Fibromuscular Dysplasia and Abdominal Aortic Aneurysms Are Dimorphic Sex-specific Diseases with Shared Complex Genetic Architecture

Abstract

Background:

The risk of arterial diseases may be elevated among family members of individuals having multifocal fibromuscular dysplasia (FMD). We sought to investigate the risk of arterial diseases in families of individuals with FMD.

Methods:

Family histories for 73 probands with FMD were obtained, which included an analysis of 463 total first degree relatives focusing on FMD and related arterial disorders. A polygenic risk score for FMD (PRS_FMD) was constructed from prior genome-wide association findings of 584 FMD cases and 7,139 controls, and evaluated for association with an abdominal aortic aneurysm (AAA) in a cohort of 9,693 AAA cases and 294,049 controls. A previously published PRS_AAA was also assessed among the FMD cases and controls.

Results:

9.3% (43) of all first-degree relatives of probands were diagnosed with FMD, aneurysms, and dissections. Aneurysmal disease occurred in 60.5% of affected relatives and 5.6% of all relatives. Among 227 female first-degree relatives of probands, 4.8% (11) had FMD, representing a relative risk (RR)_FMD of 1.5 (95%CI:0.75-2.8, p-value =0.19) compared to the estimated population prevalence of 3.3%, though not of statistical significance. 11% (8 of 72) of FMD proband fathers had abdominal aortic aneurysms (AAAs) resulting in a RR_AAA of 2.3 (95%CI 1.12-4.6, P=0.014) compared to population estimates. The PRS_FMD was found to be associated with an AAA (OR=1.03[95%CI:1.01-1.05], P=2.6x10⁻³), and the PRS_AAA was found to be associated with FMD (OR=1.53[95%CI:1.2-1.9], P=9.0x10⁻⁵) as well.

Conclusions:

FMD and AAAs appear to be sex-dimorphic manifestations of a heritable arterial disease with a partially shared complex genetic architecture. Excess risk of having an AAA according to a family history of FMD may justify screening in family members of individuals having FMD.

Introduction

Dysplasia-associated arterial disease (DAAD) encompasses a spectrum of non-atherosclerotic and non-inflammatory stenoses, dissections, and aneurysms affecting medium-sized muscular arteries, with excess burden on women, particularly those lacking otherwise common vascular disease risk factors. Multifocal fibromuscular dysplasia (FMD) is one form of DAAD, manifest by medial fibroplasia with excessive myofibroblasts amongst disorganized collagen and elastic fibrils,^1-5 resulting in multiple arterial stenoses with intervening mural dilations leading to its “string of beads” appearance.^{2, 3, 6, 7} FMD clinical manifestations often include refractory hypertension with renal artery involvement and strokes or transient ischemic attacks with cerebral, carotid, or vertebral artery involvement.^{3, 8} Patients with FMD may develop aneurysms or dissections in arteries exhibiting multifocal stenoses or they may occur in isolation.⁹

The earliest FMD pedigree studies supported autosomal dominant inheritance with incomplete penetrance^{10, 11} but were limited by small sample size and lacked diagnostic imaging. More recently, a complex genetic basis of FMD has been associated with chromosome 6p24.1 PHACTR1, a locus similarly associated with spontaneous dissections of the cervical artery (CeAD) and coronary artery (SCAD) – both having been observed in patients with FMD.^12-14 Data from the United States Registry for FMD² and the National Institute on Aging¹⁵ suggest higher rates of vascular diseases among FMD relatives compared to the general population. An increased rate of sudden death was reported in the FMD registry,² but correlates of this finding are unknown. Similarly, whether increased vascular diseases affect male relatives of FMD probands is unknown.

The current study was undertaken to define the relative risks of arterial disease in family members of individuals with FMD. When an increased risk of having an AAA was observed in male relatives of FMD probands, it was hypothesized that these two diseases may have a shared basis involving common genetic variants.

Methods

Full methods are available in the online supplement. In accordance with the Transparency and Openness Promotion (TOP) Guidelines, the data that support the findings of this study are available from the corresponding author upon reasonable request. All human subjects research was conducted with informed consent and approved by the enrolling instutition’s IRB.

Results

FMD clinical characteristics and familial relative risk (RR)

Arterial phenotypes (Figure 1), clinical phenotypes, and family pedigrees were constructed for the study’s 73 FMD probands (Table 1). Family member data were obtained by self-reporting with imaging confirmation when possible, including all relatives with a formal diagnosis of FMD (online supplement). FMD Probands were all female with an average age at diagnosis of 49±10g years, and 93.2% were of European ancestry. Hypertension affected 73% of the probands and 26% were former or current smokers (Table 1).

Figure 1:

FMD and other DAAD on angiographic imaging and family pedigrees. (a) Catheter-directed angiography demonstrating multifocal FMD of the right renal artery. Arrows denote characteristic string of beads appearance. (b) Catheter-directed angiography depicting an isolated aneurysm involving a first order branch of the left renal artery. (c) Coronary angiography demonstrating SCAD. (d) Representative pedigrees of FMD families: dark shading identifies individuals affected with FMD including probands and relatives; vertical lines denote DAAD not formally diagnosed as FMD; dotted shading represents an individual with AAA; and unshaded relatives have no evidence of arterial dysplasia.

Table 1.

Clinical characteristics of probands with multifocal FMD from the pedigree study. Values are presented as N (%) or mean ± standard deviation [range]. Denominator of reported percentages is given if different than total cohort size of N=73 to account for incomplete data.

Variable	All, N (%)
N	73
Female	73 (100)
White	68 (93.2)
Body mass index	25.4 ± 5.5 [16.7, 46.3]
Age at clinical presentation	44.4 ± 13.7 [12, 75]
Age at FMD diagnosis	49.0 ± 10.4 [13, 75]
Comorbidities
Hypertension	53 (72.6)
Hyperlipidemia	28 (38.4)
Smoking history	19 (26.0)
Diabetes	2 (2.7)
Coronary artery disease/Myocardial infarction	7 (9.6)
History of stroke	5 (6.9)
History of transient ischemic attack	13 (17.8)
Clinical Signs & Symptoms
Headache	59 (83.1)
Dizziness	40 (56.3)
Tinnitus (pulsatile or nonpulsatile)	38 (53.5)
Cervical bruit	23 (32.4)
Neck pain	35 (49.3)
Abdominal bruit	12 (16.9)
Post prandial abdominal pain	16 (22.5)
Flank pain	20 (28.2)
Abdominal pain	21 (29.6)
Renal infarction	7 (9.9)
Claudication	15 (21.1)
Chest pain	16 (22.5)
Horners syndrome	4 (5.6)
Amaurosis fugax	9 (12.7)
History of myocardial infarction	3 (4.2)
Mesenteric ischemia	3 (4.2)

A total of 463 first-degree relatives were evaluated for DAAD phenotypes, inclusive of multifocal FMD, aneurysms, dissections, and suspected signs of undiagnosed DAAD (Table 2, Table 3). Only one proband’s parental history was unknown. DAAD was definitively diagnosed in 9.3% (46) of relatives, being aneurysmal disease in 60.5% of relatives with a DAAD and 5.6% of all relatives.

Table 2.

Phenotypes of interest in first degree relatives by family relation and sex. Arterial aneurysms and arterial dissections represent individuals with these findings consistent with DAAD, but not formal diagnoses of FMD. Phenotypes are mutually exclusive (for example, if a family member was diagnosed with FMD and was also known to have an arterial aneurysm, that individual would be counted as ‘FMD’ but not ‘Arterial aneurysm’. Suspected DAAD are clinical signs that may represent undiagnosed DAAD which included: stroke or transient ischemic attack at or before age 55, hypertension or antihypertensive medication requirement before age 30, renal artery stenosis in the absence of cardiovascular disease, and/or sudden unexplained death without clear etiology. All relatives are the sum of all first-degree relatives of probands, regardless of clinical status.

	FMD	Arterial aneurysms	Arterial dissections	Suspected DAAD	All relatives
Parent
F	2	3	1	6	72
M	0	12	1	6	72
Total	2	15	2	12	144
Sibling
F	4	4	1	5	91
M	0	5	1	7	94
Total	4	9	2	12	185
Offspring
F	5	1	2	0	64
M	0	1	0	6	70
Total	5	2	2	6	134
All First-Degree Relatives
F	11	8	4	11	227
M	0	18	2	19	236
Total	11	26	6	30	463

F, Female; M, Male

Table 3.

Arterial beds affected by aneurysm in first degree relatives by family relation and sex. Individuals included in this table did not carry a diagnosis of FMD.

	Abdominal aorta	Thoracic Aorta	Cerebral aneurysm	Other or not specified	Total
Parent
F	0	0	2	1	3
M	8	0	2	2	12
Total	8	0	4	3	15
Sibling
F	0	0	2	2	4
M	1	0	2	2	5
Total	1	0	4	4	9
Offspring
F	0	1	0	0	1
M	0	0	1	0	1
Total	0	1	1	0	2
All First-Degree Relatives
F	0	1	4	3	8
M	9	0	5	4	18
Total	9	1	9	7	26

Eleven first-degree relatives were diagnosed with FMD; all affecting female members, including 2 mothers, 4 sisters, and 5 daughters. The RR_FMD among all female first-degree relatives was 1.45 (95%CI:0.75-2.82) (Table 4). Analyses of the RR_FMD focused on siblings and children in whom diagnostic imaging had been undertaken according to current clinical practice. Among female siblings and offspring, the RR_FMD was 1.74 (95%CI:0.85-3.56). Among female siblings and offspring of a subset of probands having a more severe FMD phenotype (aneurysms or dissections) the RR_FMD was 2.5 (95%CI:1.2-5.4) (Table SI).

Table 4.

Familial relative risk for FMD and AAA, as well as absolute risk for DAAD (which includes FMD, AAA, non-abdominal aortic aneurysm, and arterial dissection). Relative risk (RR) and 95% confidence intervals (CI) were computed based upon the distribution of the individuals in each category with the listed findings (n) as compared to the total number of individuals per category (N). Population prevalence (P) of 3.34% for FMD¹⁶ and 4.9% for AAA^17-20 was used to calculate relative risk. The absolute risk is represented by the probability that a relative is affected (p=n/N).

	Family members with FMD				Family members with AAA				Family Member with diagnosed DAAD+AAA
	n	N	p=n/N	RR [95% CI]	n	N	p=n/N	RR [95% CI]	n	N	p=n/N
Female Parents	2	72	2.80%	0.83 [.20 – 3.40]	0	72	-		6	72	8.30%
Male Parents	0	72	-		8	72	11.10%	2.27 [1.12-4.60]	13	72	18.10%
Female Siblings	4	91	4.40%	1.32 [.48 – 3.63	0	91	-		9	91	9.90%
Male Siblings	0	94	-		0	94	-		6	94	6.40%
Female Offspring	5	64	7.80%	2.34 [.95-5.78]	0	64	-		8	64	12.50%
Male Offspring	0	70	-		0	70	-		1	70	1.40%
All Relatives	11	463	2.40%	0.71 [.36-1.39]	8	463	1.70%	0.35 [.17-.74]	43	463	9.30%
Male Relatives	0	236	-		8	236	3.40%	0.69 [.33-1.44]	20	236	8.50%
Female Relatives	11	227	4.80%	1.45 [.75-2.82]	0	227	-		23	227	10.10%
Male Siblings + Male Offspring	0	164	-		0	164	-		7	164	4.30%
Female Siblings + Female Offspring	9	155	5.80%	1.74 [.85-3.56]	0	155	-		17	155	11.00%

Risks may be underestimated for the older relatives given that it is less likely that angiographic imaging was performed or available in these cases. In that regard we found 2 of 72 mothers (2.8%) diagnosed with FMD (RR_FMD=0.83) (95%CI:0.20-3.40) and another 6 of 72 mothers with suspected DAAD but without a formal diagnosis. Notably, male relatives did have signs of a suspected DAAD diagnosis, with 19 of 236 (8.1%) of all male relatives being affected. Among female relatives, 11 of 227 (4.8%) were diagnosed with FMD and an additional 11 of 227 (4.8%) had suspected DAAD (Table 2). The relative risks for suspected DAAD in family members was not calculated, given the uncertainty of the population prevalence of signs consistent with suspected DAAD, and whether DAAD actually represented undiagnosed FMD.

Among all first-degree relatives of probands, 5.6% (26) had an arterial (including aortic) aneurysm without a diagnosis of FMD (Table 3), supporting the characterization of DAAD as a set of related but variable arterial phenotypes having a shared underlying predisposition. The presence of aneurysmal disease, in any arterial bed, was more common (N=18/26, 69%) in the proband’s male family members, and among proband fathers, 8 AAAs were identified that corresponded to a relative risk of having an AAA (RR_AAA) of 2.3 (95%CI:1.1-4.6) (Table 4). No mother of a proband had an AAA (Table 3). Among a subset of families in which the proband had at least one aneurysm or dissection, the RR_AAA was unchanged at 2.3 (95%CI:0.95-5.4) (Table SI).

Genetic risk scores to interrogate the relationship between FMD and AAAs

The complex genetic architecture of FMD was first assessed with a GWAS based upon 584 FMD cases and 13,756 MGI controls subjects. The average age of the FMD cases was 53±12 years, 96.2% were female, 97.2% were self-reported European Ancestry, and 2.1% were African American (Figure SI). 7,193 MGI controls were selected to match for age, sex, and ancestry; average age was 52±16 years, and 95.8% were female. Our analysis was combined across ethnicity, and using principal components (PC1-PC3) estimated from LASER/TRACE program to map against HGDP samples, the samples used in our analyses were 98.2% European ancestry and 1.8% African American. Post-imputation filtering for SNPs with r²≥0.8 and MAF≥0.01 yielded 6,604,767 SNPs for association testing (Figure SII). There was no evidence of genomic inflation of association statistics which would lead to false positives (λ_GC=0.95). The previously identified FMD-associated chromosome 6 PHACTR1 locus rs9349379(A) was the single locus meeting genome-wide significance (odds ratio, OR=1.4[95%CI:1.3-1.6], P=1.10x10⁻⁸). The PRS_FMD constructed from the FMD GWAS, including independent SNPs with FDR q-value<0.1, was comprised of 26 SNPs (Table SII).

A PRS_AAA previously defined in the individuals with white-European ancestry from MVP cohort including 29 AAA-associated independent SNPs was associated with higher risk of FMD using the R package Genetics ToolboX (GTX), which uses summary statistics obtained from the primary FMD GWAS analyzed with SAIGE (OR=1.5 [95%CI:1.2–1.9], P=9.0x10⁻⁵) (Figure SIII, Table 5, Table SIII). The result was similar in a sensitivity analysis using logistic regression to analyze individual genotype data (OR=1.5[95%CI:1.2–1.9], P=3.0x10⁻⁴). Similarly, the PRS_FMD was associated with an AAA in the MVP cohort analysis of 9,693 AAA cases and 294,049 non-AAA controls (OR=1.03[95%CI:1.01-1.05, P=2.6x10⁻³) using analysis of individual level data with logistic regression. This was further supported through analysis using the UK Biobank (UKB) cohort with 97.6% European ancestry, with the association of PRS_FMD in AAAs being nomimally significant with directionally consistent odds ratio (OR=1.065 [95%CI:1.00-1.13], P=0.041) based on a smaller sample size of AAAs identified (998 AAA cases and 485,908 controls) as compared to MVP, using logistic regression of individual level data. Based upon simulations using similar effect sizes estimated from our actual data and the same sample size as in UKB, the association analyses of PRS_FMD and AAAs in the UKB cohort was quite underpowered, especially for a sex-stratified analysis (34.6% power for 876 AAA male cases versus 221,966 male controls) and therefore such was not performed. Sex-stratified analyses of the PRS_FMD association with AAAs in the MVP cohort was underpowered for women, with only 60 women with AAAs. An analysis of 9,633 men with AAAs and 272,758 controls, revealed a similar association as the analysis of both sexes combined (OR=1.03 [95%CI:1.01-1.05, P=2.1x10⁻³). Next, the association of AAAs with PRS_CeAD (5 SNPs) and PRS_SCAD (7 SNPs) were examined, given that fathers of FMD probands with arterial dissections had an elevated RR_AAA. These analyses showed similar associations (OR=1.04 [95%CI:1.01-1.06], P=8.4x10⁻⁴; and OR=1.03 [95%CI:1.01-1.05], P=2.46x10⁻³ respectively) (Table 5, Table SIV). Inspection of the 26 SNPs in the PRS_FMD in AAAs demonstrated associations with AAAs meeting P<0.05/26 at the chr9p21 and chr12q13.3 loci, and conversely of the 29 SNPs in the PRS_AAA, the same two loci met P<0.05/29 for association with FMD. A binomial test based on the finding of two SNPs associated with AAAs (P<0.05/26) among the 26 FMD-associated SNPs supported the significance of these shared associations (two-sided exact binomial test P-value=1.049x10⁻⁵, with estimated probability of reaching significance for both AAAs and FMD=0.077 (by R command binom.test(2, 26).

Table 5.

Summary of polygenic risk score (PRS) analyses. PRS analysis in FMD using known AAA SNPs based on FMD GWAS samples, and PRS analysis in AAA using known FMD, CeAD, or SCAD SNPs based on Million Veteran Program (MVP) AAA GWAS samples. PRS tests were constructed based upon logistic regression of individual genotypes, adjusting for age, sex (if applicable) and the first five PCs, except where indicated by “GTX,” the PRS was derivative of summary statistics using the GTX program. Both logistic regression and GTX methods yielded similar PRS association results. The reported PRS p-values were un-adjusted, and when meeting the Bonferroni-corrected significance threshold (0.05/10=0.005) the result is shown in bold font. For replication purposes, the association of PRS_FMD and AAA trait was tested in the UK Biobank (UKB) cohort. The replication p-value thresohold after multiple test correction was 0.05/1=0.05. Despite of the smaller sample size and limited power, the replication in UKB was positive (p-value=0.04) and displayed a similar odds ratio as that in the MVP analysis.

Phenotype	Cohort	PRS*	Total N	N cases	N controls	PRS β	PRS SE	PRS OR[95%CI]	PRS P- value
PRSAAA association with FMD
FMD	UM	PRS AAA †	4,011	573	3,438	0.40	0.11	1.50[1.20-1.87]	3.07E-04
FMD	UM	PRS AAA- GTX	7,777	584	7,193	0.43	0.11	1.53[1.24-1.90]	9.04E-05
PRSFMD association with AAA in the MVP
AAA-all	MVP	PRS FMD	303,742	9,693	294,049	0.03	0.01	1.03[1.01-1.05]	2.62E-03
AAA-male	MVP	PRS FMD	282,391	9,633	272,758	0.03	0.01	1.03[1.01-1.05]	2.11E-03
AAA-female	MVP	PRSFMD	21,351	60	21,291	−0.10	0.13	0.91[0.70-1.18]	0.48
PRSSCAD association with AAA in the MVP
AAA-all	MVP	PRS SCAD	303,742	9,693	294,049	0.03	0.01	1.03[1.01-1.05]	2.46E-03
AAA-male	MVP	PRS SCAD	282,391	9,633	272,758	0.03	0.01	1.03[1.01-1.05]	2.01E-03
AAA-female	MVP	PRSSCAD	21,351	60	21,291	−0.08	0.13	0.92[0.71-1.19]	0.53
PRSCeAD association with AAA in the MVP
AAA-all	MVP	PRS CeAD	303,742	9,693	294,049	0.03	0.01	1.04[1.01-1.06]	8.39E-04
AAA-male	MVP	PRS CeAD	282,391	9,633	272,758	0.03	0.01	1.03[1.01-1.06]	1.01E-03
AAA-female	MVP	PRSCeAD	21,351	60	21,291	0.09	0.13	1.10[0.86-1.41]	0.46
Replication analysis: PRSFMD association with AAA in UKB
AAA-all	UKB	PRS FMD	486,906	998	485,908	0.06	0.03	1.07[1.00-1.13]	0.04

^*Weighted PRS scores

^†Logistic regression PRS analysis of 573 FMD cases versus matched 3,438 MGI controls (1:6 case control ratio, after removing close relatives), adjusted for age, sex, PC1-PC5; (see eFigure 3 for PRS distribution plot).

Discussion

The current study documented an elevated risk of FMD among female relatives of FMD probands, particularly among relatives of probands exhibiting arterial dissections or aneurysms. Male and female relatives exhibited various forms of confirmed or suspected DAAD, supporting the tenet that DAADs are part of a shared systemic arteriopathy with variable manifestations of FMD. Notably, a new relationship between FMD and AAA risk was identified in our pedigrees, and a shared complex genetic architecture of FMD and AAAs was validated through PRS analyses among participants of large genotyped cohorts.

Both FMD and AAAs are relatively common vascular diseases, with FMD affecting ~3.3% of the population¹⁶ and AAAs affecting ~4.9% of the population,^17-20 yet there are important differences. FMD is approximately nine times more frequent in women,^{2, 3} while an AAA is four- to 10- times more frequent in men.²¹ The mean age of FMD diagnosis in the United States is 53.3 years⁶ whereas approximately two-thirds of AAAs are recognized after age 75.²² Current screening guidelines for AAAs exist for all men age 65 years or older with any history of smoking,^23-26 yet no such association has been established to support a screening guideline for FMD. While genetic associations for FMD are emerging, a complex genetic basis for AAAs has been better defined,^27-34 and family history of an AAA is a recognized risk factor for AAAs.^{17, 21, 22}

FMD and AAAs appear to have shared as well as distinct vascular histopathologic features. The most notable similarity is extensive remodeling of the vascular extra-cellular matrix.^{15, 35} Inflammation is not a feature of FMD, whereas AAAs exhibit marked inflammatory changes. A number of cytokine alterations have been described in a severe FMD cohort,¹⁵ but whether these promote arterial disease more broadly is unknown. Alterations in TGF-β signaling pathways in both AAAs^{36, 37} and FMD¹⁵ may play a role in the extracellular matrix and SMC changes in both diseases, particularly in promoting vascular fibrosis, but a precise mechanistic role has not been defined.

The chromosome 6p24.1 PHACTR1 locus was the only genome-wide significant locus identified by the FMD GWAS, and showed no association with AAAs. However among the 26 SNPs in the PRS_FMD, an association at the chromosome 12q13.3 LRP1 locus was found to have concordant genetic effects, with the same risk allele, across vascular outcomes including FMD, AAAs, SCAD¹⁴ and CeAD.^{12, 14} Among AAA-associated loci in the 29-SNP PRS_AAA, the chromosome 9p21.3 locus was associated with FMD, although below genome-wide significance. In a murine model, LRP1 expression in arterial SMCs has been shown to impact cell migration and vascular wall integrity.³⁸ While the FMD-, SCAD-, CeAD-, and AAA-associated allele is expected to raise LRP1 transcript expression, according to expression QTLs defined in human arterial tissues,^{14, 27} and higher LRP1 expression is protective against arterial atherosclerosis,³⁹ it is notable that actin polymerization and cellular contraction were abnormal in mice with smooth-muscle cell specific deletion of LRP1.⁴⁰ Vascular SMC proliferation and apoptosis regulated at the 9p21 locus through expression regulation of CDKN2B has potential relevance for fibroproliferation in the arterial media and aneurysm formation.^{41, 42} Future study is warranted to explore the mechanisms by which these loci affect risk of arterial vascular disease. Several cardiovascular diseases exhibit important sex differences,^{43, 44} including FMD and SCAD which are more common in women.^45-47

FMD and AAAs have not previously been considered related diseases, given the low prevalence of an AAA among FMD patients.⁴⁸ This supports a true sex dimorphism as men with an AAA have not been described to have FMD in the branch vessels of the aorta, and women with FMD, despite more frequent hypertension due to renovascular involvement, have not been reported to have any higher incidence of AAAs.⁴⁸ The influence of reproductive hormones or sex chromosome differential gene expression may affect DAAD phenotypes, including FMD proband fathers with AAAs, and such requires further study.^49,50 Given the previously reported shared associations between FMD, SCAD, and cervical artery dissection, our study’s findings support the idea of shared genetic determinants playing a role in arterial dysplasia overall. Further research to investigate commonalities between FMD, aneurysms, and potentially other vascular diseases may elucidate additional genetic associations.

The potential clinical implications of this study’s findings relate to AAA screening. We propose that such screening could be extended to men with no history of smoking, if they have a first-degree family member with FMD. The age at which this screening should be performed may need to be revisited once further data is available, but the current screening at age 65 may be extended given risk thresholds and detection rates previously defined for the current guidelines.^24-26 Tobacco smoking is estimated to increase the relative risk of having an AAA ~1.87 per 10 cigarettes per day,⁵¹ which is comparable to the risk identified in the current study’s FMD pedigree analysis. Screening men with a family history of FMD may counter the oversight of individuals having AAAs who are ineligible for screening under the current guidelines.^{24, 52}

Limitations of the current study include the small absolute numbers of affected family members, limiting assessment of absolute risks in the pedigrees, and limited knowledge of environmental factors (especially tobacco use and hypertension) among family members. Relatives of individuals with FMD may have a heightened awareness of potential vascular concerns in themselves, which could theoretically result in an ascertainment bias affecting our results, particularly because of the small sample size of affected relatives. However, this potential effect may be balanced by the fact that vascular imaging protocols such as CT or MR angiography were not routinely available to older generations, potentially leading to underdiagnosis of vascular disease. Despite these limitations, the study’s cross-trait analyses of shared complex genetic risk supported the pedigree findings.

Population prevalence of the FMD subphenotypes (specifically FMD-associated arterial aneurysms and dissections) are infrequent and difficult to estimate. Thus, this study avoided calculating relative risk in the absence of a defined population prevalence estimate for such subphenotypes, and rather focused on relative risk for FMD and AAAs. FMD and AAAs are likely underdiagnosed in the clinical setting and without systematic arterial studies of all family members, it is possible that the relative risks reported in this study are underestimated. Although kidney donor data from which FMD prevalence was estimated is primarily of asymptomatic individuals, our pedigree study was of probands having clinically evident FMD, and their family members also having clinically evident or highly suspected FMD. This would lead to the study’s underestimate of risks. A recent electronic health record-based study reported an estimated FMD prevalence of 0.012%,⁵³ which may represent a lower bound of FMD prevalence. The current study, when viewed against lower FMD population prevalence estimates, suggests an even more striking increase relative risk of arterial diseases among family members.

Although the ethnicity structure of PRS obtained and tested was not exactly the same in our study, the majority of samples analyzed was of individuals of white-European ancestry. The lack of ethnic diversity is a significant limitation of our analysis and further testing of these PRS models in more diverse cohorts is needed to determine the degree to which the findings here are applicable to individuals of non white-European ancestry.

Conclusions

FMD and AAAs are genetically related with an increased risk of FMD in female relatives and an AAA in male relatives of individuals having FMD, whereas there was no identified risk of FMD in male relatives or risk of AAAs in female relatives. These increased risks may justify enhanced screening for arterial vascular disease of family members of individuals with FMD, including AAA screening in male family members without a smoking history, such that appropriate surveillance protocols and preventive measures may be undertaken in a more timely manner. These findings contribute to our understanding of incomplete penetrance of FMD and AAAs in families and provide an important biologic insights into the genetic basis of the sex dimorphism involving FMD and AAAs. Further research is needed to more comprehensively define the genetic factors contributing to the pathogenesis of both diseases that will lead to more strategic therapies in the future.

Nonstandard Abbreviations and Acronyms:

FMD

fibromuscular dysplasia

PRS

polygenic risk score

AAA

abdominal aortic aneurysm

DAAD

dysplasia-associated arterial disease

CeAD

cervical artery dissection

SCAD

spontaneous coronary artery dissection

TOP

Transparency and Openness Promotion

GTX

Genetics ToolboX

UKB

UK Biobank

FMDSA

FMD Society of America

MVP

Million Veteran Program

Appendix:

VA Million Veteran Program: Core Acknowledgement for Publications

Updated December 10, 2020

MVP Executive Committee

• Co-Chair: J. Michael Gaziano, M.D., M.P.H.

  VA Boston Healthcare System, 150 S. Huntington Avenue, Boston, MA 02130

• Co-Chair: Sumitra Muralidhar, Ph.D.

  US Department of Veterans Affairs, 810 Vermont Avenue NW, Washington, DC 20420

• Rachel Ramoni, D.M.D., Sc.D., Chief VA Research and Development Officer

  US Department of Veterans Affairs, 810 Vermont Avenue NW, Washington, DC 20420

• Jean Beckham, Ph.D.

  Durham VA Medical Center, 508 Fulton Street, Durham, NC 27705

• Kyong-Mi Chang, M.D.

  Philadelphia VA Medical Center, 3900 Woodland Avenue, Philadelphia, PA 19104

• Christopher J. O’Donnell, M.D., M.P.H.

  VA Boston Healthcare System, 150 S. Huntington Avenue, Boston, MA 02130

• Philip S. Tsao, Ph.D.

  VA Palo Alto Health Care System, 3801 Miranda Avenue, Palo Alto, CA 94304

• James Breeling, M.D., Ex-Officio

  US Department of Veterans Affairs, 810 Vermont Avenue NW, Washington, DC 20420

• Grant Huang, Ph.D., Ex-Officio

  US Department of Veterans Affairs, 810 Vermont Avenue NW, Washington, DC 20420

• Juan P. Casas, M.D., Ph.D., Ex-Officio

  VA Boston Healthcare System, 150 S. Huntington Avenue, Boston, MA 02130

MVP Program Office

• Sumitra Muralidhar, Ph.D.

  US Department of Veterans Affairs, 810 Vermont Avenue NW, Washington, DC 20420

• Jennifer Moser, Ph.D.

  US Department of Veterans Affairs, 810 Vermont Avenue NW, Washington, DC 20420

MVP Recruitment/Enrollment

• Recruitment/Enrollment Director/Deputy Director, Boston – Stacey B. Whitbourne, Ph.D.; Jessica V. Brewer, M.P.H.

  VA Boston Healthcare System, 150 S. Huntington Avenue, Boston, MA 02130

• MVP Coordinating Centers

  • Clinical Epidemiology Research Center (CERC), West Haven – Mihaela Aslan, Ph.D.
    West Haven VA Medical Center, 950 Campbell Avenue, West Haven, CT 06516
  • Cooperative Studies Program Clinical Research Pharmacy Coordinating Center, Albuquerque – Todd Connor, Pharm.D.; Dean P. Argyres, B.S., M.S.
    New Mexico VA Health Care System, 1501 San Pedro Drive SE, Albuquerque, NM 87108
  • Genomics Coordinating Center, Palo Alto – Philip S. Tsao, Ph.D.
    VA Palo Alto Health Care System, 3801 Miranda Avenue, Palo Alto, CA 94304
  • MVP Boston Coordinating Center, Boston - J. Michael Gaziano, M.D., M.P.H.
    VA Boston Healthcare System, 150 S. Huntington Avenue, Boston, MA 02130
  • MVP Information Center, Canandaigua – Brady Stephens, M.S.
    Canandaigua VA Medical Center, 400 Fort Hill Avenue, Canandaigua, NY 14424

• VA Central Biorepository, Boston – Mary T. Brophy M.D., M.P.H.; Donald E. Humphries, Ph.D.; Luis E. Selva, Ph.D.

  VA Boston Healthcare System, 150 S. Huntington Avenue, Boston, MA 02130

• MVP Informatics, Boston – Nhan Do, M.D.; Shahpoor (Alex) Shayan, M.S.

  VA Boston Healthcare System, 150 S. Huntington Avenue, Boston, MA 02130

• MVP Data Operations/Analytics, Boston – Kelly Cho, M.P.H., Ph.D.

  VA Boston Healthcare System, 150 S. Huntington Avenue, Boston, MA 02130

• Director of Regulatory Affairs – Lori Churby, B.S.

  VA Palo Alto Health Care System, 3801 Miranda Avenue, Palo Alto, CA 94304

MVP Science

• Science Operations – Christopher J. O’Donnell, M.D., M.P.H.

  VA Boston Healthcare System, 150 S. Huntington Avenue, Boston, MA 02130

• Genomics Core – Christopher J. O’Donnell, M.D., M.P.H.; Saiju Pyarajan Ph.D.

  VA Boston Healthcare System, 150 S. Huntington Avenue, Boston, MA 02130

  Philip S. Tsao, Ph.D.

  VA Palo Alto Health Care System, 3801 Miranda Avenue, Palo Alto, CA 94304

• Data Core – Kelly Cho, M.P.H, Ph.D.

  VA Boston Healthcare System, 150 S. Huntington Avenue, Boston, MA 02130

• VA Informatics and Computing Infrastructure (VINCI) – Scott L. DuVall, Ph.D.

  VA Salt Lake City Health Care System, 500 Foothill Drive, Salt Lake City, UT 84148

• Data and Computational Sciences – Saiju Pyarajan, Ph.D.

  VA Boston Healthcare System, 150 S. Huntington Avenue, Boston, MA 02130

• Statistical Genetics – Elizabeth Hauser, Ph.D.

  Durham VA Medical Center, 508 Fulton Street, Durham, NC 27705

  Yan Sun, Ph.D.

  Atlanta VA Medical Center, 1670 Clairmont Road, Decatur, GA 30033

  Hongyu Zhao, Ph.D.

  West Haven VA Medical Center, 950 Campbell Avenue, West Haven, CT 06516

Current MVP Local Site Investigators

• Atlanta VA Medical Center (Peter Wilson, M.D.)

  1670 Clairmont Road, Decatur, GA 30033

• Bay Pines VA Healthcare System (Rachel McArdle, Ph.D.)

  10,000 Bay Pines Blvd Bay Pines, FL 33744

• Birmingham VA Medical Center (Louis Dellitalia, M.D.)

  700 S. 19th Street, Birmingham AL 35233

• Central Western Massachusetts Healthcare System (Kristin Mattocks, Ph.D., M.P.H.)

  421 North Main Street, Leeds, MA 01053

• Cincinnati VA Medical Center (John Harley, M.D., Ph.D.)

  3200 Vine Street, Cincinnati, OH 45220

• Clement J. Zablocki VA Medical Center (Jeffrey Whittle, M.D., M.P.H.)

  5000 West National Avenue, Milwaukee, WI 53295

• VA Northeast Ohio Healthcare System (Frank Jacono, M.D.)

  10701 East Boulevard, Cleveland, OH 44106

• Durham VA Medical Center (Jean Beckham, Ph.D.)

  508 Fulton Street, Durham, NC 27705

• Edith Nourse Rogers Memorial Veterans Hospital (John Wells., Ph.D.)

  200 Springs Road, Bedford, MA 01730

• Edward Hines, Jr. VA Medical Center (Salvador Gutierrez, M.D.)

  5000 South 5th Avenue, Hines, IL 60141

• Veterans Health Care System of the Ozarks (Gretchen Gibson, D.D.S., M.P.H.)

  1100 North College Avenue, Fayetteville, AR 72703

• Fargo VA Health Care System (Kimberly Hammer, Ph.D.)

  2101 N. Elm, Fargo, ND 58102

• VA Health Care Upstate New York (Laurence Kaminsky, Ph.D.)

  113 Holland Avenue, Albany, NY 12208

• New Mexico VA Health Care System (Gerardo Villareal, M.D.)

  1501 San Pedro Drive, S.E. Albuquerque, NM 87108

• VA Boston Healthcare System (Scott Kinlay, M.B.B.S., Ph.D.)

  150 S. Huntington Avenue, Boston, MA 02130

• VA Western New York Healthcare System (Junzhe Xu, M.D.)

  3495 Bailey Avenue, Buffalo, NY 14215-1199

• Ralph H. Johnson VA Medical Center (Mark Hamner, M.D.)

  109 Bee Street, Mental Health Research, Charleston, SC 29401

• Columbia VA Health Care System (Roy Mathew, M.D.)

  6439 Garners Ferry Road, Columbia, SC 29209

• VA North Texas Health Care System (Sujata Bhushan, M.D.)

  4500 S. Lancaster Road, Dallas, TX 75216

• Hampton VA Medical Center (Pran Iruvanti, D.O., Ph.D.)

  100 Emancipation Drive, Hampton, VA 23667

• Richmond VA Medical Center (Michael Godschalk, M.D.)

  1201 Broad Rock Blvd., Richmond, VA 23249

• Iowa City VA Health Care System (Zuhair Ballas, M.D.)

  601 Highway 6 West, Iowa City, IA 52246-2208

• Eastern Oklahoma VA Health Care System (Douglas Ivins, M.D.)

  1011 Honor Heights Drive, Muskogee, OK 74401

• James A. Haley Veterans’ Hospital (Stephen Mastorides, M.D.)

  13000 Bruce B. Downs Blvd, Tampa, FL 33612

• James H. Quillen VA Medical Center (Jonathan Moorman, M.D., Ph.D.)

  Corner of Lamont & Veterans Way, Mountain Home, TN 37684

• John D. Dingell VA Medical Center (Saib Gappy, M.D.)

  4646 John R Street, Detroit, MI 48201

• Louisville VA Medical Center (Jon Klein, M.D., Ph.D.)

  800 Zorn Avenue, Louisville, KY 40206

• Manchester VA Medical Center (Nora Ratcliffe, M.D.)

  718 Smyth Road, Manchester, NH 03104

• Miami VA Health Care System (Hermes Florez, M.D., Ph.D.)

  1201 NW 16th Street, 11 GRC, Miami FL 33125

• Michael E. DeBakey VA Medical Center (Olaoluwa Okusaga, M.D.)

  2002 Holcombe Blvd, Houston, TX 77030

• Minneapolis VA Health Care System (Maureen Murdoch, M.D., M.P.H.)

  One Veterans Drive, Minneapolis, MN 55417

• N. FL/S. GA Veterans Health System (Peruvemba Sriram, M.D.)

  1601 SW Archer Road, Gainesville, FL 32608

• Northport VA Medical Center (Shing Shing Yeh, Ph.D., M.D.)

  79 Middleville Road, Northport, NY 11768

• Overton Brooks VA Medical Center (Neeraj Tandon, M.D.)

  510 East Stoner Ave, Shreveport, LA 71101

• Philadelphia VA Medical Center (Darshana Jhala, M.D.)

  3900 Woodland Avenue, Philadelphia, PA 19104

• Phoenix VA Health Care System (Samuel Aguayo, M.D.)

  650 E. Indian School Road, Phoenix, AZ 85012

• Portland VA Medical Center (David Cohen, M.D.)

  3710 SW U.S. Veterans Hospital Road, Portland, OR 97239

• Providence VA Medical Center (Satish Sharma, M.D.)

  830 Chalkstone Avenue, Providence, RI 02908

• Richard Roudebush VA Medical Center (Suthat Liangpunsakul, M.D., M.P.H.)

  1481 West 10th Street, Indianapolis, IN 46202

• Salem VA Medical Center (Kris Ann Oursler, M.D.)

  1970 Roanoke Blvd, Salem, VA 24153

• San Francisco VA Health Care System (Mary Whooley, M.D.)

  4150 Clement Street, San Francisco, CA 94121

• South Texas Veterans Health Care System (Sunil Ahuja, M.D.)

  7400 Merton Minter Boulevard, San Antonio, TX 78229

• Southeast Louisiana Veterans Health Care System (Joseph Constans, Ph.D.)

  2400 Canal Street, New Orleans, LA 70119

• Southern Arizona VA Health Care System (Paul Meyer, M.D., Ph.D.)

  3601 S 6th Avenue, Tucson, AZ 85723

• Sioux Falls VA Health Care System (Jennifer Greco, M.D.)

  2501 W 22nd Street, Sioux Falls, SD 57105

• St. Louis VA Health Care System (Michael Rauchman, M.D.)

  915 North Grand Blvd, St. Louis, MO 63106

• Syracuse VA Medical Center (Richard Servatius, Ph.D.)

  800 Irving Avenue, Syracuse, NY 13210

• VA Eastern Kansas Health Care System (Melinda Gaddy, Ph.D.)

  4101 S 4th Street Trafficway, Leavenworth, KS 66048

• VA Greater Los Angeles Health Care System (Agnes Wallbom, M.D., M.S.)

  11301 Wilshire Blvd, Los Angeles, CA 90073

• VA Long Beach Healthcare System (Timothy Morgan, M.D.)

  5901 East 7th Street Long Beach, CA 90822

• VA Maine Healthcare System (Todd Stapley, D.O.)

  1 VA Center, Augusta, ME 04330

• VA New York Harbor Healthcare System (Scott Sherman, M.D., M.P.H.)

  423 East 23rd Street, New York, NY 10010

• VA Pacific Islands Health Care System (George Ross, M.D.)

  459 Patterson Rd, Honolulu, HI 96819

• VA Palo Alto Health Care System (Philip Tsao, Ph.D.)

  3801 Miranda Avenue, Palo Alto, CA 94304-1290

• VA Pittsburgh Health Care System (Patrick Strollo, Jr., M.D.)

  University Drive, Pittsburgh, PA 15240

• VA Puget Sound Health Care System (Edward Boyko, M.D.)

  1660 S. Columbian Way, Seattle, WA 98108-1597

• VA Salt Lake City Health Care System (Laurence Meyer, M.D., Ph.D.)

  500 Foothill Drive, Salt Lake City, UT 84148

• VA San Diego Healthcare System (Samir Gupta, M.D., M.S.C.S.)

  3350 La Jolla Village Drive, San Diego, CA 92161

• VA Sierra Nevada Health Care System (Mostaqul Huq, Pharm.D., Ph.D.)

  975 Kirman Avenue, Reno, NV 89502

• VA Southern Nevada Healthcare System (Joseph Fayad, M.D.)

  6900 North Pecos Road, North Las Vegas, NV 89086

• VA Tennessee Valley Healthcare System (Adriana Hung, M.D., M.P.H.)

  1310 24th Avenue, South Nashville, TN 37212

• Washington DC VA Medical Center (Jack Lichy, M.D., Ph.D.)

  50 Irving St, Washington, D. C. 20422

• W.G. (Bill) Hefner VA Medical Center (Robin Hurley, M.D.)

  1601 Brenner Ave, Salisbury, NC 28144

• White River Junction VA Medical Center (Brooks Robey, M.D.)

  163 Veterans Drive, White River Junction, VT 05009

• William S. Middleton Memorial Veterans Hospital (Robert Striker, M.D., Ph.D.)

  2500 Overlook Terrace, Madison, WI 53705