Association of FTO With Obesity-Related Traits in the Cebu Longitudinal Health and Nutrition Survey (CLHNS) Cohort

Abstract

The underlying genetic component of obesity-related traits is not well understood, and there is limited evidence to support genetic association shared across multiple studies, populations, and environmental contexts. The present study investigated the association between candidate variants and obesity-related traits in a sample of 1,886 adult Filipino women from the Cebu Longitudinal Health and Nutrition Survey (CLHNS) cohort.
We selected and genotyped 19 single nucleotide polymorphisms in 10 genes (ADRB2, ADRB3, FTO, GNB3, INSIG2, LEPR, PPARG, TNF, UCP2, and UCP3) that had been previously reported to be associated with an obesity-related quantitative trait.
We observed evidence for association of the A allele of rs9939609 (FTO intron 1) with increased BMI (P = 0.0072 before multiple test correction), baseline BMI (P = 0.0015), longitudinal BMI based on eight surveys from 1983 to 2005 (P = 0.000029), waist circumference (P = 0.0094), and weight (P = 0.021). The increase in average BMI was approximately 0.4 for each additional A allele. We also observed association of the ADRB3 Trp64Arg variant with BMI, waist circumference, percent body fat, weight, fat mass, arm fat area, and arm muscle area (P < 0.05), although the direction of effect is inconsistent with the majority of previous reports.
Our study confirms that FTO is a common obesity susceptibility gene in Filipinos, with an effect size similar to that seen in samples of European origin.

Full text

Association of FTO With Obesity-Related Traits in the
Cebu Longitudinal Health and Nutrition Survey (CLHNS)
Cohort
Amanda F. Marvelle,
1
Leslie A. Lange,
1
Li Qin,
1
Linda S. Adair,
2
and Karen L. Mohlke
1
OBJECTIVE—The underlying genetic component of obesity-
related traits is not well understood, and there is limited evidence
to support genetic association shared across multiple studies,
populations, and environmental contexts. The present study
investigated the association between candidate variants and
obesity-related traits in a sample of 1,886 adult Filipino women
from the Cebu Longitudinal Health and Nutrition Survey
(CLHNS) cohort.
RESEARCH DESIGN AND METHODS—We selected and
genotyped 19 single nucleotide polymorphisms in 10 genes
(ADRB2,ADRB3,FTO,GNB3,INSIG2,LEPR, PPARG,TNF,
UCP2, and UCP3) that had been previously reported to be
associated with an obesity-related quantitative trait.
RESULTS—We observed evidence for association of the A allele
of rs9939609 (FTO intron 1) with increased BMI (P⫽0.0072
before multiple test correction), baseline BMI (P⫽0.0015),
longitudinal BMI based on eight surveys from 1983 to 2005 (P⫽
0.000029), waist circumference (P⫽0.0094), and weight (P⫽
0.021). The increase in average BMI was ⬃0.4 for each additional
A allele. We also observed association of the ADRB3 Trp64Arg
variant with BMI, waist circumference, percent body fat, weight,
fat mass, arm fat area, and arm muscle area (P⬍0.05), although
the direction of effect is inconsistent with the majority of
previous reports.
CONCLUSIONS—Our study confirms that FTO is a common
obesity susceptibility gene in Filipinos, with an effect size similar
to that seen in samples of European origin. Diabetes 57:
1987–1991, 2008
Obesity is a worldwide epidemic, affecting indi-
viduals across all age groups, socioeconomic
classes, and ethnicities; numerous association
studies have attempted to identify genetic vari-
ants that influence susceptibility to obesity (1). As of 2005,
22 candidate genes contained a variant reported to be
associated (P⬍0.05) with an obesity-related trait in at
least five studies; however, additional reports for these
genes have been inconsistent (1).
More recently, genome-wide association (GWA) studies
have identified variants in additional genes. Single nucle-
otide polymorphism (SNP) rs7566605, near insulin-in-
duced gene 2 (INSIG2) and found to be associated with
BMI (2), has not been consistently replicated (3–7). Sev-
eral variants in the fat mass– and obesity-associated (FTO)
gene identified through two independent GWA studies
(8,9) and a third study (10) were associated with BMI and
risk of being overweight in children and adults in cohorts
of Europeans, European Americans, and Hispanic Ameri-
cans, but not in African Americans. FTO association was
also observed for hip circumference, waist circumference,
and subcutaneous fat mass assessed using skinfolds (8,9).
Two studies observed FTO association with percentage of
fat mass and dual-energy X-ray absorptiometry– derived
fat mass in children (8,10). FTO variants have the most
consistent replication across multiple populations to date,
suggesting that this locus is a likely risk factor for obesity.
In the current study, we examined 19 SNPs previously
reported to be associated with obesity-related phenotypes
for association with BMI, waist circumference, and per-
cent body fat in 1,886 Filipino women from the Cebu
Longitudinal Health and Nutrition Survey (CLHNS). For
SNPs with initial evidence of association, we performed
analysis with additional obesity phenotypes.
RESEARCH DESIGN AND METHODS
We evaluated 1,886 unrelated healthy Cebu Filipino female participants in the
ongoing CLHNS (11), mothers of a 1983–1984 birth cohort. Trained field staff
conducted in-home interviews and collected measurements and comprehen-
sive environmental data (www.cpc.unc.edu/projects/cebu). We used data
collected from nonpregnant subjects during surveys in 1983–1984 (baseline at
4 months postpartum), 1984 –1985 (1 year postpartum), 1985–1986, 1991, 1994,
1998, 2002, and 2005. For 2005 cross-sectional traits, outcome and covariate
measures from the 2002 survey were substituted for 16 women who were
pregnant or missing data in 2005.
All outcome and covariate measures, except baseline BMI, were taken
from the 2005 survey. Triceps and suprailiac skinfold thicknesses (TSF and
SiSF) represent the mean of three consecutive Harpenden caliper measure-
ments. Cross-sectional arm muscle area (AMA) and arm fat area (AFA) were
calculated using mid-arm circumference and triceps skinfold thickness. Body
density was calculated using the Durnin-Womersley sum of skinfold equation
based on TSF and SiSF for adult women aged 16 –68 years (12), and percent
body fat was derived from body density using the Siri equation (13). Fat mass
was calculated as the product of percent body fat and weight. Height was
calculated as an average of eight measures across surveys from 1983–1984 to
2005. Informed consent was obtained from all individuals, and the study
protocol was approved by the University of North Carolina Institutional
Review Board for the Protection of Human Subjects.
SNP selection and genotyping methods. We reviewed genes that exhibited
nine or more reports of association with an obesity phenotype, as summarized
by the 2004 obesity gene map (1). SNPs within these genes with more than
three positive reports of association and a minor allele frequency ⬎0.01 in the
Han Chinese Bejing HapMap samples were subsequently chosen to be
genotyped. Variants in FTO and INSIG2, identified through GWA studies, were
also genotyped (2,8).
Genotyping was performed using TaqMan allelic discrimination (Applied
From the
1
Department of Genetics, School of Medicine, University of North
Carolina at Chapel Hill, Chapel Hill, North Carolina; and the
2
Department of
Nutrition, the Schools of Public Health and Medicine, University of North
Carolina at Chapel Hill, Chapel Hill, North Carolina.
Corresponding author: Karen Mohlke, mohlke@med.unc.edu.
Received 3 December 2007 and accepted 15 April 2008.
Published ahead of print at http://diabetes.diabetesjournals.org on 21 April
2008. DOI: 10.2337/db07-1700.
© 2008 by the American Diabetes Association. Readers may use this article as
long as the work is properly cited, the use is educational and not for profit,
and the work is not altered. See http://creativecommons.org/licenses/by
-nc-nd/3.0/ for details.
The costs of publication of this article were defrayed in part by the payment of page
charges. This article must therefore be hereby marked “advertisement” in accordance
with 18 U.S.C. Section 1734 solely to indicate this fact.
BRIEF REPORT
DIABETES, VOL. 57, JULY 2008 1987

Biosystems, Foster City, CA). The genotype success rate for all SNPs was
⬎98%, and the discrepancy rate among duplicate samples was 0.1%.
Statistical analysis. Tests for consistency of genotype distributions with
expected Hardy-Weinberg equilibrium proportions were calculated using
Pearson’s ␹
2
statistic; only rs3856806 was inconsistent (P⫽0.02). ANCOVA
models were used to test for association between genotype and continuously
distributed outcomes. Logistic regression models were used for dichotomous
outcomes. We performed a longitudinal analysis incorporating all available
BMI measurements for the up to eight measurements spanning 22 years using
general linear mixed models.
Models were adjusted for age, household assets, natural log of income,
number of total past pregnancies as a categorical variable (1– 4, 5–10, and
⬎10), and menopausal status; baseline BMI was not adjusted for menopausal
status. Each of these predictors was significantly (P⬍0.05) associated with
BMI in a multivariable model in our sample. Continuously distributed traits
were transformed to satisfy the model assumption of normally distributed
residuals, conditional on the covariates. The additive mode of inheritance
assumption was used unless ⬍15 rare homozygotes existed; the dominant
mode of inheritance assumption for the minor allele was used for SNPs
rs4994, rs8179183, rs1801282, and rs1800629. The rs9939609 SNP in FTO was
also analyzed under both additive and dominant models for comparison with
previous reports. Because of low linkage disequilibrium (r
2
⬍0.5) between
pairs of SNPs, Bonferroni adjustment was used to account for multiple tests.
We estimated that a SNP must explain at least 0.45% of the total variation
in BMI to achieve at least 80% statistical power to detect an association in this
sample, assuming a significance threshold of 5% and an additive mode of
inheritance. For a SNP with a minor allele frequency (MAF) of 0.03 or 0.50,
this effect would correspond with a change in mean BMI of 1.2 or 0.42 kg/m
2
,
respectively, for each additional copy of the variant allele. For rs9939609, our
power to detect a difference in BMI of 0.8 units between the homozygotes,
approximately as observed by Frayling et al. (8), was 57%.
RESULTS
Of 19 SNPs tested for association with 2005 BMI, waist
circumference, and percent body fat (Table 1), two SNPs
were associated (P⬍0.01) with at least one trait before
correction for multiple tests (supplementary Table 1
[available in an online appendix at http://dx.doi.org/
10.2337/db07-1700]). The A allele of SNP rs9939609 (FTO
intron 1) was associated with increased BMI (P⫽0.0072)
and waist circumference (P⫽0.0094). The TT homozygote
(Trp64) of SNP rs4994 (ADRB3 Trp64Arg) was associated
with increased BMI (P⫽0.0011) and waist circumference
(P⫽0.0026). After Bonferroni correction for multiple
tests, only rs4994 in ADRB3 remained significant (P⬍
0.002); however, only the FTO association was consistent
in magnitude and direction of effect with previous reports
(8 –10).
TABLE 1
Characteristics of 1,886 women in the CLHNS
BMI (kg/m
2
)24.3 ⫾4.4
Waist circumference (cm) 81.1 ⫾10.8
Body fat (%) 36.6 ⫾5.4
Baseline BMI (kg/m
2
)* 20.6 ⫾2.4
Arm fat area (mm
2
)9.6 ⫾1.5
Arm muscle area (mm
2
)60.0 ⫾17.6
Fat mass (kg) 20.6 ⫾6.3
Suprailiac skinfold (mm) 28.8 ⫾10.1
Triceps skinfold (mm) 23.8 ⫾8.0
Weight (kg) 55.1 ⫾10.9
Average height (cm) 150.4 ⫾4.9
Age (years) 48.4 ⫾6.1
Total number of pregnancies 6.5 ⫾3.0
Menopausal status (yes/no) 1162/724
Data are means ⫾SD unless otherwise indicated. All traits are
measured from the 2005 survey except where indicated. For women
who were pregnant or missing data in 2005, measures from the 2002
survey were substituted. *Baseline BMI was collected from postpar-
tum surveys in 1983–1984 (see research design and methods).
TABLE 2
Association of FTO and ADRB3 SNPs with obesity-related traits
FTO rs9939609 (MAF 0.175) Additive
P
Dominant
P
ADRB3 rs4994 (MAF 0.085) Dominant
PTT TA AA TT TC/CC
BMI (kg/m
2
)23.9 (23.6–24.1) 24.5 (24.1–24.8) 24.7 (23.7–25.7) 0.0072 0.0080 24.2 (23.9–24.4) 23.3 (22.8–23.8) 0.0011
Waist circumference (cm) 80.1 (79.4–80.7) 81.7 (80.7–82.7) 81.1 (78.5–83.7) 0.0094 0.0040 80.8 (80.1–81.4) 78.9 (77.7–80.2) 0.0026
Body fat (%) 36.3 (36.0–36.6) 36.4 (35.9–36.9) 36.8 (35.6–38.0) 0.43 0.47 36.4 (36.1–36.7) 35.7 (35.1–36.3) 0.0499
Baseline BMI (kg/m
2
)* 20.5 (20.3–20.6) 20.9 (20.7–21.1) 21.0 (20.4–21.6) 0.0015 0.0013 20.6 (20.5–20.8) 20.5 (20.3–20.8) 0.55
Weight (kg) 54.2 (53.5–54.8) 55.3 (54.3–56.2) 55.9 (53.4–58.4) 0.021 0.024 54.8 (54.1–55.4) 52.6 (51.4–53.9) 0.0011
Fat mass (kg) 20.1 (19.7–20.5) 20.6 (20.1–21.2) 20.9 (19.5–22.3) 0.055 0.06 20.4 (20.0–20.7) 19.3 (18.6–20.0) 0.0036
Suprailiac skinfold thickness (mm) 28.3 (27.6–28.9) 28.8 (27.9–29.7) 28.5 (26.2–30.9) 0.37 0.31 28.4 (27.8–29.0) 27.4 (26.2–28.5) 0.104
Triceps skinfold thickness (mm) 23.5 (23.0–24.0) 23.6 (22.9–24.3) 24.0 (22.2–25.8) 0.64 0.87 23.6 (23.1–24.0) 22.8 (21.9–23.7) 0.0682
Arm fat area (mm
2
)9.5 (9.4–9.6) 9.5 (9.4–9.7) 9.6 (9.3–10.0) 0.33 0.45 9.5 (9.4–9.6) 9.3 (9.1–9.5) 0.0157
Arm muscle area (mm
2
)58.7 (57.6–59.8) 60.2 (58.6–61.7) 61.5 (57.4–65.6) 0.084 0.11 59.7 (58.6–60.7) 56.1 (54.1–58.1) 0.0008
Height (cm) 150.4 (150.1–150.8) 150.2 (149.7–150.6) 150.4 (149.2–151.6) 0.42 0.32 150.4 (150.1–150.7) 150.0 (149.4–150.6) 0.21
Data are untransformed means (95% CI). All data except baseline BMI were collected in the 2005 survey. For women who were pregnant or missing data in 2005, measures from the 2002
survey were substituted. Models were adjusted for age, household assets, natural log of income, number of total past pregnancies as a categorical variable (1– 4, 5–10, and ⬎10), and
menopausal status; baseline BMI is not adjusted for menopausal status. *Baseline BMI and covariates were collected from postpartum surveys in 1983–1984.
FTO ASSOCIATION WITH OBESITY IN FILIPINO WOMEN
1988 DIABETES, VOL. 57, JULY 2008

To further investigate the rs9939609 and rs4994 SNPs,
we analyzed additional obesity-related phenotypes of
baseline BMI (measured in 1983–1984), weight, fat mass,
SiSF, TSF, AFA, AMA, and height (Table 2). For FTO
variant rs9939609, evidence of association was observed
with baseline BMI (P⫽0.0015) and weight (P⫽0.021).
Marginal evidence of association (0.05 ⬍P⬍0.10) was
observed for fat mass (P⫽0.055) and AMA (P⫽0.084),
with direction of estimated effects consistent with those
seen for BMI and weight. For the ADRB3 variant rs4994,
association was observed for weight (P⫽0.0011), fat mass
(P⫽0.0036), AFA (P⫽0.016), and AMA (P⫽0.0008), and
marginal association was observed for TSF (P⫽0.068),
with the direction of estimated effects consistent with
those observed for BMI and weight. Unlike the FTO
variant, no evidence for association was observed with
baseline BMI (P⫽0.55).
We analyzed risk of being either overweight and obese
(BMI ⱖ25 kg/m
2
) or obese (BMI ⱖ30 kg/m
2
) (14) both in
1983–1984 and in 2005 (Table 3). Using these criteria, 793
and 178 women had a BMI ⱖ25 kg/m
2
or BMI ⱖ30 kg/m
2
,
respectively, in 2005, and 94 women had a BMI ⱖ25 kg/m
2
in 1983–1984. The A allele of rs9939609 was associated
with increased risk of being overweight in 2005 (odds ratio
1.30; P⫽0.0034) and in 1983–1984 (1.50; P⫽0.023). The
TT homozygote of rs4994 was associated with increased
risk of being overweight in 2005 (1.33; P⫽0.0077) and
1983–1984 (1.46; P⫽0.023) and obese in 2005 (1.27; P⫽
0.044).
A longitudinal analysis of BMI included an average of 7.3
(range 3– 8) measurements per individual spanning 22
years. The global Pvalue for the test of association with
rs9939609 was 0.000029 (additive model, Fig. 1A) and, for
the test of association with rs4994, 0.016 (Fig. 1B). The
direction of the genotypic least-squares means at each
time point was consistent with the cross-sectional analy-
sis. The test of rs9939609 and rs4994 for genotype-by-time
interaction showed evidence for an increasing effect of
genotype over time (P⫽0.047 and 0.0065, respectively).
DISCUSSION
We evaluated 19 SNPs in a sample of adult Filipino women
from the CLHNS cohort, confirmed the association of the
A allele of FTO variant rs9939609 with BMI and waist
circumference, and observed evidence for an association
with the TT homozygote of ADRB3 rs4994 with BMI, waist
circumference, and percent body fat. While only rs4994
reached statistical significance after Bonferroni correc-
tion, the direction of effect was not consistent with the
majority of previous reports (15,16). The failure to repli-
cate many of the SNP associations that have previously
been reported may reflect environmental and genetic
differences between the CLHNS cohort and previously
studied populations, limited statistical power, and/or false
positive results in the literature.
We also observed evidence for association between the
Trp64 allele of rs4994 and increased weight, percent fat
mass, AFA, AMA, and longitudinal BMI. However, we did
not observe evidence for association with baseline BMI,
which was measured at a time when few women were
overweight. In contrast to our study, two meta-analyses
A
19
21
23
25
27
1983 1986 1989 1992 1995 1998 2001 2004
Year of survey
AA AT TT
B
BMI LSmeans
FTO
19
21
23
25
27
1983 1986 1989 1992 1995 1998 2001 2004
TT CT/CC
Year of survey
BMI LSmeans
ADRB3
FIG. 1. Longitudinal analysis of BMI using measurements across eight
surveys from 1983–1984 to 2005 of FTO rs9939609 (Pⴝ0.000029) (A)
and ADRB3 rs4994 (Pⴝ0.016) (B). BMI is reported as the least-
squares means (LSmeans) at each time point. Error bars represent ⴞ1
SE.
TABLE 3
Association of FTO and ADRB3 SNPs with overweight and obesity status
FTO rs9939609 ADRB3 rs4994
Odds ratio (95% CI) POdds ratio (95% CI) P
2005 overweight and obese
(BMI ⱖ25 kg/m
2
)1.30 (1.09–1.55) 0.0034 1.33 (1.07–1.63) 0.0077
2005 obese (BMI ⱖ30 kg/m
2
)1.31 (1.00–1.72) 0.054 1.46 (1.05–2.02) 0.023
1983–1984 overweight and obese
(BMI ⱖ25 kg/m
2
)1.50 (1.06–2.12) 0.023 1.27 (1.01–1.61) 0.044
1983–1984 obesity (BMI ⱖ30 kg/m
2
) is not reported because only 2 people were observed with BMI ⱖ30 kg/m
2
. Models were adjusted for age,
household assets, natural log of income, number of total past pregnancies as a categorical variable (1– 4, 5–10, and ⬎10), and menopausal
status; 1983–1984 model is not adjusted for menopausal status.
A.F. MARVELLE AND ASSOCIATES
DIABETES, VOL. 57, JULY 2008 1989

with over 35 subgroups each, one in the Japanese popula-
tion and one in multiple populations, reported that Arg64
carriers exhibited higher mean BMI than Trp64 homozy-
gotes (15,16). The evidence of opposite alleles associated
with increased trait values across studies suggests that
these results should be interpreted with caution.
The FTO rs9939609 A allele was also associated with
several obesity-related traits including longitudinal BMI,
reflecting a relatively constant genotype effect over 22
years and strengthening the evidence that this locus
influences BMI in this population. We observed evidence
for an association with waist circumference but not with
skinfold thicknesses, which are surrogate measures for
subcutaneous adiposity, consistent with variation in FTO
influencing central adiposity to a greater extent than
subcutaneous fat. These results may be due to our limited
power of 47% to detect a change of 1.1 mm between
homozygotes, the effect for triceps skinfold previously
observed (8).
Recently, two studies reported results that did not
replicate association between rs9939609 and obesity in
samples of Japanese and Han Chinese. The authors sug-
gested that the findings could be due to relatively low
variability in BMI and/or a decreased allele frequency in
Asian populations resulting in low power to detect an
effect (17,18). The MAF of the rs9939609 variant is 0.18 in
the CLHNS sample, less frequent than estimates in Euro-
pean populations (MAF 0.45– 0.48) and similar to that in
the Han Chinese (MAF 0.11) and Japanese (MAF 0.22)
samples (17,18). The discrepancy in results could be due
to sampling variability or other differences across studies.
Both the Han Chinese and Japanese studies included both
men and women, and the mean age was greater, by ⬃10
and 18 years, respectively, than for the current sample. In
addition, the Japanese study was based on a case-control
sample for type 2 diabetes.
While the women in this sample were chosen from a
single geographic region, we cannot exclude the possi-
bility that our results are influenced by population
stratification, as ancestry for this population may in-
clude contributions from Polynesia, China and, to a
lesser extent, Spain. At the time of this study, sufficient
genotype data were not available to fully evaluate such
substructure, although we have observed that allele
frequencies and linkage disequilibrium patterns in the
CLHNS are similar to those for the HapMap Han Chinese
samples (19).
In summary, our results corroborate previous reports
that a SNP within the first intron of FTO is associated with
BMI. The FTO SNPs have the most consistent prior
evidence for association with obesity-related traits re-
ported to date, and our study replicates this evidence, both
in direction and approximate magnitude, in a Filipino
population, suggesting that FTO may be important in many
genetic backgrounds.
ACKNOWLEDGMENTS
This work was supported by National Institutes of Health
(NIH) Grant R01 DK78150. Cebu Filipino data collection
was supported by TW05596, and specimen processing and
genotyping was supported by pilot funds from NIH grants
RR20649 (Interdisciplinary Obesity Center), ES10126
(Project 7-2004-E of the Center for Environmental Health
and Susceptibility), and DK56350 (Clinical Nutrition Re-
search Center). A.F.M. was supported by an Integrative
Vascular Biology Fellowship, NIH Grant HL69768.
We thank Sandra German at the Office of Population
Studies (OPS) in Cebu, Philippines, for blood sample
collection and processing under the direction of Dr. Chris-
topher Kuzawa of Northwestern University and the entire
staff of OPS for their long-term work on the CLHNS. We
thank Amy Perou of the BioSpecimen Processing facility
and Jason Luo of the Mammalian Genotyping Core at
University of North Carolina at Chapel Hill.
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