Study on genetic epidemiology of obstructive sleep apnea hypopnea syndrome

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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. Li-Mantel-Gart method, Falconer regression method and SAGE-REGTL 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 apnea-hypopnea Study Syndrome

[Abstract] Objective To detect the genetic pattern and trait in the development of obstructive sleep apnea-hypopnea syndrome (OSAHS). Methods Genetic-epidemiologic survey of families of 143 patients with OSAHS, who were confirmed as probands. Questionnaire-type interviews were conducted with the first-degree and second-degree relatives of these probands. The segregation ratio estimation, heritability calculation and complex segregation analysis was performed with Li-Mantel-Gart method, Falconer regression method and SAGE-REGTL program. Results The segregation ratio was 0.168 (95% CI 0.127--0.209). The prevelence rate of first-degree and second-degree 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 first-degree and second-degree 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 best-fitted 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 first-degree 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 (Li-Mantel-Gart method) calculation [7]

The separation rate P = (R-J) / (T-J), the separation ratio variance S2p= (T-R) / (T-J) 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=1-qc, regression coefficient b=Pc (Xc-Xr) /ac, h2=b/r, Vb= (pc/ac) 2 x [(1-qr) /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, first-degree 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=Xg-rh2ag, 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 look-up 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 SAGE-REGTL 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 * 10-4, 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

First-degree 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 sixty-two

One thousand four hundred and ninety-two

One thousand five hundred and forty-eight

Fifteen

Sixty-five

Thirty-seven

Seventy-five

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

First-degree 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 forty-nine

Three hundred and fifteen

Three hundred and thirteen

Two hundred and ninety-nine

One hundred and eighty-eight

Two hundred and three

One hundred and twenty-five

Ninety-six

One hundred and thirty-eight

One hundred and fifteen

One hundred and fifty-three

One hundred and sixty-two

Two hundred and seventy-six

Two hundred and fifty-nine

Ninety-five

Seventy-eight

One hundred and forty-nine

One hundred and twenty-four

Five hundred and thirteen

Four hundred and ninety

Forty-five

Ten

Twenty

Five

Ten

Two

Ten

Three

Ten

Three

Thirteen

Two

Twenty-eight

Six

Fourteen

Four

Forty

Ten

Twenty-five

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

Twenty-six 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

Thirty-one point zero seven five

Forty-nine point four four seven

Forty-four point eight seven nine

Twenty-nine point four four six

Seventeen point eight eight seven

Fifty-two point seven zero six

Twenty-nine 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 first-degree relatives of A for each number, the number of OSAHS patients; the proband first-degree relatives and compared the prevalence of 2, X2 = 6.501, P=0.011; the control group compared the prevalence of first-degree 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 first-degree 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 first-degree 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 first-degree 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 first-degree 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, genome-wide 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 44106-7281 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) 67-70]

 

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