Abdominal aortic aneurysm is associated with a variant in low-density lipoprotein receptor-related protein 1

Abdominal aortic aneurysm (AAA) is a common cause of morbidity and mortality and has a significant heritability. We carried out a genome-wide association discovery study of 1866 patients with AAA and 5435 controls and replication of promising signals (lead SNP with a p value < 1 × 10-5) in 2871 additional cases and 32,687 controls and performed further follow-up in 1491 AAA and 11,060 controls. In the discovery study, nine loci demonstrated association with AAA (p < 1 × 10-5). In the replication sample, the lead SNP at one of these loci, rs1466535, located within intron 1 of low-density-lipoprotein receptor-related protein 1 (LRP1) demonstrated significant association (p = 0.0042). We confirmed the association of rs1466535 and AAA in our follow-up study (p = 0.035). In a combined analysis (6228 AAA and 49182 controls), rs1466535 had a consistent effect size and direction in all sample sets (combined p = 4.52 × 10-10, odds ratio 1.15 [1.10-1.21]). No associations were seen for either rs1466535 or the 12q13.3 locus in independent association studies of coronary artery disease, blood pressure, diabetes, or hyperlipidaemia, suggesting that this locus is specific to AAA. Gene-expression studies demonstrated a trend toward increased LRP1 expression for the rs1466535 CC genotype in arterial tissues; there was a significant (p = 0.029) 1.19-fold (1.04-1.36) increase in LRP1 expression in CC homozygotes compared to TT homozygotes in aortic adventitia. Functional studies demonstrated that rs1466535 might alter a SREBP-1 binding site and influence enhancer activity at the locus. In conclusion, this study has identified a biologically plausible genetic variant associated specifically with AAA, and we suggest that this variant has a possible functional role in LRP1 expression

Lymphatic dysfunction in the apparently clinically normal contralateral limbs of patients with unilateral lower limb swelling

PURPOSE To determine how often lymphatic dysfunction is bilateral when, clinically, lymphedema appears unilateral. METHODS Lymphoscintigraphy was performed after subcutaneous Tc-99m-nanocolloid injection in the first webspaces of both feet. The percentage of injected radioactivity accumulating in the ilioinguinal regions was recorded in dedicated images separately acquired at 60 and 180 minutes after injection. RESULTS Within a consecutive series of 204 patients, 74 had unilateral clinical lymphedema of whom 68 had abnormal scintigraphy. Of these 68 patients, 46 had unilateral abnormal scintigraphy affecting the clinically abnormal limb, but 20 patients had bilateral abnormal scintigraphy and 2 had unilateral abnormal scintigraphy in the clinically unaffected limb. Thus, 32% (22/68) of patients in whom clinical lymphedema appeared to be unilateral, nevertheless, had abnormal scintigraphy in the clinically normal limb. Twenty-nine patients had no clinical evidence of lymphedema in either limb and were scintigraphically normal bilaterally. Mean ilioinguinal nodal accumulation at 180 minutes in the 44 limbs of 22 of these clinically and scintigraphically normal patients (dedicated ilioinguinal imaging was not performed in all patients) was 13.1% (standard deviation, 8.8%), higher (P = 0.02) than the mean value of 9.3% (standard deviation, 5.0%) in the clinically and scintigraphically normal contralateral limbs of 39 patients with unilateral clinical lymphedema. CONCLUSIONS In the presence of unilateral lymphedema, the contralateral limb is often also abnormal. On lymphoscintigraphy, therefore, care should be taken before diagnosing unilateral lymphatic dysfunction. Quantification should be included in routine lymphoscintigraphy, as reduced ilioinguinal nodal accumulation may be the only apparent abnormality

Popliteal node visualization during standard pedal lymphoscintigraphy for a swollen limb indicates impaired lymph drainage

OBJECTIVE The objective of our study was to examine the frequency and significance of visualization of popliteal nodes during lymphoscintigraphy for the investigation of lower extremity swelling. MATERIALS AND METHODS Technetium-99m-labeled nanocolloid was injected subcutaneously in the first web spaces of both feet of 204 consecutive patients (69 males, 135 females; age range, 11-79 years) undergoing routine, clinically indicated lymphoscintigraphy; imaging was performed 5, 45, and 150 minutes after injection. The patients were asked not to undertake any vigorous exercise between the injection and completion of imaging. RESULTS No popliteal nodes were visualized in 29 patients in whom there was no evidence of lymphedema on clinical or lymphoscintigraphic examination (group 1). Unilateral or bilateral popliteal nodes were visualized in 10 of 39 patients (25.6%) with clinical evidence of lymphedema but normal lymphoscintigraphy findings (group 2) (p < 0.005 vs group 1). In 136 patients with clinical evidence of lymphedema and abnormal lymphoscintigraphy findings (group 3), unilateral or bilateral popliteal nodes were visualized in 59 (43.4%) (p < 0.0001 vs group 1). Popliteal nodes were visualized in 40 of 73 limbs with "dermal backflow" (54.8%) and 42 of 335 limbs without dermal backflow (12.5%) (p < 0.0001). CONCLUSION Popliteal node visualization after subcutaneous foot web space injection is an important sign of abnormal lymphatic function in patients with clinical lymphedema of the lower extremities

Abdominal Aortic Aneurysm Is Associated with a Variant in Low-Density Lipoprotein Receptor-Related Protein 1

Abdominal aortic aneurysm (AAA) is a common cause of morbidity and mortality and has a significant heritability. We carried out a genome-wide association discovery study of 1866 patients with AAA and 5435 controls and replication of promising signals (lead SNP with a p value < 1 × 10−5) in 2871 additional cases and 32,687 controls and performed further follow-up in 1491 AAA and 11,060 controls. In the discovery study, nine loci demonstrated association with AAA (p < 1 × 10−5). In the replication sample, the lead SNP at one of these loci, rs1466535, located within intron 1 of low-density-lipoprotein receptor-related protein 1 (LRP1) demonstrated significant association (p = 0.0042). We confirmed the association of rs1466535 and AAA in our follow-up study (p = 0.035). In a combined analysis (6228 AAA and 49182 controls), rs1466535 had a consistent effect size and direction in all sample sets (combined p = 4.52 × 10−10, odds ratio 1.15 [1.10–1.21]). No associations were seen for either rs1466535 or the 12q13.3 locus in independent association studies of coronary artery disease, blood pressure, diabetes, or hyperlipidaemia, suggesting that this locus is specific to AAA. Gene-expression studies demonstrated a trend toward increased LRP1 expression for the rs1466535 CC genotype in arterial tissues; there was a significant (p = 0.029) 1.19-fold (1.04–1.36) increase in LRP1 expression in CC homozygotes compared to TT homozygotes in aortic adventitia. Functional studies demonstrated that rs1466535 might alter a SREBP-1 binding site and influence enhancer activity at the locus. In conclusion, this study has identified a biologically plausible genetic variant associated specifically with AAA, and we suggest that this variant has a possible functional role in LRP1 expression