Abstract
Background:
Intracranial stenosis is one of the most common causes of stroke worldwide. Several single nucleotide polymorphisms have been associated with intracranial atherosclerosis, which is inferred to be the most common underlying cause of intracranial large artery stenosis (ILAS). We previously reviewed known genetic variants related to ILAS in predominantly Asian cohorts, but their prevalence and role in ILAS among western multiethnic populations are uncertain.
Methods:
We leveraged existing imaging and genetic data from the Northern Manhattan Study, a multiethnic prospective cohort study. Based on literature review, we selected adiponectin Q (ADIPOQ) rs2241767 and rs182052, ring finger protein 213 (RNF213) rs112735431, apolipoprotein E (APOE) rs429358, phosphodiesterase 4D (PDE4D) rs2910829, lipoprotein lipase (LPL) rs320, and aldosterone synthase (CYP11B2) rs1799998 variants as candidates to explore. We defined ILAS as luminal stenosis > 50% in any intracranial large artery using time-of-flight magnetic resonance angiography (MRA).
Results:
We included 1109 participants (mean age 70 ± 9 years, 70 % Hispanic, 60 % women) in this study. ILAS was identified in 81 (7%) NOMAS participants. Logistic regression analyses adjusted for age, sex, principal components, and vascular risk factors showed ILAS prevalence associated with CYP11B2 rs1799998 under the dominant model (OR=0.56, 95%CI: 0.35-0.89) and LPL rs320 heterozygote genotype (OR=1.68, 95%CI: 1.05-2.71). The genotype distributions of ADIPOQ rs2241767 and rs182052, APOE rs429358 and CYP11B2 rs1799998 variants were significantly different among non-Hispanic white and Black, and Hispanic groups. When participants were further stratified by race/ethnicity, the estimates were consistent for CYP11B2 rs1799998 across race/ethnic groups but not for LPL rs320.
Conclusion:
The CYP11B2 rs1799998 variant may be a protective genetic factor for ILAS across race/ethnic groups, but the risk of ILAS associated with LPL rs320 varies by race/ethnic group. Further functional studies may help elucidate the role that these variants play in the pathophysiology of ILAS.
Keywords: Intracranial large artery stenosis, Aldosterone synthase, Lipoprotein lipase, epidemiologic studies, genetic predisposition to disease
Introduction
Intracranial large artery stenosis (ILAS) is one of the most common causes of stroke worldwide and is responsible for about 10% of ischemic stroke in the United State.[1] ILAS represents the most advanced stage of intracranial atherosclerotic disease. Severe ILAS (70-99%) is associated with a high risk of first and recurrent stroke.[2] Additionally, ILAS is associated with dementia and cognitive deficits.[3] Etiology of ILAS is multifactorial. Several studies indicate that vascular risk factors, including hypertension, diabetes mellitus, dyslipidemia, obesity, family history of stroke, and heart disorders are associated with ILAS.[4]
Non-Hispanic Black, Asian, and Hispanic populations have greater prevalence of ILAS compared with non-Hispanic white populations.[5] Many studies suggest that race/ethnicity is a predisposing factor for ILAS, especially in combination with lifestyle factors, and genetic susceptibilities.[6] The prevalence of strokes secondary to ILAS is estimated to be approximately 3 per 100,000 in non-Hispanic white, 15 per 100,000 in non-Hispanic Black, and 13 per 100,000 in Hispanics.[7] Approximately 6-10% of ischemic strokes may be attributed to ILAS in non-Hispanic white, 11% in Hispanic, 15-29% in non-Hispanic Black, and up to 30-50% in Asian populations, while it is less common in Northern Europeans and Americans of European descent.[6, 8] In studies of Asian populations, ILAS causes about 33% of strokes in Chinese patients, 47% of Thai patients, 48% of Singaporean patients, and 25-50% of Korean patients.[9-11] Potential explanations for race/ethnic differences in the prevalence of ILAS include genetic susceptibility of some race/ethnic groups and differences in lifestyle and risk factor profiles among different race/ethnic groups.
Recent studies indicate that genetic traits are associated with atherosclerosis, either by predisposing to vascular risks such as hypertension or diabetes mellitus, or by a direct contribution to an established atherosclerotic mechanism.[12, 13] Variants in adiponectin Q (ADIPOQ) are likely to contribute to metabolic disorders and consequently influence atherosclerosis.[14] Ring finger protein 213 (RNF213) genetic variants may result in arterial fragility and susceptibility to hemodynamic stress, which may increase the risk of intracranial atherosclerotic disease.[15] Apolipoprotein E (APOE) ɛ4 is associated with larger coronary and aortic atherosclerotic lesion areas.[16] It is an important factor in the early stage of atherosclerosis and might interact with other risk factors to affect lipid metabolism and cellular repair mechanisms.[16]
We reviewed reported genetic risk factors for intracranial atherosclerotic disease [17] and selected seven genetic variants that have previously been associated with atherosclerosis in predominantly Asian cohorts (Table 1), including ADIPOQ rs2241767 and rs182052, RNF213 rs112735431, APOE rs429358, phosphodiesterase 4D (PDE4D) rs2910829, lipoprotein lipase (LPL) rs320, and aldosterone synthase (CYP11B2) rs1799998. In this study, we aimed to investigate the association between these genetic variants and ILAS through a cross-sectional analysis of the Northern Manhattan Study (NOMAS).
Table 1.
Genetic variations associated with atherosclerosis
Gene | Location (GRCh37) |
dbSNP | Function[17] |
---|---|---|---|
Adiponectin Q(ADIPOQ) | chr3:186571196 chr3:1865607 |
rs2241767 rs182052 |
Regulates adiponectin level |
Ring finger protein 213 (RNF213) | chr17:78358945 | rs112735431 | Results in vascular fragility, lead to vessels more vulnerable to hemodynamic stress |
Apolipoprotein E (APOE) | chr19:45411941 | rs429358 | Associated with high LDL cholesterol level |
Phosphodiesterase 4D (PDE4D) | chr5:59469899 | rs2910829 | Has a major role in the degradation of cAMP |
Lipoprotein lipase (LPL) | chr8:19819077 | rs320 | Takes part in plasma lipoprotein metabolism and transportation |
Aldosterone synthase (CYP11B2) | chr8:143999600 | rs1799998 | Involves in the aldosterone system |
Materials and Methods
Study population
NOMAS is a population-based prospective cohort study of stroke risk among residents of Northern Manhattan, in New York City, NY Participants were recruited between 1993 and 2001, as previously described.[7] From this original cohort, 1,290 participants were enrolled in the NOMAS Magnetic Resonance Imaging (MRI) Sub-Study between 2003 and 2008. All participants underwent full clinical examination, demographic interviews, and phlebotomy at the time of MRI. We performed the cross-sectional analysis for 1,109 participants who had available genotype data. Recruitment of participants was approved by the Institutional Review Boards at Columbia University and the University of Miami. All participants provided written informed consent.
Diagnosis of ILAS
Participants underwent 1.5-Tesla brain MRI (Philips Medical Systems, Best, Netherlands). The MRI processing protocol has been described in detail previously.[18] Intracranial stenosis was ascertained using time-of-flight MRA by a trained Neurologist and a Vascular Neurologist by consensus. ILAS was defined as a focal narrowing >50% in luminal reduction in any of the main large cerebral arteries, the middle, anterior, posterior, vertebral, or basilar. Images were interpreted by a neurologist and a vascular neurologist with good interrater agreement.[19]
Assessment of risk factors
Participants underwent a comprehensive assessment of vascular risk factors by interview with trained research assistants in English or Spanish as well as a clinical examination by study neurologists. Age, sex and race/ethnicity was ascertained by self-report. Principal components were included in the models as covariates to account for population substructure. Hypertension, diabetes, dyslipidemia, and atrial fibrillation were assessed by self-reported diagnoses, medication use, physical examination, and laboratory testing at the time of MRI.[18]
Genotyping
As previously described,[20] DNA samples were obtained from whole blood extraction. Genotyping was performed using Affymetrix Genome-Wide Human SNP Array 6.0 chips according to Affymetrix procedures at the Genotyping Core of the John P. Hussman Institute for Human Genomics at the University of Miami. Genotype calling was performed using Affymetrix Power Tools v.1.15.0.
Statistical analysis
Baseline characteristics were compared using descriptive statistics; categorical variables were compared with the chi-squared test, and means were compared with t tests. Logistic regression models were used to estimate odds ratios and 95% confidence intervals (CI) for the association of ILAS with genetic variants. We used Bonferroni corrected P values for multiple testing. Models were adjusted for age, sex, principal components, hypertension, diabetes mellitus, dyslipidemia, and current smoking. Two genetic inheritance models were evaluated, additive model and dominant model. All analyses were conducted using SAS version 9.4 (SAS Institute, Cary, NC).
Results
Population characteristics
A total of 1109 participants with available genotype data were included in this study (mean age 70±9 years, 70% Hispanic, 60% women). Of those, 81 participants (7%) were determined to have ILAS. The clinical characteristics and vascular risk factors of each group are described in Table 2. Significant differences were found between those with and without ILAS in age (P<0.001), race/ethnicity (P=0.012), hypertension (P=0.002), diabetes mellitus (P=0.009), statin therapy (P=0.043) and history of atrial fibrillation (P=0.005). Participants with ILAS were older and had higher systolic blood pressures than participants without ILAS. In addition, prevalences of hypertension and diabetes were higher in those with ILAS. The percentage of statin users, as well as those with a history of atrial fibrillation, was greater in the ILAS group.
Table 2.
Characteristics of NOMAS participants, overall and stratified by ILAS status
Characteristic | All n=1109 |
Non-ILAS n=1028 |
ILAS n=81 |
P-value |
---|---|---|---|---|
Age, mean (SD) (years) | 70.4 (8.8) | 70.2 (8.7) | 74.0 (9.2) | <0.001 |
Men, N (%) | 439 (39.6) | 402 (39.1) | 37 (45.7) | 0.24 |
Ethnicity | 0.01 | |||
NH White, N (%) | 154 (13.9) | 145 (14.1) | 9 (11.1) | |
Hispanic, N (%) | 771 (69.5) | 722 (70.2) | 49 (60.45) | |
NH Black, N (%) | 184 (16.6) | 161 (15.7) | 23 (28.4) | |
Hypertension, N (%) | 877 (79.1) | 802 (78.0) | 75 (92.6) | 0.01 |
Diabetes, N (%) | 289 (26.1) | 258 (25.1) | 31 (38.3) | 0.01 |
Dyslipidemia, N (%) | 993 (89.5) | 920 (89.5) | 73 (90.1) | 0.86 |
Statin therapy, N (%) | 279 (25.2) | 251 (24.4) | 28 (34.6) | 0.04 |
Current smoking, N (%) | 130 (11.7) | 123 (12.0) | 7 (8.6) | 0.37 |
History of MI, stent or CABG, N (%) | 269 (24.3) | 247 (24.0) | 22 (27.2) | 0.53 |
History of atrial fibrillation, N (%) | 44 (4) | 36 (3.5) | 8 (9.9) | 0.01 |
MAF | ||||
ADIPOQ rs2241767 (G) | 0.22 | 0.22 | 0.09 | <0.001 |
ADIPOQ rs182052 (A) | 0.37 | 0.37 | 0.38 | 0.75 |
RNF213 rs112735431 (A) | 0 | 0 | 0 | - |
APOE rs429358 (C) | 0.09 | 0.09 | 0.11 | 0.37 |
PDE4D rs2910829 (A) | 0.52 | 0.52 | 0.47 | 0.21 |
LPL rs320 (G) | 0.28 | 0.28 | 0.31 | 0.44 |
CYP11B2 rs1799998 (G) | 0.37 | 0.37 | 0.28 | 0.02 |
Abbreviations: CABG, coronary artery bypass graft; MAF, minor allele frequencies; MI, myocardial infarction; NH, non-Hispanic; SD, standard deviation.
Chi-squared test for categorical variables and t test for continuous variables.
Bold values indicate statistically significant difference with P < 0.05.
Association of variants with ILAS status
Our results showed that the LPL rs320 and CYP11B2 rs1799998 variants exhibited significant associations with ILAS status (Table 3). Heterozygosity (TG) for LPL rs320 variant was associated with ILAS status when compared to non-carriers group (OR=1.68; 95%CI: 1.05-2.71), but this effect was not observed for homozygous individuals or in the dominant inheritance models in which the presence of at least one T allele was compared to non-carriers. In addition, CYP11B2 rs1799998 variants exhibited a significant association with ILAS in the dominant inheritance model (OR= 0.56; 95%CI: 0.35-0.89), while this association was not detected in an additive model (Table 3).
Table 3.
Association between variants related to atherosclerosis and ILAS status in NOMAS
SNP | MAF | Genotype | OR | 95% CI | P-value |
---|---|---|---|---|---|
ADIPOQ rs2241767 | 0.22 | GG vs AA | 0.86 | 0.47-1.58 | 0.645 |
AG vs AA | 1.03 | 0.13-8.16 | 0.696 | ||
GG or AG vs AA | 0.87 | 0.49-1.57 | 0.658 | ||
ADIPOQ rs182052 | 0.37 | AA vs GG | 1.08 | 0.66-1.79 | 0.721 |
GA vs GG | 1.29 | 0.64-2.63 | 0.449 | ||
AA or GA vs GG | 1.13 | 0.7-1.81 | 0.586 | ||
APOE rs429358 | 0.09 | CC vs TT | 1.2 | 0.66-2.18 | 0.508 |
TC vs TT | 2.42 | 0.5-11.87 | 0.255 | ||
TT or TC vs TT | 1.27 | 0.72-2.25 | 0.364 | ||
PDE4D rs2910829 | 0.52 | AA vs GG | 1.21 | 0.69-2.12 | 0.535 |
GA vs GG | 0.69 | 0.34-1.43 | 0.289 | ||
AA or GA vs GG | 1.04 | 0.6-1.79 | 0.438 | ||
LPL rs320 | 0.28 | GG vs TT | 0.84 | 0.32-2.22 | 0.069 |
TG vs TT | 1.68 | 1.05-2.71 | 0.002† | ||
TG or GG vs TT | 1.52 | 0.96-2.41 | 0.047 | ||
CYP11B2 rs1799998 | 0.37 | GG vs AA | 0.6 | 0.37-0.98 | 0.009 |
AG vs AA | 0.42 | 0.18-0.97 | 0.013 | ||
GG or AG vs AA | 0.56 | 0.35-0.89 | 0.001† |
Abbreviations: CI, confidence interval; OR, odds ratio.
Model is adjusted for sex, age, principal components, hypertension, diabetes, dyslipidemia, current smoking.
Statistically significant (Bonferroni corrected significance level is 0.003 [0.05/18]).
We analyzed the genotype distribution across race/ethnicity, indicating ADIPOQ rs2241767, APOE rs429358 and CYP11B2 rs1799998 variants were significantly different among non-Hispanic white, non-Hispanic Black, and Hispanic groups (Table 4). Homozygosity (GG) of the CYP11B2 rs1799998 variant was found in 25% of the non-Hispanic white group, which was significantly higher than that in the Hispanic (13%) and non-Hispanic Black (6%) groups (P<0.001). Furthermore, we performed the analysis stratified by race/ethnicity, but no associations were observed (Supplemental Table 1).
Table 4.
Genotypes distribution across race/ethnicity in NOMAS
SNP | MAF | Genotype | NH White (n=154) |
Hispanic (n=771) |
NH Black (n=184) |
P-value |
---|---|---|---|---|---|---|
ADIPOQ rs2241767 | 0.22 | AA | 116 (75.3) | 602 (78.1) | 166 (90.2) | 0.002† |
AG | 37 (24.0) | 157 (20.4) | 17 (9.2) | |||
GG | 1 (0.6) | 12 (1.6) | 1 (0.5) | |||
ADIPOQ rs182052 | 0.37 | GG | 65 (42.2) | 284 (36.8) | 89 (48.4) | 0.043 |
GA | 73 (47.4) | 376 (48.8) | 73 (39.7) | |||
AA | 16 (10.4) | 111 (14.4) | 22 (12.0) | |||
APOE rs429358 | 0.09 | TT | 146 (94.8) | 691 (89.6) | 149 (81.0) | 0.001† |
TC | 8 (5.2) | 79 (10.2) | 32 (17.4) | |||
CC | 0 (0) | 1 (0.1) | 3 (1.6) | |||
PDE4D rs2910829 | 0.52 | GG | 29 (18.8) | 183 (23.7) | 41 (22.3) | 0.214 |
GA | 79 (51.3) | 378 (49.0) | 104 (56.5) | |||
AA | 46 (29.9) | 210 (27.2) | 39 (21.2) | |||
LPL rs320 | 0.28 | TT | 84 (54.5) | 412 (53.4) | 85 (46.2) | 0.110 |
TG | 51 (33.1) | 299 (38.9) | 81 (44.0) | |||
GG | 19 (12.3) | 60 (7.8) | 18 (9.8) | |||
CYP11B2 rs1799998 | 0.37 | AA | 34 (22.1) | 317 (41.1) | 91 (49.5) | 0.001† |
AG | 81 (52.6) | 354 (45.9) | 82 (44.6) | |||
GG | 39 (25.3) | 100 (13.0) | 11 (6.0) |
Data are reported as number (%). Chi-squared test was used.
Statistically significant (Bonferroni corrected significance level is 0.008 [0.05/6]).
Discussion
The present study investigated the relationship between seven genetic variants and ILAS in NOMAS. Our data indicated that CYP11B2 rs1799998 was associated with ILAS status in NOMAS, and association of LPL rs320 variant with ILAS appeared when we stratified by race/ethnicity. However, we did not find any significant association of ADIPOQ, APOE or PDE4D polymorphisms with ILAS.
LPL is the rate-limiting enzyme for lipid metabolism, and it can hydrolyze triglyceride-rich lipoprotein particles (chylomicrons and very-low-density lipoprotein). The LPL gene is cDNA translated into 475 amino acids that involves a signal peptide of 27 amino acids. LPL is linked with diabetes mellitus, obesity and atherosclerosis.[21] The rs320 polymorphism is one of the most common LPL gene polymorphisms. It exists 495 bp from intron-8 towards the splice site and affects RNA splicing that abolishes the restriction site for the enzyme HindIII. Several studies have shown that the common allele (H+) is significantly associated with high triglyceride (TG) levels and low HDL levels compared to the rare allele (H−).[22, 23] The H-allele in this variant may enhance enzyme activity.[23] The frequencies of rs320 genotype in our study were similar to those in the study reported in a Saudi Arab population (TT, 53.7%; TG, 39.2% and GG, 7.1%).[24] LPL polymorphisms' effects on lipids and coronary artery disease are variable among studies and populations. A significant association of coronary stenosis with TT of the rs320 polymorphism was shown (OR= 2.84, 95 % CI: 1.19-7.40, P=0.017) in a Tunisian population.[25] A case-control study[26] that analyzed populations comprising 22,734 coronary heart disease cases and 50,177 controls provided evidence that there is an association between the rs320 variant of HindIII and nonfatal myocardial infarction.
Clinical studies have demonstrated that the renin-angiotensin-aldosterone system (RAAS) plays a role in the development of atherosclerosis and coronary heart disease.[27] The RAAS regulates blood pressure, sodium and water balance, and cardiovascular and renal homeostasis.[28] In a case-control study, after adjusting for age, sex, cigarette smoking, and alcohol intake, the AG genotype (OR=0.72 95%CI 0.54-0.95, P=0.021) and the AG + GG genotype (OR=0.73, 95%CI 0.56-0.95, P=0.021) distributions of rs1799998 were significantly different between coronary heart disease cases and controls compared to the AA genotype.[29] Participants who carried the G allele of the CYP11B2 rs1799998 polymorphism significantly associated with coronary heart disease. Prevalence of ILAS is very distinct among different ethnic populations and significantly higher in non-Hispanic Black than in non-Hispanic white.[30] Several studies have revealed race/ethnic differences in vascular risk profile. [31, 32] Genetic variation is also an important contributor. In the present study, genotype distribution of CYP11B2 rs1799998 is highly variable from one ethnic group to another. The percentage of AG + GG genotype in non-Hispanic white (78%) is higher than that in Hispanic (59%) and non-Hispanic Black (51%) people. Moreover, we found the association of rs1799998 with ILAS status of NOMAS participants in the dominant inheritance model. A case-control study including 1090 essential hypertension cases and 700 controls was performed in a Chinese population, suggesting rs1799998 might be a protective genetic factor against hypertension.[33] The exact molecular mechanisms underlying the interaction of rs1799998 with various demographic and vascular risk factors in the development of ILAS remain to be revealed.
In this study, we didn’t find the RNF213 variant allele in the participants. RNF213 was initially identified as a susceptibility gene for moyamoya disease in a community based GWAS.[34] RNF213 genetic variants involved in the intracranial artery remodeling process, which may result in arterial fragility and susceptibility to hemodynamic stress that may increase the risk of intracranial atherosclerosis.[15] A recent study suggested RNF213 rs112735431 has a strong association with ILAS.[35] Furthermore, a clinical study revealed that RNF213 rs112735431 could increase the risk of ischemic stroke due to large artery atherosclerosis.[36] RNF213 rs112735431 occurs in 1-2% of East Asian populations, such as in Japan, China, and Korea, but is much rarer in European populations. We did not identify this variant in any individuals in this study, indicating the prevalence of the RNF213 rs112735431 variant is rare in Hispanic and non-Hispanic white and Black populations. Such race/ethnic differences in the prevalence of RNF213 rs112735431 may be one of the factors responsible for the epidemiological difference in the prevalence of ILAS.[37]
ADIPOQ rs2241767 and rs182052, APOE rs429358 and PDE4D rs2910829 are reported by other investigators to have an association with intracranial atherosclerosis,[38-40] but we did not find an association with ILAS in this study. Previous studies indicated these variants are associated with coronary stenosis. ADIPOQ regulates a variety of metabolic processes and helps inhibit the biochemical pathways that lead to metabolic syndrome. Data from both animal and human studies indicate that ADIPOQ contributes to lipid and glucose regulation, with anti-inflammatory and anti-atherogenic effects.[41, 42] The genetic deficits of ADIPOQ are likely to contribute to metabolic disorders, and consequently influence atherosclerosis.[14] The APOE gene is one of the principal regulators of lipid metabolism and plays a key role in the uptake of ApoE-containing lipoprotein particles through the cells.[16] Six well-known common APOE genotypes (ɛ22, ɛ32, ɛ33, ɛ42, ɛ43, and ɛ44) are generated by a combination of two genetic variants (g.7903T>C and g.8041C>T). The three alleles show marked variation in distribution among different racial groups and are associated with variations in plasma cholesterol levels in the general population.[16] The APOE ɛ4 allele is linked with elevated risk of carotid atherosclerosis and coronary artery disease.[43] Recently, studies indicated that the presence of APOE ɛ4+ genotype could be a risk factor for development and severity of coronary stenosis in Pakistani and Iranian populations.[44, 45] PDE4D encodes cyclic adenosine monophosphate (cAMP) -specific 3′,5′-cyclic phosphodiesterase 4D, which has a major role in the degradation of cAMP.[46] Previous studies have shown that the PDE4D gene is a susceptibility gene for ischemic stroke in North America, Australia, and Asia [46-48]. Several studies indicated PDE4D rs2910829 variants are associated with ischemic stroke, carotid atherosclerosis and coronary artery disease.[49, 50] However, the association of ADIPOQ, APOE, and PDE4D variants with ILAS are still not clear.
The present study revealed two genetic variants that might be related to ILAS among the seven SNPs studied. Although this study failed to identify an association between the other five genetic variants and ILAS, the need to carry out studies with a larger number of cases covering other populations and genetic variants remains, which would allow the uncovering of hypothetical genetic factors governing ILAS.
This study has several limitations. First, this study was limited to individuals living in Northern Manhattan; therefore, it was not based on a nationally representative sample. Second, we used a simple definition of ILAS, which looked at stenosis according to imaging-based diagnosis, and did not account for number of vessels affected or severity of ILAS. Third, this study was cross sectional, so impact on progression of ILAS cannot be assessed. Our results should be interpreted with caution due to the aforementioned limitations.
Conclusion
In the overall analysis, ADIPOQ rs2241767 and rs182052, APOE rs429358, and PDE4D rs2910829 were not found to have effects on the risk of ILAS in NOMAS. However, CYP11B2 rs1799998 and LPL rs320 might be associated with ILAS. LPL rs320 could be a risk factor for ILAS, while CYP11B2 rs1799998 variant might be a protective genetic factor. More comprehensive studies of the association of CYP11B2 and LPL genetic variation with both functional correlates and ILAS risk in larger, ethnically diverse populations are needed.
Supplementary Material
Highlights:
Intracranial large artery stenosis (ILAS) represents the most advanced stage of intracranial atherosclerotic disease.
CYP11B2 rs1799998 was associated with ILAS prevalence.
The risk of ILAS associated with LPL rs320.
The genotype distributions of ADIPOQ, APOE and CYP11B2 variants varies by race/ethnic group.
SOURCES OF FUNDING
This work was supported by the grants from National Institutes of Health (R01 AG057709, R01 AG066162, R01 NS36286, R01 NS29993).
Footnotes
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DISCLOSURES
The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
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