Replication of Genome-Wide Association Study Findings of Longevity in White, African American, and Hispanic Women: The Women's Health Initiative

Abstract

Background
No study has evaluated whether genetic factors are associated with longevity in African Americans or Hispanics, and it is unclear whether genetic factors are associated with healthy aging.

Methods
In this prospective study, we determined whether 14 genetic variants previously associated with longevity in genome-wide association studies were associated with survival to ages 85 and 90 in 11,053 postmenopausal white, African American, and Hispanic women from the Women’s Health Initiative. The associations of these variants with healthy aging, defined as survival to age 85 without chronic diseases or disability, were also determined.

Results
Among white women, three single nucleotide polymorphisms (SNPs) (rs2075650 [TOMM40], rs4420638 [APOC1], and rs429358 [APOE]) were significantly associated with survival to 90 years after correction for multiple testing (p < .001); rs4420638 and rs429358 were also significantly associated with healthy aging (p = .02). In African American women, no SNP was associated with longevity. In Hispanic women, 7 SNPs in linkage disequilibrium with a novel SNP, rs2149954, recently identified as being associated with increased longevity in a European population, were significantly associated with decreased survival to age 85 for carriers of the T versus C allele (p = .04). The association with decreased longevity was explained by higher risk of coronary heart disease in carriers of the T allele. There were no associations between FOXO3A SNPs and longevity in the analyses. In a meta-analysis, rs2075650 and rs429358 were significantly associated with longevity.

Conclusions
Future studies are needed to identify novel loci associated with longevity in African American and Hispanic women to determine biologic pathways regulating life span in these groups.

Full text

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Journals of Gerontology: Medical Sciences
cite as: J Gerontol A Biol Sci Med Sci, 2016, Vol. 00, No. 00, 1–6
doi:10.1093/gerona/glw198
Advance Access publication October 5, 2016
Research Article
Replication of Genome-Wide Association Study Findings
of Longevity in White, African American, and Hispanic
Women: The Women’s Health Initiative
Aladdin H. Shadyab,1 Charles Kooperberg,2 Alexander P. Reiner,3 Sonia Jain,4
JoAnn E.Manson,5,6 ChancellorHohensee,2 Caroline A.Macera,7 Richard A. Shaffer,7
Linda C.Gallo,8 and Andrea Z.LaCroix1
1Division of Epidemiology, Department of Family Medicine and Public Health, University of California, San Diego School of Medicine. 2Division
of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington. 3Department of Epidemiology, University of
Washington, Seattle. 4Division of Biostatistics and Bioinformatics, Department of Family Medicine and Public Health, University of California,
San Diego School of Medicine. 5Division of Preventive Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston,
Massachusetts. 6Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts. 7Division of Epidemiology,
Graduate School of Public Health, San Diego State University, California. 8Department of Psychology, San Diego State University, California.
Address correspondence to Aladdin H.Shadyab, PhD, Division of Epidemiology, Department of Family Medicine and Public Health, University of
California, San Diego School of Medicine, 9500 Gilman Drive 0725, La Jolla, CA 92093. E-mail: ahshadya@ucsd.edu
Received May 10, 2016; Accepted September 18, 2016
Decision Editor: Stephen Kritchevsky, PhD
Abstract
Background: No study has evaluated whether genetic factors are associated with longevity in African Americans or Hispanics, and it is unclear
whether genetic factors are associated with healthy aging.
Methods: In this prospective study, we determined whether 14 genetic variants previously associated with longevity in genome-wide association
studies were associated with survival to ages 85 and 90 in 11,053 postmenopausal white, African American, and Hispanic women from the
Women’s Health Initiative. The associations of these variants with healthy aging, dened as survival to age 85 without chronic diseases or
disability, were also determined.
Results: Among white women, three single nucleotide polymorphisms (SNPs) (rs2075650 [TOMM40], rs4420638 [APOC1], and rs429358
[APOE]) were signicantly associated with survival to 90years after correction for multiple testing (p < .001); rs4420638 and rs429358 were
also signicantly associated with healthy aging (p= .02). In African American women, no SNP was associated with longevity. In Hispanic
women, 7 SNPs in linkage disequilibrium with a novel SNP, rs2149954, recently identied as being associated with increased longevity
in a European population, were signicantly associated with decreased survival to age 85 for carriers of the T versus C allele (p= .04).
The association with decreased longevity was explained by higher risk of coronary heart disease in carriers of the T allele. There were no
associations between FOXO3A SNPs and longevity in the analyses. In a meta-analysis, rs2075650 and rs429358 were signicantly associated
with longevity.
Conclusions: Future studies are needed to identify novel loci associated with longevity in African American and Hispanic women to determine
biologic pathways regulating life span in these groups.
Keywords: Gene—Aging—Successful aging—Minority
By 2060, it is expected that approximately 12 million women will be aged
85 and older, commonly referred to as the “oldest-old” age group (1).
Although attaining longevity is becoming increasingly common, healthy
aging, or reaching old age free of morbidity and disability, is more impor-
tant from a public health perspective. However, factors contributing to
longevity and healthy aging in women are not completely understood.
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Heritability estimates for longevity range from 25% to 30%
(2). In previous candidate gene association studies, only variants
of apolipoprotein E (APOE) and forkhead box O3A (FOXO3A)
genes, which are involved in Alzheimer’s disease risk and insulin-
signaling pathways, respectively, have been consistently associated
with longevity (2–11). Although several longevity genome-wide
association studies (GWAS) and meta-analyses of GWAS have been
performed (12–16), only variants near the APOE locus have consist-
ently achieved genome-wide signicant associations with longevity
(13–16). However, prior GWAS were conducted among populations
of European descent, and no study has evaluated associations of
genetic variants with longevity in African Americans or Hispanics.
We determined whether genetic variants previously associated
with longevity in prior GWAS among European populations were
associated with survival to ages 85 and 90 and healthy aging in post-
menopausal white, African American, and Hispanic women from the
Women’s Health Initiative(WHI).
Methods
Study Population
The WHI is a large, prospective study investigating major deter-
minants of chronic diseases in 161,808 postmenopausal women
(17,18). Details of the study, including the use of existing genetic
data for this study and data collection, are discussed in greater detail
in the Supplementary Methods. All participants provided written
informed consent, and Institutional Review Board approval was
received by all participating institutions.
This study was exclusive to women with genetic data who were
born on or before August 29, 1929 and thus could survive to age
85 during follow-up ending August 29, 2014, representing up to
21 years of follow-up (Supplementary Figure1). All women were
from a similar birth cohort, minimizing bias due to varying lifetime
exposures. Only those whose survival status could be ascertained
were included. After quality control procedures, the nal sample size
consisted of 11,053 women (8,656 white, 1,858 African American,
and 539 Hispanic women).
SNP Selection
Single nucleotide polymorphisms (SNPs) signicantly associated with
longevity at the genome-wide level (p<5 × 10−8) in previous GWAS,
replication of GWAS ndings, and meta-analyses of GWAS pub-
lished through January 2015 were selected (5–7,10–16). All GWAS
were conducted in populations of European ancestry. The two SNPs
that dene the three isoforms of APOE and SNPs signicantly asso-
ciated with longevity in candidate gene studies for FOXO3A were
also selected; candidate gene studies were all conducted in European
populations except for one (11) that was conducted in Japanese
Americans. For candidate gene studies, SNPs were selected if statisti-
cally signicant after correction for multiple testing (eg, Bonferroni
correction). Henceforth, SNPs selected from previous studies will
be referred to as “index SNPs.” In total, 14 index SNPs were cho-
sen (5–7,10–16): rs2075650 (TOMM40); rs4420638 (APOC1);
rs7412 and rs429358 (APOE); rs2149954 (on chromosome 5);
and rs10457180, rs2764264, rs13217795, rs2802292, rs9400239,
rs3800231, rs479744, rs1935949, and rs4946935 (FOXO3A).
Individuals from different genetic ancestries exhibit divergent
linkage disequilibrium (LD) and allele frequency patterns. Index
SNPs associated with longevity in prior studies may thus not be in
LD with functional variants among African Americans or Hispanics,
and previous associations may be population specic. Therefore, for
African Americans and Hispanics, proxy SNPs in LD with the index
SNPs were chosen to fully explore replication of prior ndings in
these groups (see Supplementary Material).
Study Outcomes
Women were classied as having survived to age 85 or died before
age 85, and in a separate outcome, as having survived to age 90 or
died before age 90. The use of a dead comparison group from the
same birth cohort was important to be certain that these participants
never reached advanced old age. Death was conrmed by trained
physician adjudicators based on hospital records, autopsy or coro-
ner’s reports, or death certicates. Periodic linkage to the National
Death Index was performed for all participants, including those lost
to follow-up. Approximately 89% of women eligible for inclusion in
this study had complete survival status ascertainment.
Healthy aging was dened as survival to age 85years or older
without a history of major age-related diseases and with no impair-
ment of physical function or assistance in activities of daily living
(ADL). Physical function and ADL were assessed during study fol-
low-up using the RAND 36-item Health Survey (19). Good physi-
cal function for healthy aging was dened as not reporting any of
these limitations (20): limited at least “a little” on moderate activities
(moving a table, vacuuming, bowling, or golng; climbing one ight
of stairs; walking more than one mile; walking several blocks; or
bathing or dressing) or limited “a lot” on difcult performance items
(running, lifting heavy objects, or strenuous sports; lifting or carry-
ing groceries; climbing several ights of stairs; or bending, kneeling,
or stooping). Being able to perform all six ADL (feeding, dressing
and undressing, getting in and out of bed, taking a bath or shower,
doing own grocery shopping, and keeping track of and taking medi-
cines) without any help was also a criterion for healthy aging. This
resulted in three categories: healthy survivors, usual survivors, and
nonsurvivors.
Statistical Analysis
Comparisons of survivors and nonsurvivors on baseline characteris-
tics were performed using χ2 tests for categorical variables and two-
sample t tests or Wilcoxon’s rank-sum tests for normally distributed
and non-normally distributed continuous variables, respectively.
Comparisons of healthy aging categories were performed using χ2
tests for categorical variables and analysis of variance or Kruskal–
Wallis tests for continuous variables.
For all SNPs, count and reference alleles were dened. Separate
analyses were conducted in white, Hispanic, and African American
women. Logistic regression models assuming a log-additive genetic
effect were used to assess associations of SNPs with survival to age
85. For SNPs that were directly genotyped, SNP data were coded
as 0/1/2 (indicating the number of count alleles present), and for
imputed SNPs, the mean dosage of the count allele (a value between
0 and 2) was used. In the models, SNPs were used as continuous
variables. All models adjusted for the top ve principal components
to control for population stratication. Models also adjusted for
potential confounders including baseline age, WHI study compo-
nent, education, marital status, body mass index, physical activity,
alcohol consumption, smoking behavior, and history of age-related
diseases (see Supplementary Methods). Analyses were repeated with
survival to age 90 as the outcome in white and African American
women only, as a limited number of Hispanic women survived to
age 90. Multinomial logistic regression models were used to examine
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associations of SNPs with healthy aging in white women, using non-
survivors as the reference category. Similar variable inclusion criteria
as previously described were used. Healthy aging analyses were not
performed in African American or Hispanic women due to lower
sample sizes of aging categories in these groups. Because of varying
patterns of missing data in covariates, multivariable logistic regres-
sion models had lower sample sizes resulting from the complete case
analysis. Thus, models only adjusting for age and the rst ve prin-
cipal components were also t to make use of all of the available
genetic data. Results are reported as odds ratios and 95% condence
intervals. The odds ratios represent the change in the odds of lon-
gevity for each additional copy of the count allele. Atrans-ethnic
meta-analysis using a random-effects model was conducted to cal-
culate odds ratios combining white, African American, and Hispanic
women (see Supplementary Material for more detailed methods).
p Values were corrected for multiple testing using the Benjamini–
Hochberg procedure (21), which controls for the false discovery
rate and is a more powerful and less conservative approach than
Bonferroni correction. p Values were two tailed and considered
nominally statistically signicant at p less than .05 after correc-
tion. Analyses were conducted using Statistical Analysis Software
(SAS), Version 9.3 (SAS Institute, Cary, NC) and METASOFT for
the meta-analysis.
Results
Comparisons of survivors and nonsurvivors on baseline character-
istics are shown in the Supplementary Material and Supplementary
Tables 1–6. In white women, no index SNP was signicantly asso-
ciated with survival to age 85 after correction for multiple test-
ing (Supplementary Table7). However, in an analysis comparing
women who lived to age 90 with those who died before this age,
3 of 14 SNPs were replicated after correction for multiple testing
(Table1). The SNPs rs2075650 and rs4420638, which tag the lon-
gevity effects of APOE, were signicantly associated with survival
to age 90 (p < .001). Of the two SNPs that dene the three APOE
isoforms, only rs429358 was signicantly associated with survival to
age 90 (p < .001). To determine whether associations of rs2075650
and rs4420638 with survival to age 90 were independent of APOE,
models additionally adjusting for rs7412 and rs429358 were t.
After adjustment for these SNPs, rs2075650 and rs4420638 were
no longer signicantly associated with survival to age 90 (data
not shown). Other SNPs, including rs2149954 on chromosome 5,
and SNPs located at FOXO3A, failed to replicate in white women
(Supplementary Table 8). Findings were similar in models only
adjusting for age and population stratication, and rs7412 was
also signicantly associated with survival to age 90 in this analysis
(Supplementary Tables 9 and 10).
In African American women, no SNP was signicantly associated
with longevity (Supplementary Tables 11–13). In Hispanic women, no
SNP was signicantly associated with survival to age 85 after correc-
tion for multiple testing in the fully adjusted models (Supplementary
Table14); analyses for survival to age 90 were not performed due to
inadequate sample size. However, in models only adjusting for age
and population stratication, only seven SNPs in LD with rs2149954
were signicantly associated with survival to age 85 after correction
for multiple testing (p=.037; Table2 and Supplementary Table15).
Carriage of the T versus C allele was associated with decreased sur-
vival to age 85. To determine potential mechanisms that may explain
the link between these SNPs and longevity, associations with age-
related diseases, hypertension, and diastolic and systolic blood pres-
sures were evaluated (Supplementary Tables 16 and 17). There were
signicant associations between SNPs in LD with rs2149954 and
increased risk of coronary heart disease (p < .001) for carriers of the
T allele. Associations with other phenotypes were not observed.
Analyses for healthy aging were only performed in white women
due to small sample sizes of survival categories in the other ethnic
groups. Of the 14 SNPs, rs4420638 and rs429358 were signicantly
associated with healthy aging (Table3 and Supplementary Table18;
p=.021 and p=.021, respectively). After adjustment for rs7412 and
rs429358, rs4420638 was no longer signicantly associated with
healthy survival (data not shown). In analyses adjusting only for age
and population stratication, ndings were similar (Supplementary
Table19).
In a meta-analysis among white, African American, and Hispanic
women, rs2075650 (p= .04) and rs429358 (p=.04) were signi-
cantly associated with survival to age 85 (Supplementary Table20).
Furthermore, rs2149954 showed evidence of heterogeneity (I2=75;
p value for heterogeneity = .02). In a meta-analysis among white
and African American women, rs2075650 (p = .001), rs4420638
(p= .006), rs7412 (p=.02), and rs429358 (p < .001) were signi-
cantly associated with survival to age 90 (Supplementary Table21).
In sensitivity analyses, ndings were similar when comparing
women who survived to age 85 with those who died before age 80
Table1. Associations of Significant Loci From Previous Studies With Longevity in Postmenopausal White Women From the Women’s Health
Initiative
SNP Chromosome Position
Count Allele/Reference Allele
(count allele frequency)
OR (95% CI)
Uncorrected p Value Corrected p Value
Survived to 90 vs.
Died Before 90a
TOMM40b
rs2075650 19 45395619 G/A (0.13) 0.75 (0.63–0.87) <.001 <.001
APOC1b
rs4420638 19 45422946 G/A (0.16) 0.72 (0.61–0.85) <.001 <.001
APOEb
rs7412 19 45412079 T/C (0.08) 1.27 (1.04–1.54) .020 .069
rs429358 19 45411941 C/T (0.13) 0.68 (0.57–0.80) <.001 <.001
Notes: CI=condence interval; OR=odds ratio; SNP=single nucleotide polymorphism.
Bold p values are signicant at p < .05 after correction for multiple testing using the Benjamini-Hochberg procedure.
aMultivariable model adjusts for age, study membership, body mass index, physical activity, education, marital status, alcohol consumption, smoking behavior,
history of age-related diseases, and population stratication (N=3,380).
bGene.
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and women who survived to age 90 with those who died before age
80. Findings persisted after adjustment for genotyping source in the
models (data not shown).
Discussion
This was the rst study to determine whether genetic factors associated
with longevity in previous studies replicate in African American and
Hispanic women. No index SNP or SNP in LD with any index SNP was
signicantly associated with longevity in African American women. In
Hispanic women, SNPs in LD with a novel locus (rs2149954) identi-
ed as being associated with longevity in a recent meta-analysis of
GWAS of Europeans (14) were associated with survival to age 85.
Among white women, three SNPs were associated with survival to age
90: rs2075650, located at TOMM40; rs4420638, located at APOC1;
and rs429358, one of two SNPs dening the three APOE isoforms.
In a meta-analysis among all ethnic groups, rs2075650 and rs429358
were signicantly associated with survival to age85.
In previous GWAS among European populations, only genetic
variants near APOE have reached genome-wide signicance (13–16).
Among white women, we observed that rs2075650 and rs4420638 were
no longer signicantly associated with survival to age 90 after adjusting
for the two APOE SNPs, indicating that TOMM40 and APOC1 do not
have independent effects on exceptional survival but rather tag variation
at APOE (13). Index SNPs were not associated with survival to age 85 in
white women, supporting the observation that genetic factors may be of
greater importance at more advanced ages such as 90years and older (2).
In the current study, rs4420638 and rs429358 were signicantly
associated with healthy aging in white women. However, effect sizes
for healthy survival and usual survival were similar in magnitude,
suggesting that the association may be driven by survival to age 85
and not healthy aging per se. Limited genetic studies of healthy aging
have been conducted (2,22). Mechanisms allowing exceptional sur-
vivors to markedly delay or avoid disease and disability entirely are
currently unknown, but it is possible that genetic factors may play
a role. Aprevious study showed that nonagenarians carry the same
number of risk alleles for chronic diseases including cardiovascular
disease, type 2 diabetes, and cancer as younger controls, suggesting
that there may be genetic variants specically promoting longevity,
healthy aging, and a delay in disease (23).
Table3. Associations of SNPs With Healthy Aging in Postmenopausal White Women From the Women’s Health Initiative
SNP Chromosome Position
Count Allele/Reference
Allele (count allele
frequency)
OR (95% CI) OR (95% CI)
Uncorrected p
Value
Corrected p
Value
Healthy Survival
vs. Died Before
85a
Usual Survival
vs. Died Before
85a
TOMM40b
rs2075650 19 45395619 G/A (0.13) 0.83 (0.70–0.97) 0.84 (0.72–0.98) .027 .094
APOC1b
rs4420638 19 45422946 G/A (0.16) 0.78 (0.66–0.93) 0.80 (0.68–0.93) .003 .021
APOEb
rs7412 19 45412079 T/C (0.08) 1.16 (0.94–1.45) 1.15 (0.95–1.41) .236 .661
rs429358 19 45411941 C/T (0.13) 0.76 (0.64–0.90) 0.79 (0.68–0.93) .002 .021
Notes: CI=condence interval; OR=odds ratio; SNP=single nucleotide polymorphism.
Bold p values are signicant at p < .05 after correction for multiple testing using the Benjamini-Hochberg procedure.
aMultivariable model adjusts for age, study membership, body mass index, physical activity, education, marital status, alcohol consumption, smoking behavior,
and population stratication (N=4,517).
bGene.
Table2. Associations of SNPs With Longevity in Postmenopausal Hispanic Women From the Women’s Health Initiative
SNP Chromosome Position
Count allele/Reference allele
(count allele frequency)
OR (95% CI)
Uncorrected p Value Corrected p Value
Survived to 85 vs.
Died before 85a
rs2149954 5 157820602 T/C (0.31) 0.69 (0.52–0.93) .015 .053
rs7721599 5 157819991 T/C (0.31) 0.69 (0.52–0.93) .015 .053
rs7724836 5 157826281 A/G (0.35) 0.64 (0.48–0.85) .002 .037
rs4704775 5 157824556 A/G (0.27) 0.80 (0.59–1.08) .142 .368
rs7701003 5 157824481 G/A (0.33) 0.71 (0.53–0.95) .022 .070
rs13163917 5 157832300 G/A (0.35) 0.64 (0.48–0.85) .002 .037
rs17694395 5 157851580 T/C (0.35) 0.67 (0.50–0.90) .007 .037
rs9313775 5 157856776 A/G (0.35) 0.68 (0.51–0.91) .008 .037
rs10044792 5 157861839 T/C (0.35) 0.67 (0.50–0.90) .007 .037
rs10037337 5 157862392 G/T (0.35) 0.67 (0.50–0.90) .007 .037
rs12716344 5 157876908 G/C (0.36) 0.65 (0.49–0.88) .005 .037
Notes: CI=condence interval; OR=odds ratio; SNP=single nucleotide polymorphism.
Bold p values are signicant at p < .05 after correction for multiple testing using the Benjamini-Hochberg procedure.
aMultivariable model adjusts for age and population stratication (N=539).
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In the current study, variants at FOXO3A, which is involved
in the insulin/insulin-like growth factor 1 signaling pathway, were
not replicated in any ethnic group and were not signicant in the
meta-analyses. The association of FOXO3A with longevity has been
shown to be stronger in persons aged 95 and older and especially in
centenarians (6,11), which may partially explain the lack of associa-
tions between FOXO3A SNPs and longevity in ourstudy.
SNPs previously associated with longevity did not reach statis-
tical signicance among African American women, and the major-
ity did not reach signicance among Hispanic women. Lack of
signicance may be due to smaller sample size and lower power to
detect previous effect sizes compared with whites in these groups
(Supplementary Tables 22–24). Among whites, power was more than
99% for almost all SNPs. However, among African Americans, power
estimates ranged from 11.2% to 99.9% and were 80% or more for
TOMM40, APOC1, and some FOXO3A SNPs. Among Hispanics,
power was less than 80% for almost all SNPs. However, effect sizes
for SNPs among African Americans and Hispanics were similar to
those among white women and in the meta-analysis, rs2075650 and
rs429358 were signicantly associated with survival to age 85. These
ndings suggest that APOE may also be associated with longevity in
African American and Hispanic women. Although no study has eval-
uated genetic factors in relation to longevity in African Americans or
Hispanics, GWAS and replication studies of phenotypes such as type
2 diabetes, cancer, and obesity have revealed that there are ethnic
variations in SNP associations with various health outcomes (24–26).
They have also revealed novel loci associated with these phenotypes,
suggesting that there may also be other, unknown genes and mecha-
nisms that may inuence longevity in these populations.
In analyses only adjusting for age and population stratication,
several SNPs in LD with rs2149954, located on chromosome 5
downstream of EBF1 (11), were signicantly associated with lon-
gevity among Hispanic women. Furthermore, in the meta-analysis,
rs2149954 showed evidence of heterogeneity. Astudy in more than
12,000 European nonagenarians and younger controls observed
that carriage of the T allele at rs2149954 was signicantly associ-
ated with increased odds of longevity at the genome-wide level (14).
However, we observed that carriage of the T allele was associated
with decreased likelihood of longevity among Hispanic women. This
previous study also observed that the T allele at rs2149954 was
associated with lower cardiovascular mortality risk. However, our
ndings were explained by increased risk of coronary heart disease.
Collectively, these ndings support ethnic variations in the associa-
tion of rs2149954 with longevity.
This study has several limitations. There was lower power
to detect effect sizes reported in previous studies among African
Americans and Hispanics in our study due to smaller sample sizes in
these groups (Supplementary Tables 22–24). Women who enrolled
for additional follow-up were more likely to be white, educated, and
healthier at baseline than those who withdrew, thus our ndings may
be biased by selective attrition. It is possible that those who dropped
out were more likely to be cognitively impaired, which may have
biased APOE ndings.
Strengths of this study include a large, multiethnic sample of
women. This study was novel in that it was the rst to evaluate the
association of genetic factors with exceptional survival in African
American and Hispanic women. Additional strengths include the
prospective design with up to 21years of follow-up, high retention
of study participants over time, and adjudicated outcome ascertain-
ment. Finally, our population had a narrow age range, limiting birth
cohortbias.
Longevity is a complex phenotype that may be regulated by
multiple pathways (2). Recent studies are uncovering novel genes
that may be associated with longevity in different populations
(27,28). In our study, variation at APOE was signicantly associ-
ated with survival to age 90 among postmenopausal white women.
In Hispanic women, SNPs in LD with a novel SNP recently iden-
tied as being associated with longevity in Europeans were sig-
nicantly associated with decreased survival to age 85. Additional
studies will be important in identifying novel loci and biologic
pathways regulating life span in African American and Hispanic
women. In the future, when there are sufcient numbers of long-
lived ethnic minorities from different studies, data from multiple
cohorts should be combined to evaluate genetic factors associated
with longevity in these groups.
Supplementary Material
Please visit the article online at http://biomedgerontology.oxford-
journals.org/ to view supplementary material.
Funding
This work was supported by the National Heart, Lung, and Blood Institute,
National Institutes of Health, US Department of Health and Human
Services (contracts HHSN268201100046C, HHSN268201100001C,
HHSN268201100002C, HHSN268201100003C, HHSN268201100004C,
and HHSN271201100004C).
Acknowledgments
Role of the Sponsor: The National Heart, Lung, and Blood Institute has
representation on the WHI Steering Committee, which governed the design
and conduct of the study, the interpretation of the data, and preparation and
approval of manuscripts.
WHI Investigators:
Program Ofce: (National Heart, Lung, and Blood Institute, Bethesda,
Maryland) Jacques Rossouw, Shari Ludlam, Dale Burwen, Joan McGowan,
Leslie Ford, and Nancy Geller
Clinical Coordinating Center: (Fred Hutchinson Cancer Research Center,
Seattle, WA) Garnet Anderson, Ross Prentice, Andrea LaCroix, and Charles
Kooperberg
Investigators and Academic Centers: (Brigham and Women’s Hospital,
Harvard Medical School, Boston, MA) JoAnn E.Manson; (MedStar Health
Research Institute/Howard University, Washington, DC) Barbara V.Howard;
(Stanford Prevention Research Center, Stanford, CA) Marcia L. Stefanick;
(The Ohio State University, Columbus, OH) Rebecca Jackson; (University of
Arizona, Tucson/Phoenix, AZ) Cynthia A.Thomson; (University at Buffalo,
Buffalo, NY) Jean Wactawski-Wende; (University of Florida, Gainesville/
Jacksonville, FL) Marian Limacher; (University of Iowa, Iowa City/Davenport,
IA) Robert Wallace; (University of Pittsburgh, Pittsburgh, PA) Lewis Kuller;
(Wake Forest University School of Medicine, Winston-Salem, NC) Sally
Shumaker
Conflict of Interest
None declared.
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