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Objective to investigate the genetic pattern and characteristics of obstructive sleep apnea hypopnea syndrome (OSAHS). Methods the prevalenc
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Objective to investigate the genetic pattern and characteristics of obstructive sleep apnea hypopnea syndrome (OSAHS). Methods the prevalence of OSAHS in 143 OSAHS probands and 130 control families was studied. LiMantelGart method, Falconer regression method and SAGEREGTL software were used to calculate the separation ratio, heritability and complex segregation analysis of OSAHS patients. Results the separation ratio of OSAHS was 0.168, and the confidence interval of 95% was from 0.127 to 0.209. The proband prevalence rate of class I and II relatives of OSAHS were 9.819% and 4.845%, the difference was statistically significant (x2 = 2 16.723, P< 0.01, two respectively) and the control group I and II degree relatives prevalence rate between 2.443% and 2.480% corresponding, there was a significant difference between the 2, respectively. 26.109 and 11.131, P was 0.01 <. The heritability of the first and second degree relatives of OSAHS probands were 56.138% and 25.007%, respectively, and the weighted heritability was. Complex segregation analysis showed that Mendel, additive and dominant and recessive major gene model assumptions are accepted (P> 0.05), the environment and no transmission model is rejected (P< 0.05); the AIC value, the best fitting degree of dominance model. Conclusion genetic factors play an important role in the pathogenesis of OSAHS. OSAHS is consistent with polygenic inheritance, and there is a major gene effect.
Sleep; genetic model; polygenic inheritance; genetic epidemiology
Genetic Epidemiologic for Obstructive Sleep apneahypopnea Study Syndrome
[Abstract] Objective To detect the genetic pattern and trait in the development of obstructive sleep apneahypopnea syndrome (OSAHS). Methods Geneticepidemiologic survey of families of 143 patients with OSAHS, who were confirmed as probands. Questionnairetype interviews were conducted with the firstdegree and seconddegree relatives of these probands. The segregation ratio estimation, heritability calculation and complex segregation analysis was performed with LiMantelGart method, Falconer regression method and SAGEREGTL program. Results The segregation ratio was 0.168 (95% CI 0.1270.209). The prevelence rate of firstdegree and seconddegree relatives in cases were 9.819% and 4.845% respectively, which were significantly different (x 2=16.723, P< 0.01) and were higher than that noticed 2.443% and 2.480% in controls (x 2=26.109 and 11.131, two P< 0.01). The heritability of the firstdegree and seconddegree relatives of OSAHS probands was 56.138%and 25.007% respectively and the, weighing heritability was 37.469%. The results of model including the Mendelian dominant recessive complex segregation analysis suggested that major gene and additive hypotheses were not rejected (P> 0.05). The environmental model and no transmission model were rejected at a 0.05 significance level. According to AIC, Mendelian dominant inheritance was the bestfitted hypothesis. Conclusion Genectic factors played an important role in the development of OSAHS, and the genetic model of OSAHS could as multifactorial with major gene serve inheritance trait.
[Key words] Sleep; Hereditary pattern; Multifactorial inheritance; Genetic Epidemiology
Obstructive sleep apnea hypopnea syndrome (OSAHS) causes including genetic and environmental induced craniofacial morphology, deposition, adipose tissue of the upper respiratory tract abnormalities and different susceptibility to sleepiness, all these may be the common cause of concern in genetics [1]. Snoring is a risk factor for snoring in children, that is, snoring may be genetically related to [2]. OSAHS is a complex disease characterized by a combination of genetic and environmental factors. Many studies have shown that OSAHS is familial and has obvious familial aggregation of [3,4,5,6]. At present, the genetic mode has not been clear yet, and it is affected by genetic factors, so there is no quantitative index. This study was to explore the genetic mode and characteristics of the disease.
Materials and methods
Research object and data collection
OSAHS patients admitted to hospital from September 2005 to September 2008 were identified as probands. The data acquisition OSAHS pedigrees for the probands and their relatives in the newly diagnosed and the patient, the patient informed consent, the Calgary sleep apnea disease specific quality of life questionnaire [7], Epworth sleepiness score table (Epworth sleepiness scale, ESS)  [8] questionnaire, to snoring on the basis of the questionnaire survey. Sleep screening test and polysomnography (PSG) to identify patients with OSAHS. Record the clinical data and pedigree data of proband. The family history data should be confirmed by at least one firstdegree relative of the proband to reduce the retrospective bias. All questionnaires were reviewed in detail, found contradictions or Loutian, return telephone confirmation, excluding not confirm the questionnaire, a total of 143 cases with complete OSAHS complete data card data and their family first. There were 105 males and females, aged from 5 to 74 years old, with an average age of 43 years old, and a total of 143 patients with first degree relatives of the first grade and a second degree relatives of 1548 persons in the 143 cases of the disease in. Since the health physical examination in 130 cases as control group, and the proband age and sex by relatives at all levels had no significant difference (P> 0.05), male 88 cases, female 22 cases, aged 5 to 74 years old, the average age of 43 years; 130 cases of control were collected the data of patients with family Department of the first degree relatives of 614 people, 1492 people of relatives. If there were multiple OSAHS patients in the same family, the first identified patients were identified as probands to determine the core family.
Two, separation ratio (LiMantelGart method) calculation [7]
The separation rate P = (RJ) / (TJ), the separation ratio variance S2p= (TR) / (TJ) 3; separation ratio standard error Sp=; separation ratio of 95% confidence interval CI=P + 1.96Sp. Where T is the total number of siblings, R is the total number of OSAHS among the siblings, J is the only family of 1 patients with OSAHS (the total number of children).
Three, heritability (Falconer method) calculation [9]
The heritability of h2=b/r, pc=1qc, regression coefficient b=Pc (XcXr) /ac, h2=b/r, Vb= (pc/ac) 2 x [(1qr) /ar2 * A], Sh2=Vb1/2/r, where q is the prevalence of H2 heritability, B is susceptible to the regression coefficients of relatives of probands susceptibility, Vb variance regression the coefficients of B, R is the coefficient of parentage, firstdegree relatives of 1/2, grade II relatives of R 1/4, said the subscript c as the control group, the subscript r expressed as relatives of probands, X is normal with the average deviation threshold, a is the average deviation of patients with groups, according to the corresponding Q value [10] can be obtained check table.
Four, the heritability of the significance test and weighted average [9]
H2 weighted average = (h12/S12+ h22/S22+ h32/S32+)... +hn2/Sn2) / (1/S12+1/S22+1/S32+)... =1/ (+1/Sn2), the weighted average value of H2 standard error (1/S12+1/S22+1/S32+)... +1/Sn2) 1/2, H12, H22, h32,... HN2, respectively, at all levels of relatives in the estimated heritability, S1, S2, S3,... Sn is the standard error of the corresponding genetic degrees. Heritability of the significance of the test of the application of the formula: t=h2/Sh2, check t value table P value.
Five. Use the threshold model to calculate the expected value of OSAHS and compare it with the observed value [9]
The calculation formula of threshold model: Xr=Xgrh2ag, where X is the threshold value and the average value of the normal deviation, average deviation and average value of group A patients, H2 r heritability, coefficient of parentage, subscript g refers to the general population, here for the control group, the subscript r refers to the relatives of patients, here is OSAHS relatives of probands were calculated after Xr, [10] get the expected value of the lookup table (%).
Six, compound separation analysis
Using the REGTL statistical analysis (SAGE 5.3.1) software package to carry on the complex segregation analysis of the genetic model, and establish the regression model. In the proposed genetic model, the general model does not define the parameters, and the other models achieve the maximum likelihood (L) by defining the specific parameter values. The genetic model by likelihood ratio test (LRT= 2 lnL lnL general special mode) for x value of 2, the number of parameters of the differential degree of freedom for the special mode and general mode. When P< 0.05, the model is rejected; when P> 0.05, the pattern is accepted, that is, it may be a genetic model of the disease.
Seven, statistical analysis
All the epidemiological data of the cases and controls were input into the database, and the data were processed by Falconer regression, SPSS14.0 software and SAGEREGTL software. Statistical process including t test, 2 test, variance analysis and rank sum test, inspection level a= 0.05.
Result
Estimation of OSAHS separation ratio
Of the 143 probands with OSAHS, only 1 of the OSAHS patients had a family of (J), and the total number of siblings (including probands) was (T), of which OSAHS patients (including probands) were R. Therefore, the crude separation ratio of OSAHS is 0.168, the separation ratio variance is 4.417 * 104, the standard error is 0.021, and the confidence limit of 95% is about 0.127 ~ 0.209. OSAHS the separation ratio and separation of autosomal dominant genetic disease than 1/2 and isolation of recessive genetic disease than 1/4 compared by 2 test, there were significant differences, 2 were 12.364 and 13.321, P < 0.05, suggesting that the disease does not accord with monogeni in OSAHS disease the genetic genes are.
Two, the heritability of OSAHS
Rates were higher than the control group in the proband group I and II degree relatives of OSAHS, the difference was statistically significant, 2 were 26.109 and 11.131, P was 0.01 <. The proband of relatives and compared the prevalence of OSAH x 2 = 16.723, P< 0.01. Using the Falconer threshold model estimated with OSAHS class I and II relative heritability was 56.138 + 5.548% and 25.077 + 4.522% respectively, the difference was statistically significant (x2 = 2 8.548, P< 0.01), the first and second level relative weighted heritability was 37.469 + 2.831%, see Table 1; the prevalence rate of observation the calculated value and the expected value of the difference was not significant in grade I and II level relatives of relatives of OSAHS, 2 were 0.043 and 0.041, P were 0.837 and 0.840, were more than 0.05, are greater than 0.05, indicating the observation value and the expected value is consistent, see Table 2; first degree relatives of probands according to some factors such as gender, women before and after menopause, obesity and age stratification after the corresponding genetic calculation, see table 3.
Table 1 Comparison of OSAHS prevalence rate (%) and Falconer threshold model to estimate the heritability of OSAHS in the control group
Relatives at all levels
N
A
Q (%)
X
A
B
Vb (* 104)
H2 + Sh2 (%)
T
P
Firstdegree relatives
Control family C
Proband family R
Second degree relatives
Control family
Proband family
Weighted average of the first and second degree relatives
Six hundred and fourteen
Six hundred and sixtytwo
One thousand four hundred and ninetytwo
One thousand five hundred and fortyeight
Fifteen
Sixtyfive
Thirtyseven
Seventyfive
Two point four four three
Nine point eight one nine
Two point four eight zero
Four point eight four five
One point nine seven zero
One point two eight nine
One point nine six two
One point six six one
Two point three four seven
One point seven six five
Two point three four one
Two point zero seven six
Zero point two eight one
Zero point one two five
Seven point six nine five
Five point one zero eight
56.138 + 5.548
25.077 + 4.522
37.469 + 2.831
Ten point one one nine
Five point five two nine
Thirteen point two three five
< 0.05
< 0.05
< 0.05
Table 2 calculate the expected value of OSAHS by using the threshold model theory and compare with the observed value
Proband relative
Observed value (%)
Expected value (%)
The value of P
Firstdegree relatives
Second degree relatives
Nine point eight one nine
Four point eight four five
Nine point five zero
Four point six two
> 0.05
> 0.05
Table 3 the level of heritability of the first degree relatives of the proband, who were stratified by sex, menopause, obesity, age, and so on in 662 cases
Stratification factor
N
A
Q (%)
X *
A*
B
Vb (* 104)
H2 + Sh2 (%)
T
Male group
Proband family
Control family
Female group
Proband family
Control family
Premenopausal
Proband family
Control family
Postmenopausal
Proband family
Control family
Under 16 years old
Proband family
Control family
16  35 years
Proband family
Control family
35  60 years
Proband family
Control family
Above 60 years old
Proband family
Control family
Obese people
Proband family
Control family
Non obese
Proband family
Control family
Three hundred and fortynine
Three hundred and fifteen
Three hundred and thirteen
Two hundred and ninetynine
One hundred and eightyeight
Two hundred and three
One hundred and twentyfive
Ninetysix
One hundred and thirtyeight
One hundred and fifteen
One hundred and fiftythree
One hundred and sixtytwo
Two hundred and seventysix
Two hundred and fiftynine
Ninetyfive
Seventyeight
One hundred and fortynine
One hundred and twentyfour
Five hundred and thirteen
Four hundred and ninety
Fortyfive
Ten
Twenty
Five
Ten
Two
Ten
Three
Ten
Three
Thirteen
Two
Twentyeight
Six
Fourteen
Four
Forty
Ten
Twentyfive
Five
Twelve point eight nine four
Three point one seven five
Six point three nine zero
One point six seven two
Five point three one nine
Zero point nine eight five
Eight
Three point one two five
Seven point two four six
Two point six zero seven
Eight point four nine seven
One point two three five
Ten point one four five
Two point three one seven
Fourteen point seven three seven
Five point one two eight
Twentysix point eight four six
Eight point zero six five
Four point eight seven three
One point zero two zero
One point one three one
One point eight five two
One point five two two
Two point one two seven
One point six two seven
Two point three three two
One point four Zero Five
One point eight five nine
One point four six one
One point nine four three
One point three seven two
Two point two four six
One point two seven three
One point nine nine three
One point zero four eight
One point six three three
Zero point six two three
One point four zero one
One point six five five
Two point three one nine
One point six three one
Two point two four five
One point nine zero four
Two point four eight six
Two point zero four seven
Two point six seven zero
One point eight five eight
Two point two four nine
One point nine zero six
Two point three two three
One point eight six three
Two point five nine two
One point seven four eight
Two point three six seven
One point five six four
Two point zero six two
One point two three eight
One point eight five five
Two point zero seven one
Two point six five eight
Zero point three one one
Zero point two three nine
Zero point two six one
Zero point one nine five
Zero point two zero two
Zero point three three three
Zero point two nine seven
Zero point two seven zero
Zero point three eight six
Zero point two four seven
Thirteen point five three five
Twenty point one nine eight
Thirtyone point zero seven five
Fortynine point four four seven
Fortyfour point eight seven nine
Twentynine point four four six
Seventeen point eight eight seven
Fiftytwo point seven zero six
Twentynine point three one three
Twelve point three zero two
62.192 + 7.358
47.859 + 8.493
52.289 + 11.148
39.061 + 14.064
40.416 + 13.399
66.605 + 10.854
59.427 + 8.460
54.153 + 14.520
77.121 + 10.828
49.453 + 7.015
Eight point four five two
Five point six three five
Four point six nine zero
Two point seven seven seven
Three point zero one six
Six point one three six
Seven point zero two five
Three point seven two nine
Seven point one two two
Seven point zero five zero
Note: * Falconer are available in table [8] to obtain the corresponding value for the corresponding groups; n probands of firstdegree relatives of A for each number, the number of OSAHS patients; the proband firstdegree relatives and compared the prevalence of 2, X2 = 6.501, P=0.011; the control group compared the prevalence of firstdegree relatives of men and women, 2 = x 1.384, P=0.239; first degree relatives of probands and heritability comparison x 2 = 1.152, P=0.283; female probands of relatives of postmenopausal and premenopausal compared the prevalence of x 2 = 0.790, P=0.374; the control group of relatives of postmenopausal and premenopausal compared the prevalence of x 2 = 1.742, P=0.187; the proband first degree relatives of premenopausal and postmenopausal genetic x 2 = 1.279, P=0.258; first degree relatives of probands in non obese and obese group compared the prevalence of x 2 = 46.868, P=0.000; the control group of relatives of non obese and obese group compared the prevalence of x 2 = 18.861, P=0.000; the proband 1 Relatives of non obese and obese group compared heritability x 2 = 3.846, P=0.049. The population under the age of 16 was less than the other three groups of age group, 2 were 42.852, 24.810 and 14.137, P were less than 0.01.
Three, OSAHS genetic model of the complex segregation analysis
The detected genetic patterns included Mendel's genetic model (dominant and recessive), environmental model, no dominant gene model and multi gene accumulation pattern. According to the calculation results of REGTL module, and LRT test and AIC value (Table 4), Mendel genetic model hypothesis, showed additive, dominant and recessive model assumptions are accepted, OSAHS polygenic additive genetic model (P> 0.05). In this genetic model, a group of non allelic effects with a common phenotypic traits, each allele produces only a small role, at the same time can enhance the effect of other alleles on the phenotype, they accumulated by the number of non dominant or recessive way to transfer genetic information, phenotype the variation is influenced by genetic variation and environmental variation. It is suggested that OSAHS occurs in individuals carrying a number of susceptible genes and at the same time being exposed to harmful environmental factors.
Table 4 complex segregation analysis of OSAHS genetic model
project
Non Mendel genetic model
General model free transfer model environment model
Mendel genetic model
Dominant model recessive model additive model primary gene model
2InL
AIC
X 2
DF
P
563.161874
564.162874


587.463789
589.443789
14.6211894
Seven
< 0.05
572.304078
579.345078
24.7498094
Three
< 0.05
558.974936
563.784936
7.67156928
Five
> 0.05
573.078893
587.129893
6.62856642
Five
> 0.05
572.977632
581.967632
4.60366806
Five
> 0.05
570.294342
582.314342
6.0923877
Four
> 0.05
Natural logarithm of InL: maximum likelihood; AIC: Akaike information criterion; df: degree of freedom; N: for environmental model, no genotype transmission
Discussion
Heritability or heritability refers to the role of genetic basis in determining the genetic basis of susceptibility and environmental factors in the formation of a disease or disease. The higher the heritability, the greater the role of genetic factors in the pathogenesis of the disease; on the contrary, the lower the heritability, indicating that genetic factors play a more important role in the pathogenesis of the disease. As early as in the last seventy years, Strohl et al. Proposed that there is a clustering phenomenon in many family members of obstructive sleep apnea syndrome ([11]). Since then, several familial aggregation studies have shown a similar conclusion [12]. According to Redline and Guilleminault et al., the chance of OSAHS in relatives of patients with OSAHS was 21~84%, while the control group was 10~12%[13, 14]. This study shows that OSAHS patients with firstdegree relatives heritability was 56.138% and 25.077%, two relatives of the weighted heritability was 37.469%, can be said that there are 56.138% pathogenic factors and genetic factors in the firstdegree relatives of other related environmental factors. With the decline in the relative level, the impact of genetic decline. Under the same pathogenic factors, only a small number of people had OSAHS, which showed that there were individual differences in response to pathogenic factors. May include genetic patients with craniofacial morphology and upper respiratory tract soft tissue structure and bone structure related pathogenic factors and genetic factors in 56.138%. Foreign scholars study shows that: according to the study of craniofacial morphology, lateral pharyngeal wall, tongue and all soft tissue volume were also familial aggregation or genetic predisposition in [15,16]
The results of this study showed that the prevalence rate of firstdegree relatives of patients was higher than that of grade II relatives, and the prevalence of the second class relatives was higher than that of the population, which indicated that the family aggregation of OSAHS. The combination of the above and the proband closer genetic relationship the higher incidence of the fact that the genetic pattern of OSAHS with multiple genetic characteristics; estimate based on OSHAS weighted heritability was 37.469 + 2.831% Falconer, the Redline and S on genetic factors accounted for 40% of the human factors in the pathogenesis of OSAHS is similar to [17] conclusion. The prevalence rate of OSAHS was significantly higher than that of the first degree relatives of probands. This shows that with the relative levels of relatives of patients with OSAHS, the risk decreased significantly; in addition, the research results show that the separation ratio of OSAHS separation and single gene genetic disease than the comparison, the difference was statistically significant, were less than the dominant genetic disease and isolation of recessive genetic disease; in addition, we can compare the results from table 2 in the proband of relatives at all levels OSAHS prevalence of the expected value and the observed value shows that the two groups had no significant difference, indicating that the two are in agreement with the. The results show that OSAHS is consistent with polygenic inheritance model by using the method of mathematical statistics. Therefore, [18] OSAHS features of polygenic diseases, confirmed that genetic factors play an important role in the onset of this disease, but because heritability of not more than 50%, so the environmental factors in the pathogenesis of the disease also occupies a very important position.
This study shows that in people over the age of 16, with the increase of age with heritability decreased gradually, indicating that patients with genetic factors and the incidence rate decreased gradually, influenced by environmental factors, such as some of the risk factors of influence. With the increase of age, the proportion of genetic factors in the incidence of all factors gradually decreased, that is, with the increase of age, the impact of environmental factors on the incidence of OSAHS increased. The heritability of postmenopausal women was significantly lower than that in premenopausal women, show the effects of increasing age and estrogen levels decline and other environmental factors favoring the occurrence of OSAHS, the genetic male OSAHS patients were lower than that of female, male patients are more likely than women affected by environmental factors and produce OSAHS, such as male smoking and drinking. Contribute to the occurrence of OSAHS factors far more than women, so these environmental factors increased, relatively speaking, many risk factors of genetic factors in OSAHS proportion is low. This study shows that in patients with OSAHS grade of genetic population under the age of 16 the relative degree is 40.416%, far lower than other age groups, it increased with age gradually reduced with OSAHS heritability, why there is such a result may be: most of the children patients with OSAHS associated with tonsil and adenoid hypertrophy related many patients, resection of adenoid and tonsil after OSAHS was released, without as adult patients as needed treatment of upper respiratory tract and other soft tissue (or) bone structure, and these other upper respiratory tract of soft tissue and (or) genetic bone structures may not show its role in the pathogenesis of OSAHS in pediatric patients. The pathological hypertrophy of tonsils and adenoids is mostly affected by environmental factors, such as respiratory infections and allergic reactions. Therefore in pediatric patients, the role of genetic factors in the pathogenesis of OSAHS has not been fully displayed, so the heritability of lower than those above 16 years old, though, in children and adolescents with OSAHS in firstdegree relatives, significantly increase the incidence of OSAHS, suggesting that genetic factors play a role in the pathogenesis of OSAHS. The results of similar studies and foreign scholars [13]. Foreign scholars have shown that, even after the control of obesity, OSAHS has obvious genetic characteristics [16]. In this study, we found that 49.453% of the non obese patients in the non obese group were genetically related. The heritability of obesity patients was significantly higher than that in non obese patients, obese patients affected by genetic factors than non obese, and these genetic factors in both obese and non obese genetic, genetic factors.
Using the SAGE software, we can not explain the familial aggregation of OSAHS in the pathogenesis of the disease. Accept the genetic model of Mendel, which suggests that the role of genetic factors, OSAHS may be in a certain mode of inheritance from parent to offspring transfer. In an assumption of main gene model, further analysis of Mendel's genetic model hypothesis, showed additive, dominant and recessive model assumptions are accepted, suggesting that the disease may have multiple effects of major genes, which at the same time there are many different main genes. In the genetic model analysis to non major gene model, suggesting that effect may occur by the master OSAHS gene. Recently, genomewide scans of OSAHS showed that chromosome 1, No. 2, chromosome 12 and chromosome AHI were associated with [17], suggesting that the disease has a different genetic background. At present, it is found that some genetic diseases are not as simple as monogenic diseases, but are determined by multiple alleles, but do not exclude the existence of major gene effects and environmental factors. The genetic heterogeneity revealed by the results of complex segregation analysis is of great significance for the future development of gene mapping. To further distinguish between various genetic types of family OSAHS, looking for the same type of clear genetic pedigrees, combined with molecular genetics of OSAHS gene positional cloning, genetic regularity of the only way to gradually reveal the OSAHS.
The above comprehensive analysis, OSAHS is a multifactorial genetic disease, with the characteristics of multiple genes, genetic factors for the comprehensive performance of a major gene effect, and genetic model, low rate of the disease allele, support major gene effect in multiple genes with Mendel genetic basis.
Thank
Thanks to Wedig S.A.G.E. Registration Western Reserve Cleveland OH 441067281 licensed for use in genetic epidemiology software S.A.G.E.5.3.1 Paula,, University.
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[Abstract] it has been published in Journal of Guangxi Medical University 2011,28 (1) 6770]
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