title: A common functional variant on the pro-inflammatory Interleukin-6 gene may modify the association between long-term PM10 exposure and diabetes.
abstract: BACKGROUND
  Air pollutants have been linked to type 2 diabetes (T2D), hypothesized to act through inflammatory pathways and may induce interleukin-6 gene (IL6) in the airway epithelium. The cytokine interleukin-6 may impact on glucose homeostasis. Recent meta-analyses showed the common polymorphisms, IL6 -572G > C and IL6 -174G > C to be associated with T2D risk. These IL6 variants also influence circulatory interleukin-6 levels. We hypothesize that these common functional variants may modify the association between air pollutants and T2D.
  
  
  METHODS
  We cross-sectionally studied 4410 first follow-up participants of the Swiss Cohort Study on Air Pollution and Lung and Heart Diseases (SAPALDIA), aged 29 to 73 years who had complete data on genotypes, diabetes status and covariates. We defined diabetes as self-reported physician-diagnosed, or use of diabetes medication or non-fasting glucose >11.1 mmol/L or HbA1c > 0.065. Air pollution exposure was 10-year mean particulate matter <10 μm in diameter (PM10) assigned to participants' residences using a combination of dispersion modelling, annual trends at monitoring stations and residential history. We derived interaction terms between PM10 and genotypes, and applied mixed logistic models to explore genetic interactions by IL6 polymorphisms on the odds of diabetes.
  
  
  RESULTS
  There were 252 diabetes cases. Respective minor allele frequencies of IL6 -572G > C and IL6 -174G > C were 7 and 39 %. Mean exposure to PM10 was 22 μg/m(3). Both variants were not associated with diabetes in our study. We observed a significant positive association between PM10 and diabetes among homozygous carriers of the pro-inflammatory major G-allele of IL6 -572G > C [Odds ratio: 1.53; 95 % confidence interval (1.22, 1.92); P interaction (additive) = 0.003 and P interaction (recessive) = 0.006]. Carriers of the major G-allele of IL6 -174G > C also had significantly increased odds of diabetes, but interactions were statistically non-significant.
  
  
  CONCLUSIONS
  Our results on the interaction of PM10 with functionally well described polymorphisms in an important pro-inflammatory candidate gene are consistent with the hypothesis that air pollutants impact on T2D through inflammatory pathways. Our findings, if confirmed, are of high public health relevance considering the ubiquity of the major G allele, which puts a substantial proportion of the population at risk for the development of diabetes as a result of long-term exposure to air pollution.
authors.affiliation: Swiss Tropical and Public Health Institute, Basel, Switzerland. ikenna.eze@unibas.ch.|University of Basel, Basel, Switzerland. ikenna.eze@unibas.ch.
authors.forename: Ikenna C
authors.initials: IC
authors.lastname: Eze
authors.affiliation: Swiss Tropical and Public Health Institute, Basel, Switzerland. medea.imboden@unibas.ch.|University of Basel, Basel, Switzerland. medea.imboden@unibas.ch.
authors.forename: Medea
authors.initials: M
authors.lastname: Imboden
authors.affiliation: Swiss Tropical and Public Health Institute, Basel, Switzerland. ashish.kumar@unibas.ch.|University of Basel, Basel, Switzerland. ashish.kumar@unibas.ch.|Karolinska Institutet, Stockholm, Sweden. ashish.kumar@unibas.ch.
authors.forename: Ashish
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Swiss Tropical and Public Health Institute, Basel, Switzerland. martin.adam@unibas.ch.|University of Basel, Basel, Switzerland. martin.adam@unibas.ch.
authors.forename: Martin
authors.initials: M
authors.lastname: Adam
authors.affiliation: Institute of Clinical Chemistry, University Hospital Zurich, Zurich, Switzerland. arnold.voneckardstein@ikc.usz.ch.
authors.forename: Arnold
authors.initials: A
authors.lastname: von Eckardstein
authors.affiliation: Clinic of Pneumology and Respiratory Cell Research, University Hospital Basel, Basel, Switzerland. daiana.stolz@usb.ch.
authors.forename: Daiana
authors.initials: D
authors.lastname: Stolz
authors.affiliation: Faculty of Medicine, University of Geneva, Geneva, Switzerland. margaret.gerbase@unige.ch.
authors.forename: Margaret W
authors.initials: MW
authors.lastname: Gerbase
authors.affiliation: Swiss Tropical and Public Health Institute, Basel, Switzerland. nino.kuenzli@unibas.ch.|University of Basel, Basel, Switzerland. nino.kuenzli@unibas.ch.
authors.forename: Nino
authors.initials: N
authors.lastname: Künzli
authors.affiliation: Zürcher Höhenklinik Wald, Faltigberg-Wald, Switzerland. alexander.turk@zhw.ch.
authors.forename: Alexander
authors.initials: A
authors.lastname: Turk
authors.affiliation: Swiss Tropical and Public Health Institute, Basel, Switzerland. christian.schindler@unibas.ch.|University of Basel, Basel, Switzerland. christian.schindler@unibas.ch.
authors.forename: Christian
authors.initials: C
authors.lastname: Schindler
authors.affiliation: Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria. florian.kronenberg@i-med.ac.at.|Department of Epidemiology and Public Health, Swiss Tropical and Public Health Institute, Socinstrasse 57, CH-4002, Basel, Switzerland. florian.kronenberg@i-med.ac.at.
authors.forename: Florian
authors.initials: F
authors.lastname: Kronenberg
authors.affiliation: Swiss Tropical and Public Health Institute, Basel, Switzerland. nicole.probst@unibas.ch.|University of Basel, Basel, Switzerland. nicole.probst@unibas.ch.
authors.forename: Nicole
authors.initials: N
authors.lastname: Probst-Hensch
mesh_terms: D000328:Adult; D000368:Aged; D000393:Air Pollutants / Q000032:analysis / Q000633:toxicity*; D000483:Alleles; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology / Q000235:genetics* / Q000276:immunology; D004781:Environmental Exposure / Q000009:adverse effects; D005260:Female; D005838:Genotype; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008962:Models, Theoretical; D052638:Particulate Matter / Q000032:analysis / Q000633:toxicity*; D020641:Polymorphism, Single Nucleotide; D013557:Switzerland / Q000453:epidemiology
chemical_list: D000393:Air Pollutants; C508600:IL6 protein, human; D015850:Interleukin-6; D052638:Particulate Matter