A novel interaction between the FLJ33534 locus and smoking in obesity: a genome-wide study of 14 131 Pakistani adults.
BACKGROUND
Obesity is a complex disease caused by the interplay of genetic and lifestyle factors, but identification of gene-lifestyle interactions in obesity has remained challenging. Few large-scale studies have reported use of genome-wide approaches to investigate gene-lifestyle interactions in obesity.


METHODS
In the Pakistan Risk of Myocardial Infraction Study, a cross-sectional study based in Pakistan, we calculated body mass index (BMI) variance estimates (square of the residual of inverse-normal transformed BMI z-score) in 14 131 participants and conducted genome-wide heterogeneity of variance analyses (GWHVA) for this outcome. All analyses were adjusted for age, age(2), sex and genetic ancestry.


RESULTS
The GWHVA analyses identified an intronic variant, rs140133294, in the FLJ33544 gene in association with BMI variance (P-value=3.1 × 10(-8)). In explicit tests of gene × lifestyle interaction, smoking was found to significantly modify the effect of rs140133294 on BMI (Pinteraction=0.0005), whereby the minor allele (T) was associated with lower BMI in current smokers, while positively associated with BMI in never smokers. Analyses of ENCODE data at the FLJ33534 locus revealed features indicative of open chromatin and high confidence DNA-binding motifs for several transcription factors, providing suggestive biological support for a mechanism of interaction.


CONCLUSIONS
In summary, we have identified a novel interaction between smoking and variation at the FLJ33534 locus in relation to BMI in people from Pakistan.
Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University Diabetes Centre, Skåne University Hospital, Lund University, Malmö, Sweden.
S
S
Ahmad
Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
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http://orcid.org/0000-0002-8301-9297
W
Zhao
Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University Diabetes Centre, Skåne University Hospital, Lund University, Malmö, Sweden.
F
F
Renström
Center for Non-Communicable Diseases Pakistan, Karachi, Pakistan.
A
A
Rasheed
Center for Non-Communicable Diseases Pakistan, Karachi, Pakistan.
M
M
Zaidi
Center for Non-Communicable Diseases Pakistan, Karachi, Pakistan.
M
M
Samuel
Center for Non-Communicable Diseases Pakistan, Karachi, Pakistan.|Department of Pharmacy, COMSATS Institute of Information Technology, Abbottabad, Pakistan.
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N
Shah
Punjab Institute of Cardiology, Lahore, Pakistan.
N H
NH
Mallick
Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University Diabetes Centre, Skåne University Hospital, Lund University, Malmö, Sweden.|Department of Public Health and Clinical Medicine, Section for Medicine, Umeå University, Umeå, Sweden.|Department of Odontology, Umeå University, Umeå, Sweden.
D
D
Shungin
National Institute of Cardiovascular Diseases, Karachi, Pakistan.
K S
KS
Zaman
Karachi Institute of Heart Diseases, Karachi, Pakistan.
M
M
Ishaq
Karachi Institute of Heart Diseases, Karachi, Pakistan.
S Z
SZ
Rasheed
Red Crescent Institute of Cardiology, Hyderabad, Karachi, Pakistan.
F-Ur-R
FU
Memon
Tabba Heart Institute, Karachi, Pakistan.
B
B
Hanif
Tabba Heart Institute, Karachi, Pakistan.
M S
MS
Lakhani
Department of Cardiology, Liaquat National Hospital, Karachi, Pakistan.
F
F
Ahmed
Department of Microbiology, University of Karachi, Karachi, Pakistan.
S U
SU
Kazmi
William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.|Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, Saudi Arabia.
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P
Deloukas
Center for Non-Communicable Diseases Pakistan, Karachi, Pakistan.|Nazarbayev University, Astana, Kazakhstan.
P
P
Frossard
Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University Diabetes Centre, Skåne University Hospital, Lund University, Malmö, Sweden.|Department of Public Health and Clinical Medicine, Section for Medicine, Umeå University, Umeå, Sweden.|Department of Nutrition, Harvard School of Public Health, Boston, MA, USA.
P W
PW
Franks
Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.|Center for Non-Communicable Diseases Pakistan, Karachi, Pakistan.|Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA, USA.
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Saleheen
D000328:Adult; D044466:Asian People / Q000235:genetics; D015992:Body Mass Index; D003430:Cross-Sectional Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008019:Life Style; D008297:Male; D009765:Obesity / Q000150:complications / Q000453:epidemiology / Q000235:genetics*; D010154:Pakistan / Q000453:epidemiology; D020641:Polymorphism, Single Nucleotide; D011978:Receptors, Nicotinic; D012907:Smoking / Q000453:epidemiology / Q000235:genetics*
D011978:Receptors, Nicotinic