Smoking and allergic respiratory disease · The prevalence of allergic respiratory diseases such as...

CAUSAL ANALYSIS RESEARCH IN TOBACCO AND ALCOHOL (CARTA)

Smoking and allergic respiratory disease

Analysis plan

April 24, 2015

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Writing group

Allan Linneberg, Professor, MD, PhD

Research Centre for Prevention and Health, Capital Region of Denmark, Denmark

Department of Clinical Experimental Research, Glostrup University Hospital, Glostrup, Denmark

Department of Clinical Medicine, University of Copenhagen, Denmark

Contact: [email protected]

Lise Lotte Nystrup Husemoen, cand.scient., PhD



Tea Skaaby, MD, PhD



Rikke Kart Jacobsen, cand.scient



Amy Taylor, PhD

MRC Integrative Epidemiology Unit (IEU), University of Bristol, United Kingdom

UK Centre for Tobacco and Alcohol Research Studies, University of Bristol, United Kingdom


mailto:[email protected]





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Contents

BACKGROUND AND AIMS............................................................................................................................................ 4

ELIGIBLE STUDIES ......................................................................................................................................................... 4

Inclusion criteria ............................................................................................................................................................ 4

Exclusion criteria ........................................................................................................................................................... 5

Sample information ........................................................................................................................................................ 5

POWER CALCULATION ................................................................................................................................................. 5

OUTLINE OF ANALYSES ............................................................................................................................................... 5

Outcome measures ......................................................................................................................................................... 6

Exposure measure .......................................................................................................................................................... 6

Definitions of smoking status ........................................................................................................................................ 6

Additional considerations .............................................................................................................................................. 7

Other covariates ............................................................................................................................................................. 7

Hardy Weinberg ............................................................................................................................................................. 7

Summary statistics ......................................................................................................................................................... 7

MR analysis ................................................................................................................................................................... 7

Observational statistical analyses ................................................................................................................................... 8

The instrument ............................................................................................................................................................... 9

Output ............................................................................................................................................................................ 9

REFERENCES ................................................................................................................................................................. 10

APPENDIX ...................................................................................................................................................................... 12

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Background and aims

The prevalence of allergic respiratory diseases such as allergic rhinitis and allergic asthma has

increased over recent decades in countries living a Westernized, urbanized, and affluent lifestyle

(1;2). However, the causes of this increase are largely unknown (3). Allergic diseases are costly for

both patients and society and affect the patient’s quality of life (1). Persons who are sensitized to

inhalant allergens by a specific IgE mediated immune response or skin prick test (SPT) reactivity

are considered at risk of developing allergic respiratory disease, and both are accepted objective

biomarkers of allergic respiratory disease in clinical assessment and in epidemiological studies.

Smoking has been suggested to increase the risk of allergic symptoms by increased

inflammation in the airways, and smoking is a known risk factor for asthma, but it is still

unresolved whether smoking confers an increased or a decreased risk of allergy (1). Some studies

have found a negative association between smoking and allergic sensitization (17;20;21), whereas

other studies have not (22). Of interest, a recent meta-analysis of observational studies found no

associations between active smoking and allergic rhinitis (1).

We will perform a meta-analysis of population-based studies in adults (>=16y at

outcome and smoking measurement) with data on the rs1051730/rs16969968 genotype, smoking

status, and hay fever, asthma or allergic sensitization. The aims are to examine the effects of the

smoking increasing allele of the rs1051730/rs16969968 SNP on hay fever, asthma and allergic

sensitization. The effects will be examined for never, former, current, and ever smokers separately.

It is expected that the effects will be seen only among current and ever smokers.

Eligible studies

A study needs to have data on at least one of the following three phenotypes: hay fever, asthma or

allergic sensitization. The following studies have data on hay fever, asthma or allergic sensitization

according to the data sheets/information received so far:

1) 1958 BC

2) MONICA10

3) Inter99

4) Health2006

5) Health2008

6) Goya Males

7) ALSPAC Mothers

8) FINRISK

9) HUNT2

Inclusion criteria

Studies must have data on at least one of the three allergic respiratory disease phenotypes (hay fever, asthma or

allergic sensitization), SNP genotype, and smoking status

Studies must have at least 200 smokers with genotype and phenotype data to be included in the analyses

Individuals must be of European ethnic origin (self-report, genetic or registry-based)

Individuals must be ≥16 years (at collection of data on hay fever, asthma and allergic sensitization and

smoking)

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Exclusion criteria

Occasional smokers (See “Definitions of smoking status”)

Pipe/Cigar/cigarillo smokers, who do not smoke cigarettes (See “Definitions of smoking status”)

Sample information

Where data on hay fever, asthma or allergic sensitization from multiple phases of data collection are

available:

Use the phase with the maximum N for the analysis of a specific phenotype

Use current smoking status obtained at the same phase of assessment of hay fever, asthma or allergic

sensitization. This applies also for other covariates.

Power calculation

For a range of effect sizes, the required number of cases and controls among current/ever smokers

has been calculated in Quanto 1.2 (University of Southern California, US). For example, with a

power of 0.80, we need approximately 3000 smokers with hay fever and 20000 smokers without

hay fever to detect an odds ratio of 0.92 for having hay fever per smoking increasing allele.

Outline of analyses

The included variables are shown in Table A.

Table A. Overview of variables

Variable name Values Definitions Comments

snp 0, 1, 2 0: major homozygotes

1: heterozygotes

2: minor homozygotes

The genetic variant: Rs1051730 or

rs16969968

sex 1, 2 1: male

2: female

If only men or women in the study,

please set sex=1 for all.

age 16+ Age in years Continuous variable

smoking_status 0, 1, 2 0: never smoker

1: ex/former smoker

2: current smoker

Current smoking status of the person.

If smoking status is only available as

a binary variable, please code

never/ex=1 and current=2

cigarettesperday 0+ Number of cigarettes per day (or if in categories,

please recode to the midpoint of the category for

the regression analysis) in current smokers

Only among current smokers!

hayfever 0, 1 0: persons without hay fever

1: Persons with hay fever

According to the definition in Table

B

asthma 0, 1 0: persons without asthma

1: Persons with asthma


B

atopy 0, 1 0: persons without allergic sensitization

1: Persons with allergic sensitization


B

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Outcome measures

Analyses will be run for the following binary outcomes (see definitions in Table B):

a) Hay fever

b) Asthma

c) Allergic sensitization

Table B. Case definitions for hay fever, asthma and allergic sensitization

Hay fever Asthma Allergic sensitization

Self-reported or doctor-diagnosed

hay fever

OR


allergic rhinitis or rhinitis in the

absence of infection

OR


nasal allergy


asthma or allergic asthma

Serum specific IgE positivity

against inhalant allergens

OR

Skin prick test positivity against

inhalant allergens

Exposure measure

Analyses will use one of two SNPs, rs1051730/rs16969968 (use the SNP with the largest N if both

available), located within the 15q25 nicotinic acetylcholine receptor gene cluster (CHRNA5-

CHRNA3-CHRNB4). The SNP should be coded additively, i.e. 0, 1, 2 minor alleles/T-alleles (A-

alleles if opposite strand) for the rs1051730 SNP according to the number of risk (smoking

increasing) alleles and run as a continuous covariate in the regression analyses.

Definitions of smoking status

Smoking status should be defined within each participating study. A uniform definition cannot be

applied across all studies due to the different information collected in each study. However, the

following guidelines should be used. Current smokers

Current smokers include individuals reporting cigarette smoking at the time of data collection on

hay fever, asthma or allergic sensitization. If information on smoking frequency is available, please

restrict this sample to daily smokers or near daily smokers (smoking 5/6 days a week). Smokers

who report smoking less frequently than this should be excluded from analyses.

Former smokers

Former smokers include individuals reporting ever having smoked cigarettes that no longer smoke

at the time of data collection. If information on past smoking frequency is available, please restrict

this sample to daily smokers or near daily smokers (smoking 5/6 days a week). Smokers who report

smoking less frequently than this should be excluded from analyses.

Ever smokers

Ever smokers include current and former smokers.

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Never smokers

Never smokers include individuals reporting never having smoked cigarettes, pipe, cigars or

cigarillos in their lifetime.

Additional considerations

Non-cigarette smokers

In studies that distinguish between pipe/cigar/cigarillo and cigarette smokers, individuals who only

smoke pipe, cigars or cigarillos should be excluded from all analyses. Individuals who smoke

cigarettes as well as pipe, cigars or cigarillos should be included in analyses. In studies that do not

distinguish between pipe/cigar/cigarillo and cigarette smokers, all smokers should be included.

Adolescent smokers

Studies of adolescent smokers (e.g. ALSPAC, NFBC 1986) should restrict analyses to two

categories of smokers: daily smokers and never smokers. Daily smokers are individuals who report

smoking cigarettes at least 5 days per week. Never smokers are individuals who have never tried a

cigarette.

Other covariates

Smoking quantity in current smokers (number of cigarettes/day or if in categories, please recode to the

midpoint of the category for the regression analysis)

Sex

Age (years) at the time of measurement of the outcome

Principal component (if available)

Hardy Weinberg

Please provide minor allele frequency and exact p-value with 3 decimals (Chi-Square test) from

Hardy Weinberg Equilibrium for sample with genotype, smoking and data on hay fever, asthma or

allergic sensitization in Table 1 (see Appendix). I.e., use the same N in all analyses, unless this

results in substantial decrease in N.

Summary statistics

For each population/cohort, summary statistics should be supplied in Tables 2 and 3 (see Appendix).

Include only participants with complete information on the included outcomes and smoking status.

I.e., use the same N in all analyses, unless this results in substantial decrease in N.

MR analysis

All analyses are performed by logistic regression models. Please complete Table 4. Complete case

analyses are requested. Please provide N, log odds ratio, corresponding standard errors and p-values

(3 decimals) for the following logistic regression models, stratified by the smoking status categories

(never, former, current, and ever smokers):

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Logistic regression models performed only in never smokers

1. Hay fever = SNP

2. Hay fever = SNP + sex + age (continuous)

3. Asthma = SNP

4. Asthma = SNP + sex + age (continuous)

5. Allergic sensitization = SNP

6. Allergic sensitization = SNP + sex + age (continuous) Logistic regression models performed only in former smokers

7. Hay fever = SNP


9. Asthma = SNP



12. Allergic sensitization = SNP + sex + age (continuous)

Logistic regression models performed only in current smokers

13. Hay fever = SNP


15. Asthma = SNP




Logistic regression models performed only in ever smokers (combined former and current smokers)

19. Hay fever = SNP


21. Asthma = SNP




If principal components data are available in your study, and you are able to do so, please provide

MR analyses adjusted for principal components.

Observational statistical analyses Observational effects of smoking status (please complete Table 5)

‘Never smokers’ are used as reference category in all analyses. The other two categories are current

and former smokers (see Table 5).

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The following logistic regression analyses are performed:

25. Hay fever = smoking_status

26. Hay fever = smoking_status + sex + age (continuous)

27. Asthma = smoking_status

28. Asthma = smoking_status + sex + age (continuous)

29. Allergic sensitization = smoking_status

30. Allergic sensitization = smoking_status + sex + age (continuous)

Observational effects of smoking heaviness (please complete Table 6)

The following logistic regression analyses are performed only in current smokers:

31. Hay fever = Cigarettes/day

32. Hay fever = Cigarettes/day + sex + age (continuous)

33. Asthma = Cigarettes/day

34. Asthma = Cigarettes/day + sex + age (continuous)

35. Allergic sensitization = Cigarettes/day

36. Allergic sensitization = Cigarettes/day + sex + age (continuous)

The instrument

To validate the association between the SNP and smoking quantity, the following linear regression

analyses are performed in current smokers (Table 7):

37. Smoking quantity (cigarettes/day) = SNP

38. Smoking quantity (cigarettes/day) = SNP + sex + age (continuous)

Output

Please fill in Table 1-8 in Appendix. If you use the provided STATA-script, you only need to fill

in Table 8 by hand, since STATA will create the results from Table 1-7: Create a dataset with the

variables described in Table A and use the provided STATA-script (.do-file) to generate the results

in Tables 1-7 in Appendix. Please then return Table 8, the .log-file and the .dta-files that are

generated by the STATA-script.

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References

(1) Saulyte J, Regueira C, Montes-Martinez A, Khudyakov P, Takkouche B. Active or passive

exposure to tobacco smoking and allergic rhinitis, allergic dermatitis, and food allergy in

adults and children: a systematic review and meta-analysis. PLoS Med 2014

Mar;11(3):e1001611.

(2) Ring J, Kramer U, Schafer T, Behrendt H. Why are allergies increasing? Curr Opin

Immunol 2001 Dec;13(6):701-8.

(3) van GR, van der Ent CK, Rovers MM, Kimpen JL, van Essen-Zandvliet LE, de MG.

Excessive body weight is associated with additional loss of quality of life in children with

asthma. J Allergy Clin Immunol 2007 Mar;119(3):591-6.

(4) Visness CM, London SJ, Daniels JL, Kaufman JS, Yeatts KB, Siega-Riz AM, et al.

Association of childhood obesity with atopic and nonatopic asthma: results from the

National Health and Nutrition Examination Survey 1999-2006. J Asthma 2010

Sep;47(7):822-9.

(5) Guh DP, Zhang W, Bansback N, Amarsi Z, Birmingham CL, Anis AH. The incidence of co-

morbidities related to obesity and overweight: a systematic review and meta-analysis. BMC

Public Health 2009;9:88.

(6) Flaherman V, Rutherford GW. A meta-analysis of the effect of high weight on asthma. Arch

Dis Child 2006 Apr;91(4):334-9.

(7) Boulet LP. Obesity and atopy. Clin Exp Allergy 2014 Oct 16.

(8) Chen Y, Rennie D, Cormier Y, Dosman J. Atopy, obesity, and asthma in adults: the

Humboldt study. J Agromedicine 2009;14(2):222-7.

(9) Chen Y, Rennie D, Cormier Y, Dosman J. Association between obesity and atopy in adults.

Int Arch Allergy Immunol 2010;153(4):372-7.

(10) Hersoug LG, Linneberg A. The link between the epidemics of obesity and allergic diseases:

does obesity induce decreased immune tolerance? Allergy 2007 Oct;62(10):1205-13.

(11) Yeh YF, Huang SL. Enhancing effect of dietary cholesterol and inhibitory effect of

pravastatin on allergic pulmonary inflammation. J Biomed Sci 2004 Sep;11(5):599-606.

(12) Schafer T, Ruhdorfer S, Weigl L, Wessner D, Heinrich J, Doring A, et al. Intake of

unsaturated fatty acids and HDL cholesterol levels are associated with manifestations of

atopy in adults. Clin Exp Allergy 2003 Oct;33(10):1360-7.

(13) Fessler MB, Jaramillo R, Crockett PW, Zeldin DC. Relationship of serum cholesterol levels

to atopy in the US population. Allergy 2010 Jul;65(7):859-64.

(14) Assing K, Bodtger U, Linneberg A, Malling HJ, Poulsen LK. Association between alcohol

consumption and skin prick test reactivity to aeroallergens. Ann Allergy Asthma Immunol

2007 Jan;98(1):70-4.

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(15) Gonzalez-Quintela A, Gude F, Boquete O, Rey J, Meijide LM, Suarez F, et al. Association

of alcohol consumption with total serum immunoglobulin E levels and allergic sensitization

in an adult population-based survey. Clin Exp Allergy 2003 Feb;33(2):199-205.

(16) Gonzalez-Quintela A, Vidal C, Gude F. Alcohol, IgE and allergy. Addict Biol 2004

Sep;9(3-4):195-204.

(17) Linneberg A, Nielsen NH, Madsen F, Frolund L, Dirksen A, Jorgensen T. Factors related to

allergic sensitization to aeroallergens in a cross-sectional study in adults: The Copenhagen

Allergy Study. Clin Exp Allergy 2001 Sep;31(9):1409-17.

(18) Linneberg A, Petersen J, Nielsen NH, Madsen F, Frolund L, Dirksen A, et al. The

relationship of alcohol consumption to total immunoglobulin E and the development of

immunoglobulin E sensitization: the Copenhagen Allergy Study. Clin Exp Allergy 2003

Feb;33(2):192-8.

(19) Vidal C, Armisen M, Dominguez-Santalla MJ, Gude F, Lojo S, Gonzalez-Quintela A.

Influence of alcohol consumption on serum immunoglobulin E levels in atopic and

nonatopic adults. Alcohol Clin Exp Res 2002 Jan;26(1):59-64.

(20) Linneberg A, Nielsen NH, Madsen F, Frolund L, Dirksen A, Jorgensen T. Smoking and the

development of allergic sensitization to aeroallergens in adults: a prospective population-

based study. The Copenhagen Allergy Study. Allergy 2001 Apr;56(4):328-32.

(21) Wuthrich B, Schindler C, Medici TC, Zellweger JP, Leuenberger P. IgE levels, atopy

markers and hay fever in relation to age, sex and smoking status in a normal adult Swiss

population. SAPALDIA (Swiss Study on Air Pollution and Lung Diseases in Adults) Team.

Int Arch Allergy Immunol 1996 Dec;111(4):396-402.

(22) Gergen PJ, Turkeltaub PC. The association of allergen skin test reactivity and respiratory

disease among whites in the US population. Data from the Second National Health and

Nutrition Examination Survey, 1976 to 1980. Arch Intern Med 1991 Mar;151(3):487-92.

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Appendix

Table 1. Information about the genetic marker

rs-number of the SNP

Minor allele

Major allele

Number of subjects homozygous for minor allele

Number of heterozygous subjects

Number of subjects homozygous for major allele

Hardy Weinberg Equilibrium test

(chi-square test, p-value with 3 decimals)

Table 2. Prevalence of outcomes stratified by smoking status

Median/IQR/range Prevalence, n

Age N Male sex Hay fever

Asthma

Allergic

sensitization*

Never smokers

Former smoker

Current smokers

Ever smokers

Total

* variable name ‘atopy’. Abbreviations: IQR, interquartile range

Table 3. Prevalence of outcomes stratified by genotype and smoking status

Prevalence, n

Genotype by smoking

status

Ntotal

Hay fever

Asthma

Allergic

sensitization*

Never smokers

Major homozygotes*

Heterozygotes*

Minor homozygotes*

Former smokers

Major homozygotes*

Heterozygotes*

Minor homozygotes*

Current smokers

Major homozygotes*

Heterozygotes*

Minor homozygotes*

Ever smokers

Major homozygotes*

Heterozygotes*

Minor homozygotes*

* variable name ‘atopy’

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Table 4. Results of logistic regression analyses stratified by smoking status

Model Ntotal Log OR*

Log (standard

error)

P-value

(3 decimals)

Never smokers

Hay fever = SNP

Hay fever = SNP + sex + age

Asthma = SNP

Asthma = SNP + sex + age

Allergic sensitization** = SNP

Allergic sensitization **= SNP + sex + age

Former smokers

Hay fever = SNP


Asthma = SNP


Allergic sensitization **= SNP

Allergic sensitization** = SNP + sex + age

Current smokers

Hay fever = SNP


Asthma = SNP


Allergic sensitization** = SNP

Allergic sensitization** = SNP + sex + age

Ever smokers

Hay fever = SNP


Asthma = SNP


Allergic sensitization **= SNP

Allergic sensitization **= SNP + sex + age

*estimate per smoking increasing allele.

** variable name ‘atopy’.

Abbreviations: OR, odds ratio; CI, confidence intervals

Table 5. Observational effects of smoking status

Logistic regression models Unadjusted Age and sex adjusted

Outcome Smoking

status

Ntotal Log OR Log

(standard

error)

P-value

(3 decimals)

Log OR Log

(standard

error)

P-value

(3 decimals)

Hay fever Never 0 (reference) 0 (reference)

Former

Current

Asthma Never 0 (reference) 0 (reference)

Former

Current

Allergic sensitization* Never 0 (reference) 0 (reference)

Former

Current * variable name ‘atopy’. Abbreviations: OR, odds ratio; CI, confidence intervals

Table 6: Observational effects of smoking heaviness in current smokers only

Unadjusted Age and sex adjusted

Outcome Ntotal Log OR * Log (standard

error)

P-value

(3 decimals)

Log OR* Log (standard

error)

P-value

(3 decimals)

Hay fever

Asthma

Allergic sensitization**

* Estimate per 1 cigarette increase. **

variable name ‘atopy’.

Abbreviations: OR, odds ratio; CI, confidence intervals

Table 7. Linear regression analyses of the association between the genotype and smoking quantity in current

smokers

Model N**

ß-estimate per

allele*

Standard

error

P-value

(3 decimals)

Current smokers

Smoking quantity = SNP

Smoking quantity = SNP + sex + age *i.e. estimate per smoking increasing allele.

** Please notice that only current smokers are included in this table.

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Table 8. General information (please provide references where available)

Study name

Co-authors

Name

Title

Position (senior

author, PI,

analyst…)

Affiliations

E-mail address

Do you have any

disclosures

(conflicts of

interest) in relation

to the present

project/paper?

Description of study

population

Study design*

Sampling frame**

SNP: rs-number,

minor, major allele

Description of

method for

genotyping and call

rate (%)

Description of

definition of hay

fever (incl. % missing

data relative to hay

fever)

Description of

definition of asthma (incl. % missing data

relative to asthma)

Method for

determining allergic

sensitization***

(incl. % missing data

relative to allergic

sensitization)

Are the analyses in this table adjusted for

principal component (Yes/no)?

Has the observational or genetic data been

published? * E.g., cohort, case control etc.

** E.g., population, hospital etc.

*** Serum specific IgE sensitivity or skin prick test

against inhalant allergens, variable name ‘atopy’. Abbreviations: PI, principal investigator.

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