NAT1 in an important genetic effect modifier of tobacco smoke exposure in multiple sclerosis susceptibility in 5,453 individuals. F. B. S. Briggs1, B. Acuna2, L. Shen2, H. Quach1, A. Bernstein3, I. Kockum4, A. K. Hedström5, M. W. Gustavsen6,7, P. Berg-Hansen6, S. D. Bos6,7, E. Gulowsen Celius6, H. F. Harbo6,7, L. Alfredsson5, T. Olsson4, C. Schaefer2, L. F. Barcellos1,2 1) Genetic Epidemiology and Genomics Laboratory, Division of Epidemiology, School of Public Health, University of California, Berkeley, Berkeley, CA; 2) Division of Research, Kaiser Permanente, Oakland, CA; 3) Palm Drive Hospital, Sebastopol, CA; 4) Center for Molecular Medicine, Department of Medicine, Karolinska Institute, Sweden; 5) Institute of Environmental Medicine, Karolinska Institute, Sweden; 6) Department of Neurology, Oslo University Hospital, Oslo, Norway; 7) University of Oslo, Norway.

   Multiple sclerosis (MS) is a neuro-inflammatory autoimmune disease with genetic and environmental components. Tobacco smoke (TS) is one of a few environmental exposures known to increase MS risk. However, not all smokers develop MS and only some individuals with MS were smokers. We hypothesized that host genetics contributing to TS metabolism modifies risk conferred by TS. A multi-stage gene-environment (GxE) analysis assessed variation within NAT1, NAT2, GSTM1, GSTP1 and GSTT1, and metabolic phenotypes (GSTM1 and GSTT1 null, NAT1 and NAT2 slow/fast acetylators) and TS. Data from three large White population-based studies were utilized: Northern California, Norway, and Sweden. The 1st stage analysis was comprised of 2576 subjects with densely imputed genetic data. History of TS conferred MS risk (OR=1.4, P<0.0005), adjusted for age, gender, education, and population ancestry. In the discovery analysis of 1588 subjects, 42 NAT1 variants showed evidence for interaction with TS (Pcorrected<0.05). 41 NAT1 SNPs were studied in a replication data set of 988 subjects, and a significant GxE interaction replicated. In the combined 1st stage meta-analysis of 2576 subjects NAT1 rs7388368 had an OR of interaction (ORI)=1.7 (P<0.0005). In stratified analyses, TS was associated with MS risk among rs7388368A carriers only; homozygote individuals (A/A) had highest risk (C/C: OR=1.1, P=0.3; A/C: OR=1.6, P=0.001; A/A: OR=5.2, P<0.0005). Similar GxE associations were observed when smoking status at age 20 was used (ORI=1.4, P<0.05); and the TS conferred the greatest risk among rs7388368A homozygote subjects (OR=3.4, P=0.006). We have identified and replicated a GxE interaction in MS, identifying NAT1 as a strong genetic effect modifier of TS exposure on MS risk in 2576 subjects. Rs7388368 variation affects four regulatory motifs where three transcription factors (TFs) bind, and resides adjacent to an insulator. Also, SNPs in linkage disequilibrium with rs7388368 (r2>0.65), have been correlated with decreased NAT1 expression in lymphoblastoid cells, suggesting a role in transcription. Therefore, all subjects are being genotyped for NAT1 SNPs within 8 TF binding sites on a custom TaqMan OpenArray platform. These TF sites are within/near two promoters that result in transcription of various NAT1 isoforms. A 2nd stage meta-analysis of the independent 2877 subjects demonstrated similar associations for TS and MS risk (OR=1.5, P=9x10-8), and GxE analyses are currently underway.

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