APOE ε4 and late-life cognition: mediation by structural brain imaging markers

European Journal of Epidemiology - The apolipoprotein E allele 4 (APOE-ε4) is established as a major genetic risk factor for cognitive decline and late-onset Alzheimer’s disease....     

Mediation Analysis of Aortic Stiffness and Renal Microvascular Function

Aortic stiffening, assessed by carotid-femoral pulse wave velocity, is associated with CKD. Transmission of excessive flow pulsatility into the low-impedance renal microvasculature may mediate this association. However, direct analyses of macrovascular–microvascular relations in the kidney are limited. Using arterial tonometry, iohexol clearance, and magnetic resonance imaging, we related arterial stiffness, GFR, urinary albumin excretion, and potential mediators, including renal artery pulsatility index, renal vascular resistance, and arterial volume in the cortex, in 367 older adults (ages 72–92 years) participating in the Age, Gene/Environment Susceptibility-Reykjavik Study. In a model adjusted for age, sex, heart rate, and body size, aortic stiffness was related to GFR (Slope of regression B=−2.28±0.85 ml/min per SD, P=0.008) but not urine albumin (P=0.09). After accounting for pulsatility index, the relation between aortic stiffness and GFR was no longer significant (P=0.10). Mediation analysis showed that 34% of the relation between aortic stiffness and GFR was mediated by pulsatility index (95% confidence interval of indirect effect, −1.35 to −0.29). An additional 20% or 36% of the relation was mediated by lower arterial volume in the cortex or higher renal vascular resistance, respectively, when offered as mediators downstream from higher pulsatility index (95% confidence interval of indirect effect including arterial volume in the cortex, −2.22 to −0.40; 95% confidence interval of indirect effect including renal vascular resistance, −2.51 to −0.76). These analyses provide the first evidence that aortic stiffness may contribute to lower GFR by transferring excessive flow pulsatility into the susceptible renal microvasculature, leading to dynamic constriction or vessel loss.     

Loss of heterozygosity on chromosome arm 3p in nasopharyngeal carcinoma

We have examined 17 primary undifferentiated nasopharyngeal carcinoma biopsies for allelic loss on 3p, comparing the findings in tumors with those in normal lymphocyte DNA from the same patients. Ten polymorphic microsatellite markers were used between 3p13 and 3p26. Allelic loss was observed in 12 samples (70%). Two loci were most frequently affected: D3S1067 (3p21.1-14.3) in 60% and D3S1217 (3p14.2-14.1) in 58%. One tumor seemed to have a homozygous deletion at 3p26, detected by the D3S1297 marker. Analysis of the clinical data showed that an increased number of aberrations in 3p was correlated with more advanced tumor stages. Genes Chromosom Cancer 17:118–126 (1996). © 1996 Wiley-Liss, Inc.     

Loss of heterozygosity on chromosome 9 in human breast cancer: Association with clinical variables and genetic changes at other chromosome regions

Primary breast tumors were tested for loss of heterozygosity (LOH), on chromosome 9p with microsatellite markers restricted to a 28 cM region including the MTS1 gene. LOH was found with at least I marker in 38% of the 201 cases analyzed. A high frequency of deletions was detected at the 9p23-p21 region, indicating a tumor suppressor gene(s) important for breast cancer tumorigenesis. Tumors with and without LOH on 9p were compared with respect to clinico-pathological factors using X² analysis. Tumors with 9p LOH were significantly associated with high S-phase status and aneuploidy, but not with type, node status, estrogen and progesterone receptor content or age of the patients at diagnosis. Survival analysis showed that LOH at 9p did not significantly affect the survival rate of breast cancer patients. Our results indicate that the aberrations on 9p detected in this study are not of independent prognostic value. A significant association was found between LOH at 9p and LOH at chromosomal arms 3p and 6q, which is an additional contribution toward understanding the genetic events in breast tumor pathogenesis. © 1995 Wiley-Liss, Inc.     

Adipose Tissue,Muscle, and Function: Potential Mediators of Associations Between Body Weight and Mortality in Older Adults With Type 2 Diabetes

OBJECTIVEStudies in type 2 diabetes report both increased mortality for normal weight and no evidence of an obesity paradox. We aimed to examine whether adipose tissue, muscle size, and physical function, which are known to vary by weight, mediate associations between BMI and mortality.RESULTSThe median follow-up was 6.66 years, and there were 85, 59, and 44 deaths among normal weight, overweight, and obese participants, respectively. There was no mortality risk for obese participants and an increased risk among normal weight compared with overweight participants (HR 1.72 [95% CI 1.12–2.64]). Associations remained with adjustment for adipose tissues and knee extensor strength; however, mortality risk for normal weight was attenuated following adjustment for thigh muscle (HR 1.36 [95% CI 0.87–2.11]) and gait speed (HR 1.44 [95% CI 0.91–2.27]). Linear regression confirmed with bootstrapping indicated that thigh muscle size mediated 46% of the relationship between normal weight and mortality.CONCLUSIONSNormal weight participants had elevated mortality risk compared with overweight participants. This paradoxical association was mediated in part by muscle size.     

Increasing sex difference in bone strength in old age: The Age, Gene/Environment Susceptibility-Reykjavik study (AGES-REYKJAVIK)

INTRODUCTION: It is important to identify possible pathological mechanisms that underlie the known sexual dimorphism in bone fragility in old age. In this cross-sectional population-based study, we use data from three different skeletal sites to examine sex differences in volumetric bone density, geometry and strength indices and determine whether sex differences in these bone strength measures continue to increase into very old age. MATERIALS AND METHODS: A total of 1715 elderly individuals (807 men and 908 women) age 67-93 years, participants in a population-based study, the Age, Gene/Environment Susceptibility-Reykjavik Study (AGES-REYKJAVIK) and not taking medications affecting bone metabolism, were studied. Quantitative computed tomography (QCT) was performed in the lumbar spine, hip and mid-femoral shaft to estimate volumetric trabecular, cortical and integral BMD, bone geometry and bone strength indices. Regression models were used to assess the effects of age and gender-adjustment for standing midlife height and current weight. RESULTS: At age 67-69 years, men had 24.9-31.7% larger cross-sectional bone size at measured sites than women. At all bone sites, women had two- to fivefold diminution in net bone mass with age compared to men but had comparable increments in bone size (1.8-6.0% per 10 years). This was reflected in significantly worse (more than twofold) bone strength measures with age in women, including compressive strength indices at the spine, femoral neck and trochanter and bending strength indices at the femoral neck. CONCLUSION: With the limitations of a cross-sectional study, our data support the hypothesis that sex differences in bone strength continue into old age. These sex differences appear to be due to greater net bone loss in women rather than due to greater bone gain in men.     

CUBN is a gene locus for albuminuria

Identification of genetic risk factors for albuminuria may alter strategies for early prevention of CKD progression, particularly among patients with diabetes. Little is known about the influence of common genetic variants on albuminuria in both general and diabetic populations. We performed a meta-analysis of data from 63,153 individuals of European ancestry with genotype information from genome-wide association studies (CKDGen Consortium) and from a large candidate gene study (CARe Consortium) to identify susceptibility loci for the quantitative trait urinary albumin-to-creatinine ratio (UACR) and the clinical diagnosis microalbuminuria. We identified an association between a missense variant (I2984V) in the CUBN gene, which encodes cubilin, and both UACR (P = 1.1 × 10(-11)) and microalbuminuria (P = 0.001). We observed similar associations among 6981 African Americans in the CARe Consortium. The associations between this variant and both UACR and microalbuminuria were significant in individuals of European ancestry regardless of diabetes status. Finally, this variant associated with a 41% increased risk for the development of persistent microalbuminuria during 20 years of follow-up among 1304 participants with type 1 diabetes in the prospective DCCT/EDIC Study. In summary, we identified a missense CUBN variant that associates with levels of albuminuria in both the general population and in individuals with diabetes.