Familial Aggregation of Aortic Valvular Stenosis

Abstract

Background Aortic stenosis (AS) is the most common cause of cardiac valvular replacement surgery. During the last century the etiology of AS has undergone transitions in developed countries, from rheumatic heart disease to a degenerative calcific etiology. Although a familial component has been described for a subset of cases with a bicuspid valve, data is limited on the overall familial aggregation of this disease. Methods and Results Contemporary information on 6,117,263 Swedish siblings, of which 13,442 had a clinical diagnosis of AS, were collected from the nationwide Swedish Multi-generation Register and the National Patient Register. A total of 4.8% of AS cases had a sibling history of AS. Having at least one sibling with AS was associated with a hazard ratio of 3.41 (95% CI=2.23–5.21) to be diagnosed with AS in an adjusted model. Individuals with more than one sibling with AS had an exceptionally high risk (hazard ratio=32.84) but were uncommon (34 siblings from 11 sibships). In contrast, spouses of subjects with AS were only slightly more likely to be diagnosed with AS compared to subjects without spousal AS (hazard ratio 1.16 for husbands and 1.18 for wives). Conclusions A sibling history of clinically diagnosed AS was associated with increased risk of AS. Spouses of AS patients only had a modest risk increase, suggesting that shared adult environmental factors contribute less to the development of AS than genetic factors.

Genetic association analyses highlight IL6, ALPL, and NAV1 as three new susceptibility genes underlying calcific aortic valve stenosis

“…The pathophysiological mechanisms associated with the development of CAVS remain elusive. Previous epidemiological studies on CAVS described familial patterns compatible with genetic inheritance and indicated that genetics contribute more than environmental factors to disease susceptibility 6,7 . Unbiased genomic approaches are just starting to elucidate the genetic determinants of CAVS [8][9][10] .…”

Autotaxin and Lipoprotein Metabolism in Calcific Aortic Valve Disease

“…Previous work conducted in the western part of France underscored that CAVD is clustering in some extended families (14). More recently, nationwide epidemiological assessment in Sweden reported an increased risk of developing CAVD among subjects with at least one sibling diagnosed with the disorder (15). The risk was magnified among siblings (HR = 3.4) as compared to spouses of index cases (HR = 1.2), suggesting that the genetic component is likely having a stronger effect compared to shared environmental risk factors (15).…”

“…More recently, nationwide epidemiological assessment in Sweden reported an increased risk of developing CAVD among subjects with at least one sibling diagnosed with the disorder (15). The risk was magnified among siblings (HR = 3.4) as compared to spouses of index cases (HR = 1.2), suggesting that the genetic component is likely having a stronger effect compared to shared environmental risk factors (15). Rare mutations in NOTCH1 have been documented in some families with BAV, an abnormal valve configuration with two cusps instead of three and a risk factor for CAVD (16).…”

Sibling rank and sibling number in relation to cardiovascular disease and mortality risk: a nationwide cohort study

“…4 So far this register has been mostly used to describe the risk of some selected CVD manifestations of individuals in relation to the risk of their siblings, for example, for thromboembolic disease 5 or other diseases. [6][7][8][9] In a previous report based on the MGR, it was shown that increased number of sibling reflecting family size was not associated with increased total and cause-specific mortality risk in ages 40-74 years, but no analyses were made for risk of non-fatal CVD or coronary disease. 10 However, another corresponding study based on MGR data could show that total and cause-specific mortality in ages 30-69 years increased with increasing birth order.…”