疾病的多基因遗传.ppt

06疾病的多基因遗传,Polygenic Inheritance,疾病的多基因遗传,前言 数量性状的多基因遗传 多基因病的遗传,前言,微效基因（minor gene） 人类的一些遗传性状或某些遗传病的遗传基础不是一对主基因，而是几对基因，每一对基因对遗传性状或遗传病形成的作用是微小的。,多基因遗传（polygenic inheritance） 性状或疾病的遗传方式取决于两个以上微效基因的累加作用，还受环境因子的影响，因此这类性状也称为复杂性状或复杂疾病（complex 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 dominance 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 final phenotype.,多基因遗传受环境因子的影响,常见的多基因疾病 近视 高血压 糖尿病 精神分裂症 哮喘,数量性状的多基因遗传,质量性状（qualitative character）,数量性状（quantitative character）,数量性状的遗传规规律,数量性状的遗传规律,多基因病的遗传,易患性（liability） 在多基因遗传病发生中，遗传因素和环境因素共同作用决定一个个体患某种遗传病的可能性称为易患性。,易感性（susceptibility） 易感性特指由遗传因素决定的患病风险，仅代表个体所含有的遗传因素；但在一定的环境条件下，易感性高低可代表易患性高低。,发病阈值 （threshold） 当一个个体易患性高到一定限度就可能发病。这种由易患性所导致的多基因遗传病发病最低限度称为发病阈值。,群体易患性变异分布图,正态分布曲线中与关系,易患性的平均值和阈值距离与患病率关系,遗传度及其估算,遗传度（heritability） 多基因累加效应对疾病易患性变异的贡献大小。遗传度愈大，表明遗传因素对病因的贡献愈大。,疾病 遗传度 精神分裂症 80% 哮喘 80% 唇裂腭裂 76%,唇裂 遗传度76%,精神分裂症遗传度 80%,遗传度的估算,Falconer公式,Xg一般群体易患性平均值与阈值之间的标准差数 Xc对照组亲属中的易患性平均值与阈值之间的标准差数 Xr先证者亲属易患性平均值与阈值之间的标准差数 ag一般群体易患性平均值与一般群体中患者易患性平均值之间的标准差数 r亲属系数 ar先证者亲属易患性平均值与先证者亲属中患者易患性平均值之间的标准差数 qg一般群体发病率 qc对照亲属发病率，Pc1- qc qr先证者亲属发病率,例题1,先天性房间隔缺损在一般群体中的患病率为0.1，在100个先证者的家系中调查，先证者的一级亲属共有 669人(双亲200人，同胞279人，子女190人)，其中有22人发病。,先证者一级亲属的患病率226691003.3 查Falconer表，按群体患病率查得Xg和ag，再根据亲属患病率查得Xr，然后代入公式求出b值。 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%,例题2,江苏启东调查结果：肝癌一级亲属6591人，359人发病，q=5.45%，对照组5227名一级亲属，54人发病，q=1.03%。,q=5.45%， X=1.603 q=1.03%，X=2.315 a=2.655 P=1-q=10.0103=0.987 b=0.2654 h2=b/r=0.2654/0.5=0.53=53%,Holzinger公式,Holzinger公式 CMZ一卵双生子的同病率 CDZ二卵双生子的同病率,例题,对躁狂抑郁性精神病的调查表明，在15对单卵双生子中，共同患病的有10对；在40对双卵双生子中，共同患病的有2对。依此来计算单卵双生子的同病率为67，双卵双生子的同病率为5。代入上式：,影响多基因遗传病再发风险估计的因素,患病率与亲属级别有关,例如：无脑畸形和脊柱裂的患病率为0.38，在图中横轴上查出0.38之点，作一垂直线与纵轴平，已知此病的遗传度为60，从图中找出遗传度60的斜线，把它和0.38的垂直线相交点作一横线在纵轴上的一点近于4，即表明该病的一级亲属患病率接近4。,影响多基因遗传病再发风险估计的因素,患者亲属再发风险与亲属中受累人数有关 患者亲属再发风险与患者畸形或疾病严重程度关,影响多基因遗传病再发风险估计的因素,多基因遗传病的群体患病率存在性别差异时，亲属再发风险与性别有关,群体患病率较低即阈值较高的那种性别罹患，则患者亲属的发病风险较高。 例如人群中男性先天性幽门狭窄的患病率高于女性，男性患病率为0.5，女性患病率为0.1，男性的患病率比女性高5倍，即男性发病阈值低于女性。男性患者的儿子患病率是5.5，女儿的患病率2.4。如为女性患者，其儿子的患病率达到19.4，女儿的患病率达到7.3。表明女性患者比男性患者带有更多的致病基因。,(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 likely 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 most 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 affects 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 persons life, that person has suffered two or more of the following: Delusions Hallucinations Disorganized speech Grossly disorganized or catatonic behavior Negative symptoms,Negative symptoms are the most insidious behavioral effects of schizophrenia. They can include low levels of: Interest Motivation Emotional arousal Mental activity Social drive 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 generally present with schizophrenia at later ages, but the phenomenon of late onset schizophrenia (40+ years) is almost entirely a female one.,Subtypes of Schizophrenia Disorganized Type Catatonic Type Paranoid Type 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 individuals 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.,Because 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 professionals generally begin advising their patients of the schizophrenic likelihood of suicide.,Related genesDRD genes,DRD3 gene dopamine receptor D3, located on 3q13.3 normal function of the DRD3 gene The DRD3 gene provides 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, including signals involved in producing physical movement.,excitatory neurotransmitter DRD3 expressed in endbrain、hippocampi（Emotional arousal Mental activity ） antagonist of DRD3 receptor,DRD2 gene (11q22.1-11.3) 141c missing DRD4 gene (11q15.5),5-HTR2A（13q14） 5-HTR：inhibitory transmitter agonist,KCNN3 gene (1q21.3) K+ channel of cell membrane,MTHFRRGS4CH13L1DISC1ERBB4SYN2PMX2BEPNRDTNBPNOTCH4TRAR4NRG1GRIN1BDNFFYXD6DAONOS1G72AKT1CHRNA7SLC6A4SLC6A4GNALC3APOECOMTZDHHC8PRODHRTN4R,2. diabetes mellitus,The term diabetes mellitus describes a metabolic disorder of multiple aetiology characterized by chronic 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. In its most severe forms: ketoacidosis ,state may develop and lead to stupor, coma and, in absence of effective treatment, complication， death.,risk： potential blindness foot ulcers, features of autonomic dysfunction, including sexual dysfunction. cardiovascular, peripheral vascular and cerebrovascular disease.,Aetiological Classification of Disorders of Glycaemia Type 1 : (beta-cell destruction, usually leading to absolute 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 ：Blood sugar, urine sugar Treatment: food control (starch fructose？) medicine （Glucobay） insulin injection,Genetic defects Several forms 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 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 chromosomes 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 .,HNF1alpha 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. 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. Because 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 on 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 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 position 3243 in the tRNA leucine gene, leading to an A to G substitution.,Environmental factors: Fat Pregnant Unhealthy food Without exercise,3. bronchial asthma,Bronchial asthma, including shortness of breath and wheezing (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 alternate 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; wheezing; 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 decrease 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 and cockroaches, and having a family history of asthma or allergy.,Indoor allergens, such as dust mites and cockroaches, Outdoor allergens such as pollen Food such as seafood, peanut,Bronchial asthma attacks can be triggered (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 can be triggered by inhaled