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* Dept of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands # Dept of Pulmonology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands ¶ Dept of Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
CORRESPONDENCE: Cleo C. van Diemen, Dept of Epidemiology, University of Groningen, University Medical Center, Groningen, The Netherlands
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ABSTRACT |
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 TOP ABSTRACT Polymorphisms in surfactant...MY JOB AND THE...MY WINNING ABSTRACT AS...MY RESEARCH AS PART...THE IMPACT OF MY...REFERENCES |
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To assess whether SNPs in ADAM33 are associated with accelerated lung function loss in the general population and with chronic obstructive pulmonary disease (COPD).
We have collected DNA from subjects of the Vlagtwedde/Vlaardingen cohort participating in the last survey in 1989/1990 after a follow up of 25 years. Information was collected every 3 years, including lung function measurements. We defined COPD as GOLD stage 2 or higher at the last survey. 1390 subjects from the cohort were genotyped for the following SNPs in ADAM33: F+1, Q–1, S_1, S_2, T_1, T_2, V_4, ST+5. Differences in prevalence of SNPs were analyzed with chi-square tests. Linear mixed effects models were used to analyze FEV1 decline according to genotype.
In the whole population mean adjusted decline was 18.7 and 12.7 ml·y–1 in females and males respectively. Individuals homozygous for minor alleles of SNPs S_2 and Q–1 and heterozygous for SNP S_1 had a significantly accelerated decline in FEV1 of respectively 4.9, 9.6 and 3.6 ml·y–1 compared with wild type. We found a significantly higher prevalence of SNPs F+1, S_1, S_2 and T_2 in subjects with COPD.
We demonstrated that SNPs in ADAM33 are associated with accelerated lung function decline in the general population. These SNPs are also risk factors for COPD.
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Polymorphisms in surfactant proteins are associated with FEV1 decline and development of COPD in the general population |
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TOPABSTRACTPolymorphisms in surfactant...MY JOB AND THE...MY WINNING ABSTRACT AS...MY RESEARCH AS PART...THE IMPACT OF MY...REFERENCES |
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*Dept of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
#Dept of Pulmonology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
WINNING ABSTRACT: Surfactant proteins (SP) are involved in the first response to microorganisms in the lung, regulation of inflammation and structure of alveoli. Single nucleotide polymorphisms (SNPs) in these genes have been associated with COPD prevalence.
To assess whether SNPs in SP-A1, -A2, -B, and -D are associated with development of COPD and FEV1 decline in the general population.
1390 Caucasians from a longitudinal follow-up study (characteristics median (range): 51% male, pack-years 8 (0–161), age 52 (35–79) years, FEV1 92 (15–137) %pred). COPD was defined as GOLD 
stage II. We analyzed: SP-A1 Val19Ala, Leu50Val, Arg219Trp; SP-A2 Asn9Thr, Pro91Ala, Ser140Ser; SP-B Ile131Thr; SP-D Met11Thr, Thr160Ala; haplotypes of SP-A1 and -A2. Differences in prevalence of genotypes were analyzed with X2-tests. FEV1 decline according to genotype was analyzed using linear mixed effect models with adjustment for confounders.
Heterozygous subjects for the SP-D Met11Thr SNP had a significantly larger decline in FEV1 of 2.9 ml·y–1 compared to wild type (P = 0.03). In COPD subjects, those heterozygous for SNP SP-A1 Leu50Val had 11.0 ml·y–1 less FEV1 decline compared to wild type (p = 0.018). SNPs SP-D Met11Thr, SP-A1 Leu50Val, and SP-A2 Ala91Pro were differently distributed in subjects with and without COPD (P-values respectively 0.045, 0.002, 0.024).
This is the first study to show that the SP-D Met11Thr SNP is associated with faster decline in FEV1 and with development of COPD in the general population. SNP SP-A1 Leu50Val was only associated with FEV1 decline within subjects with COPD, indicating that SNPs may have different effects depending on disease state.
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MY JOB AND THE UNIT IN WHICH I WORK |
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TOPABSTRACTPolymorphisms in surfactant...MY JOB AND THE...MY WINNING ABSTRACT AS...MY RESEARCH AS PART...THE IMPACT OF MY...REFERENCES |
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Nowadays, a large part of the research is specifically focused on the role of genetics and gene–environment interaction in the development of respiratory disease. In addition to this specific line of research, the Dept of Epidemiology offers statistical and methodological advice to other research groups of the UMCG, and scientific and methodological training to MD and PhD students of the UMCG.
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MY WINNING ABSTRACT AS PART OF MY RESEARCH |
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TOPABSTRACTPolymorphisms in surfactant...MY JOB AND THE...MY WINNING ABSTRACT AS...MY RESEARCH AS PART...THE IMPACT OF MY...REFERENCES |
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COPD is almost completely caused by the environmental factor smoking, with the exception of the genetic predominance of 
1-antitrypsin (AT) deficiency gene, the carriers of which need no further environmental smoke exposure to develop a phenotypic expression of COPD. However, 1-AT deficiency accounts for only a small number of COPD cases worldwide (<1%) and therefore cannot explain the majority of individuals who develop COPD at elderly age ("the garden variety COPD").
COPD is characterised by reduced levels of forced expiratory volume in one second (FEV1), which provides the most important and robust phenotype of COPD, and predicts the progression of the disease and overall mortality [1, 2]. The level of lung function is both environmentally and genetically determined. In past decades, the environmental determinants have been studied extensively, i.e. smoking, air pollution, occupational exposure, diet and exposure to respiratory allergens. These studies have shown clear associations between certain exposures, e.g. cigarette smoking, and the development of COPD. However, it is less clear why some smokers develop COPD and other smokers do not. It is important to understand why some people are genetically susceptible to developing COPD while others are not, since it may provide new insights into the disease, potentially leading to better treatments. The genetic determinants have been studied less frequently and consistently, partly because they are more complicated to study, as COPD is a disease that is merely expressed at older ages. The "traditional" types of genetic studies, like those performed within families, are difficult to perform because the parents of individuals with COPD have often already died and the children of subjects with COPD are likely to be too young to manifest airway obstruction at that age.
Case–control studies investigating COPD patients and healthy controls are generally used to study the genetics of COPD. So far these studies have been small in size. Furthermore, the disease is only investigated when symptoms are present, without acknowledging the different patterns of lung function loss that evolve, i.e. abnormally high rate of decline in lung function, submaximally attained level of lung function, or abnormally early age of onset of decline. Genetic factors may affect any or a combination of these different patterns of lung function loss. Therefore, it is important to study multiple measurements of lung function in a well-characterised cohort followed throughout life. We have the unique opportunity to investigate susceptibility genes for excess lung function decline in the Vlagtwedde/Vlaardingen cohort. This large cohort of male and female smokers and nonsmokers from a general population sample has been followed over a 25-yr period. This will not only allow us to study the contribution of genetic variations to decline in lung function, but also to study the genes involved in previously well-established risk factors for lung function course and decline in this population, i.e. airway hyperresponsiveness and blood eosinophilia.
In our studies, we have chosen to study a robust phenotype, namely level of FEV1 and rate of decline in FEV1. The publication that was awarded best paper (third prize) in the Occupation and Epidemiology assembly describes the results obtained in a study in which we analysed the effects of single nucleotide polymorphisms (SNPs) in ADAM33 on FEV1 decline and the development of COPD in the Vlagtwedde/Vlaardingen population [3]. We found that SNPs in ADAM33 are predictive of excess FEV1 decline in this general population and development of COPD. Combined with the previous findings that the ADAM33 gene is associated with FEV1 decline in asthmatics [4], these results suggest that SNPs in ADAM33 affect lung function decline overall, independently of asthma or COPD status, and may thus constitute a lung function ageing gene.
The abstract belonging to the best poster award describes the association of polymorphisms in surfactant proteins-A1, -A2, -C and -D with development of COPD and FEV1 decline in the Vlagtwedde/Vlaardingen population.
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MY RESEARCH AS PART OF MY WORKING GROUP/RESEARCH TEAM |
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TOPABSTRACTPolymorphisms in surfactant...MY JOB AND THE...MY WINNING ABSTRACT AS...MY RESEARCH AS PART...THE IMPACT OF MY...REFERENCES |
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The PhD project that I perform fits into the first and second aims of the GRIAC, namely identifying genes associated with COPD and lung function decline regarded in an epidemiological background.
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THE IMPACT OF MY WORK ON CLINICAL OR RESEARCH PRACTICE |
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TOPABSTRACTPolymorphisms in surfactant...MY JOB AND THE...MY WINNING ABSTRACT AS...MY RESEARCH AS PART...THE IMPACT OF MY...REFERENCES |
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TOPABSTRACTPolymorphisms in surfactant...MY JOB AND THE...MY WINNING ABSTRACT AS...MY RESEARCH AS PART...THE IMPACT OF MY...REFERENCES |
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