative insulin deficiency to a predominantly secretory defect with or without insulin resistance) Gestational diabetes,,Diagnosis

33、：Blood sugar, urine sugarTreatment: food control (starch fructose？) medicine （Glucobay） insulin injection,,Genetic defects Several forms

34、 of the diabetic state may be associated with monogenic defects in beta-cell function, frequently characterized by onset of mild hyperglycaemia at an early age (generally before age 25 years). They are usually

35、 inherited in an autosomal dominant pattern. Patients with these forms of diabetes, have impaired insulin secretion with minimal or no defect in insulin action .,,Abnormalities at several genetic loci on different chromo

36、somes have now been characterized.,,HNF1alpha（hepatocyte nuclear factor） The most common form is associated with mutations on chromosome 12 in a hepatic nuclear transcription factor referred to as HNF1alpha .,,HNF

37、1alpha is a key transcription factor that is essential for pancreatic beta-cell development and function,,glucokinase gene A second form is associated with mutations in the glucokinase gene on chromosome 7p.

38、 Glucokinase converts glucose to glucose-6-phosphate, the metabolism of which in turn stimulates insulin secretion by the beta cell.,,Thus, glucokinase serves as the "glucose sensor" for the beta cell. Be

39、cause of defects in the glucokinase gene, increased levels of glucose are necessary to elicit normal levels of insulin secretion.,,HNF4alpha gene A third form is associated with a mutation in the HNF4alpha gene o

40、n chromosome 20q . HNF4alpha is a transcription factor which is involved in the regulation of the expression of HNF1alpha.,,IPF-1 A fourth variant has recently been ascribed to mutations in another transcription

41、factor gene, IPF-1, which form leads to total pancreatic agenesis . 13q12.1,,Point mutations in mitochondrial DNA have been found to be associated with diabetes mellitus. The most common mutation occurs at positi

42、on 3243 in the tRNA leucine gene, leading to an A to G substitution.,,Environmental factors:FatPregnantUnhealthy foodWithout exercise,3. bronchial asthma,Bronchial asthma, including shortness of breath and wheezing

43、(a whistling sound in the chest).,,For most people with bronchial asthma, the pattern is periodic attacks of wheezing alternating with periods of quite normal breathing. However, some people with bronchial asthma alterna

44、te between chronic shortness of breath and episodes of even worse shortness of breath.,,The symptoms of bronchial asthma include: a feeling of tightness in the chest; difficulty in breathing or shortness of breath; wh

45、eezing; coughing (particularly at night).,,Asthma is found in 3-5% of adults and 7-10% of children. Half of the people with asthma develop it before age 10, and most develop it before age 30. Asthma symptoms can decreas

46、e over time, especially in children.,,Strong risks for developing bronchial asthma include being a person who is genetically susceptible to asthma and being exposed early in life to indoor allergens, such as dust mites a

47、nd cockroaches, and having a family history of asthma or allergy.,,Indoor allergens, such as dust mites and cockroaches, Outdoor allergens such as pollenFood such as seafood, peanut,,,Bronchial asthma attacks can be tr

48、iggered (precipitated or aggravated) by various factors, including: respiratory tract infections; cold weather; exercise; cigarette smoke and other air pollutants; stress.,,In sensitive individuals, asthma symptoms

49、can be triggered by inhaled allergens (allergy triggers), such as pet dander, dust mites, cockroach allergens, molds, or pollens. Asthma symptoms can also be triggered by respiratory infections, exercise, cold air, tobac

50、co smoke and other pollutants, stress, food, or drug allergies.,,Gene-environment interactions in the early life origins of asthma,,Genetic and Molecular Regulation of ADAM33 ADAM33 was the first asthma susceptib

51、ility gene identified as a result of a genome-wide positional cloning effort. The identification of ADAM33 as a major risk factor involved in the pathogenesis of bronchial hyper-responsiveness (BHR) and airway wall remod

52、eling. ADAM33, which causes the bronchiole smooth muscles to be hypersensitive.,,PHF11, comes from chromosome 13 The gene appears to regulate the blood B cells that produce Immunoglobulin E, the allergic antibody,,TCQ2（

53、14q11.12） T cell receptor，can regulate the reaction of IGgE,,ADRB3 Beta-adnephrin receptor，related with airway reactivity One such gene would be TGFB1 which plays an important role in control of expression of