Soluble apoE/Aß complex: mechanism and therapeutic target for APOE4-induced AD risk.

The APOE4 allele of apolipoprotein E (apoE) is the greatest genetic risk factor for Alzheimer's disease (AD) compared to APOE2 and APOE3. Amyloid-ß (Aß), particularly in a soluble oligomeric form (oAß), is considered a proximal cause of neurodegeneration in AD. Emerging data indicate that levels of soluble oAß are increased with APOE4, providing a potential mechanism of APOE4-induced AD risk. However, the pathway(s) by which apoE4 may increase oAß levels are unclear and the subject of continued inquiry. In this editorial review, we present the hypothesis that apoE isoform-specific interactions with Aß, namely apoE/Aß complex, modulate Aß levels. Specifically, we propose that compared to apoE3, apoE4-containing lipoproteins are less lipidated, leading to less stable apoE4/Aß complexes, resulting in reduced apoE4/Aß levels and increased accumulation, particularly of oAß. Evidence that support or counter this argument, as well as the therapeutic significance of this pathway to neurodegeneration, are discussed.

Association between a Tetranucleotide Repeat Polymorphism of SPAG16 Gene and Cataract in Male Children.

Purpose. Studies involving genotyping of STR markers at 2q34 have repeatedly found the region to host the disease haplotype for pediatric cataract. Present study investigated the association of D2S2944 marker, in sperm associated antigen 16 (SPAG16) gene and rs2289917 polymorphism, in γ-crystallin B gene, with childhood cataract. Methods. 97 pediatric cataract cases and 110 children with no ocular defects were examined for tetranucleotide repeat marker/SNP using PCR-SSLP/RFLP techniques. Polymorphisms were assessed for association using contingency tables and linkage disequilibrium among alleles of the markers was estimated. Energy-optimization program predicted the secondary structure models of repeats of D2S2944. Results. Seven alleles of D2S2944, with 9-15 "GATA" repeats, were observed. Frequency of the longer allele of D2S2944, ≥(GATA)13 repeats, was 0.73 in cases and 0.56 in controls (P = 0.0123). Male children bearing ≥(GATA)13 repeats showed >3-fold higher risk for cataract (CI95% = 1.43-7.00, P = 0.0043, P c = 0.0086) as compared to female children (OR = 1.19, CI95% = 0.49-2.92, P = 0.70). Cases with haplotype-≥(GATA)13 of D2S2944 and "C" allele rs2289917-have a higher risk for pediatric cataract (OR = 2.952, CI95% = 1.595~5.463, P = 0.000453). >(GATA)13 repeats formed energetically more favorable stem-loop structure. Conclusion. Intragenic microsatellite repeat expansion in SPAG16 gene increases predisposition to pediatric cataract by probably interfering posttranscriptional events and affecting the expression of adjacent lens transparency gene/s in a gender bias manner.

Common genetic link between metabolic syndrome components and senile cataract.

Relationship between cataract and metabolic syndrome (MetS) is well established, but genetic link remains to be explored. D2S439 at 2q37 linked with QTL controlling visceral fat was investigated for its association with senile cataract. Two hundred and twenty-seven subjects including 119 cataract cases were genotyped for D2S439, tetra nucleotide repeat marker. Statistical tools assessed the association of marker's allele with anthropometric, clinical and oxidation stress parameters. Cases with longer allele ≥ (CTAT)(12) repeats, differed significantly from controls (0.77 vs. 0.58, p < 0.0001). Cases with at least one longer allele had higher waist circumference (50% vs. 15%, p = 0.0090), hyper-triglyceridemia (28% vs. 11%), hypo-HDL cholesterolemia (80% vs. 74%) and high diastolic blood pressure (37% vs. 26%) when compared to cases bearing the shorter allele. Cataract subjects with at least one longer allele had significantly raised lipid peroxidation levels (p = 0.0095) and showed an increased risk for cataract (OR = 5.86, CI(95%) = 1.49-23.11, p = 0.0114) after controlling for dependent variables. This exploratory study suggests that presence of even a single longer allele of D2S439 is associated with both cataract and MetS components in Asian Indians, unraveling the existence of a shared genetic locus.

Genetic variation in D7S1875 repeat polymorphism of leptin gene is associated with increased risk for depression: a case-control study from India.

BACKGROUND: Epidemiologic data suggest an association between obesity and depression, however findings vary considerably across different studies. Both depression and obesity are disabling disorders associated with loss over appetite control, influenced by genetic and environmental factors and are risk factors for diseases like hypertension, cardiovascular disorders, etc. This study attempts to establish a link between the symptoms of depression, metabolic disorders, and obesity, to unravel the underlying association/s. METHODS: This exploratory case-control study comprises 133 clinically diagnosed depressed individuals and 136 age matched controls. DNA from all 269 subjects was genotyped for D7S1875 repeat polymorphism in the promoter region of Leptin (LEP) gene using polymerase chain reaction. RESULTS: Frequency of the shorter allele of D7S1875 (<208 bp) was 0.73 in the depressive group versus 0.67 in the control group (P=.01). Cases homozygous for D7S1875> or =208 bp alleles had significantly higher value of systolic (130 versus 122; P<.009) and diastolic (85.4 versus 81; P=.01) blood pressure (SBP and DBP) than the individuals homozygous for<208 bp allele. A similar trend was observed for SBP (127.8 versus 123.6; P=.03) among controls homozygous for the longer or the shorter allele. Thus, the LEP gene appears to be an important genetic determinant for susceptibility to depression in the Indian population (OR=1.4913, 95% CI=1.0334-2.1522; P=.04). CONCLUSIONS: Our findings suggest that LEP gene variants could be related to depression and associated co-morbidities such as hypertension.

Analysis of single nucleotide polymorphisms of CRYGA and CRYGB genes in control population of western Indian origin.

AIM: Polymorphisms in gamma-crystallins ( CRYG ) can serve as markers for lens differentiation and eye disorders leading to cataract. Several investigators have reported the presence of sequence variations within crystallin genes, with or without apparent effects on the function of the proteins both in mice and humans. Delineation of these polymorphic sites may explain the differences observed in the susceptibility to cataract observed among various ethnic groups. An easier Restriction Fragment Length Polymorphism (RFLP)-based method has been used to detect the frequency of four single nucleotide polymorphisms (SNPs) in CRYGA / CRYGB genes in control subjects of western Indian origin. MATERIALS AND METHODS: A total of 137 healthy volunteers from western India were studied. Examination was performed to exclude volunteers with any ocular defects. Polymerase chain reaction (PCR)-RFLP based method was developed for genotyping of G198A (Intron A), T196C (Exon 3) of CRYGA and T47C (Promoter), G449T (Exon 2) of CRYGB genes. RESULTS: The exonic SNPs in CRYGA and CRYGB were found to have an allele frequency 0.03 and 1.00 for ancestral allele respectively, while frequency of non-coding SNP in CRYGA was 0.72. Allele frequency of T90C of CRYGB varied significantly ( P = 0.02) among different age groups. An in-silico analysis reveals that this sequence variation in CRYGB promoter impacts the binding of two transcription factors, ACE2 (Member of CLB2 cluster) and Progesterone Receptor (PR) which may impact the expression of CRYGB gene. CONCLUSIONS: This study establishes baseline frequency data for four SNPs in CRYGA and CRYGB genes for future case control studies on the role of these SNPs in the genetic basis of cataract.