Genetic Protective Factors Research Articles

Trends in human papillomavirus-related oropharyngeal cancer in Israel.

The role of human papillomavirus (HPV) infection in oropharyngeal cancer (SCC) is well established. The annual incidence of oropharyngeal SCC in Israel is considerably lower than that in the United States. The purpose of this study was to assess the rate of HPV-related oropharyngeal SCC in Israel. The cohort included patients with oropharyngeal SCC who were treated during 1999 to 2011 in Israel. HPV typing was carried out using reverse hybridization and immunohistochemistry. Of the 74 patients analyzed, 25 (33.7%) had detectable HPV DNA. Patients in the HPV-positive group tended to be younger, with a higher rate of nodal metastases, and no history of smoking (p < .02). This study demonstrated a rate of HPV-related oropharyngeal SCC in Israel as approximately 3-fold lower than in Western countries. Low exposure to HPV-16, a lower rate of transformation, to cancer or protective genetic factors may contribute to the lower rate of oropharyngeal SCC in Israel. © 2015 Wiley Periodicals, Inc. Head Neck 38: E274-E278, 2016.

A promoter polymorphism (rs17222919, -1316T/G) of ALOX5AP gene is associated with decreased risk of ischemic stroke in two independent Chinese populations.

No coding sequence variants of the gene encoding 5-lipoxygenase-activating protein (ALOX5AP) leading to amino acid substitutions have been identified. Therefore, variants in the ALOX5AP promoter region have received attention recently. The purpose of this study was to explore whether the promoter polymorphism rs17222919 is involved in the etiology of ischemic stroke (IS) in the Chinese Han population. We investigated the rs17222919 polymorphism by TaqMan genotyping in two independent Chinese Han samples: the first comprised 910 IS patients and 925 healthy inhabitants from the northern Henan Province, while the second included 1003 IS patients and 889 healthy controls from the southern Henan Province. Functional characterization of rs17222919 was performed by an in vitro luciferase assay. After adjusting for conventional risk factors, the G allele frequencies in the IS groups were significantly lower than that in the control groups of the two independent Chinese cohorts (19.0% vs. 22.9%, P = 0.004, odds ratio (OR) = 0.792, 95% confidence interval (CI) = 0.675–0.929; 18.8% vs. 22.9%, P = 0.002, OR = 0.782, 95% CI = 0.668–0.915, respectively). This was also observed in the large-artery atherosclerosis (LAA) and stroke of other undetermined etiology (SUE) subtypes (P = 0.019, OR = 0.815, 95% CI = 0.687–0.967; P = 0.021, OR = 0.815, 95% CI = 0.685–0.970, respectively). Additionally, the TG genotype and G allele frequencies were significantly lower in the IS compared with the control group in two female cohorts (P<0.05). Finally, the in vitro luciferase assay demonstrated that the G allele has a significantly lower transcription activity than the T allele (P = 0.031). Our study provides evidence that the promoter single nucleotide polymorphism (SNP) rs17222919 is a potential genetic protective factor for IS in the Chinese Han population.

Functional Polymorphism Of The Interleukin-1beta Gene Promoter Is Associated With Increased Risk For Cerebral Palsy In Mexican Children With Perinatal Hypoxia-Ischemia Antecedents

Background: The genetic polymorphism that contributes to the development of infantile cerebral palsy (ICP) after a perinatal hypoxia-ischemia episode remains unknown. Because IL-1? plays a crucial role in the pathogenesis of hypoxic-ischemic encephalopathy, we evaluated whether the interleukin 1, beta (IL-1?) promoter single-nucleotide polymorphisms (SNPs) correlate with the increased risk for ICP following a perinatal hypoxia-ischemia. We assessed -511 C>T and -31 T>C IL-1? SNPs known to be involved in IL-1? expression. Methods: Genomic DNAs were purified from peripheral leukocytes of 48 ICP patients and 57 healthy children, amplified by using polymerase chain reaction (PCR), and then analyzed by using the restriction-fragment-length polymorphism technique. The SNP genotypes were established using real time PCR and validated with the restriction enzymes AvaI for -511C-T and AluI for -31T-C in Restriction fragment length polymorphism (RFLP) analysis. Results: Allelic frequencies of the IL-1? -511 T carrier in patients were significantly higher when compared with those determined in healthy controls. The -511 TT genotype frequency showed a significant difference [odds ratio = 2.4 (95% confidence interval 1.7-3.5), P = 0.0001, and relative risk = 1.5 (95% confidence interval 1.3-1.7)] between patients and controls. The SNP frequencies of -31 genotypes in cerebral palsy patients were not statistically different from the healthy controls. Conclusions: Mexican children with the homozygous TT mutation in the -511 SNP of the IL-1? gene promoter are 2.4 times more susceptible to develop ICP after suffering perinatal asphyxia than healthy children and the presence of a single allele C could be considered as a genetic protective factor.

Estrogen Receptor Genes Polymorphisms and Susceptibility to Juvenile and Adult Onset Systemic Lupus Erythematous in Egyptian Patients

Abstract Background:Estrogens, acting through their cellular receptors namely alpha and beta, have a role in the development of systemic lupus erythematosus (SLE). Objectives: To investigate whether polymorphisms of ESR1 and ESR2 genes is related to the susceptibility of juvenile (jSLE) and adult Systemic lupus erythematosus (aSLE) and to detect their association with clinical and laboratory characteristics of the disease. Methods: Genomic DNA was extracted from 32 adult onset SLE (aSLE), 33 juvenile onset SLE (jSLE) and 60 age and gender matched controls. Genotyping of ESR1 and ESR2 was done using the restriction fragment length polymorphism (RFLP) and tetra primer ARM-PCR methods respectively. Results: There was a statistically significant difference in the genetic polymorphisms of ESR2 between the two studied groups (aSLE, jSLE) and the control group as regards the homomutant AA genotype (OR:0.058, p value: 0.000) and the A allele(OR: 0.195, p value:0.007) in case of aSLE, and in homomutant AA genotype (OR:0.269, p value:0.017) and the A allele (OR: 0.397, p value: 0.003) in case of jSLE but the study could not find any statistically significant difference in the genetic polymorphisms of ESR1 between the control and the two groups. Conclusion: This study revealed that ESR1 genetic polymorphism is not genetic risk or protective factor for neither aSLE nor jSLE susceptibility, but ESR2 genetic polymorphism is reported as protective factor for aSLE and jSLE among our studied population. Certain alleles are associated with certain clinical and laboratory parameters.

G-395A polymorphism in the promoter region of the KLOTHO gene and hypertension among elderly (90 years and older) Chinese individuals.

The aim of this study was to examine the possible associations between the KLOTHO G-395A gene polymorphism and hypertension in Chinese nonagenarians and centenarians. The G-395A (rs1207568) in the promoter region of the KLOTHO gene was genotyped using a standard TaqMan allelic discrimination assay. We included 710 participants aged 93.5 ± 3.2 years in the analyses. The expression of the A allele of the KLOTHO G-395A polymorphism was significantly downregulated in the hypertension group compared to the control group (0.137 vs 0.200, P < 0.001). The genotype distribution of the G-395A polymorphism between the hypertension and control groups was significantly different in women and smokers, and not in men or non-smokers. The mean systolic blood pressure, percentage of hypertension, and percentage of isolated systolic hypertension was significantly higher in the group with the GG genotype than in the group with the GA+AA genotype. Subjects expressing the GA+AA genotype demonstrated a significantly lower risk of hypertension even after adjusting for age, gender, and other relevant risk factors compared to the population expressing the GG genotype (odds ratio, 0.68; 95% confidence interval: 0.49 to 0.95).The -395A allele of the KLOTHO gene may be a protective genetic factor for hypertension in the Chinese population.

Polymorphisms in genes in the RANKL/RANK/OPG pathway are associated with bone mineral density at different skeletal sites in post-menopausal women.

Association between 22 single nucleotide polymorphisms (SNPs) in the TNFSF11, TNFRSF11A, and TNFRSF11B genes in the RANKL/RANK/OPG pathway with bone mineral density (BMD) in 881 post-menopausal women. Our results suggest that TNFSF11 and TNFRSF11A, but not TNFRSF11B, genetic polymorphisms influence BMD mainly in the femoral neck in post-menopausal Chinese women. The aim of this study was to assess the relationship of polymorphisms in the TNFSF11, TNFRSF11A, and TNFRSF11B genes in the RANKL/RANK/OPG pathway with bone mineral density (BMD) in a cohort of Chinese post-menopausal women. A cross-sectional study was conducted in 881 post-menopausal women aged 50-89years. All participants underwent lumbar spinal (LS) and femoral neck (FN) BMD evaluation by dual-energy X-ray absorptiometry. Twenty-two TNFSF11, TNFRSF11A, and TNFRSF11B SNPs were genotyped. We tested whether a single SNP or a haplotype was associated with BMD variations. Two SNPs in the TNFSF11 gene (rs2277439 and rs2324851) and one in the TNFRSF11A gene (rs7239261) were found to be significantly associated with FN BMD (p = 0.014, 0.013, and 0.047, respectively). Haplotype TGACGT of TNFSF11 rs9525641-rs2277439-rs2324851-rs2875459-rs2200287-rs9533166 was a genetic risk factor toward a lower FN BMD (beta = -0.1473; p = 0.01126). In contrary, haplotype TAGCGT of TNFSF11 rs9525641-rs2277439-rs2324851-rs2875459-rs2200287-rs9533166 was genetic protective factor for LS BMD (beta = 0.3923; p = 0.04917). Our findings suggest that TNFSF11 and TNFRSF11A, but not TNFRSF11B, genetic polymorphisms influence BMD mainly in the femoral neck in post-menopausal Chinese women. This contributes to the understanding of the role of genetic variation in this pathway in determining bone health.

Association between single-nucleotide polymorphisms in six hypertensive candidate genes and hypertension among northern Han Chinese individuals.

Hypertension is one of the leading risk factors for mortality. The renin-angiotensin-aldosterone system (RAAS) is a potent and powerful mediator in the homeostasis of hypertension. Here, the association between six candidate genes, renin, adrenoceptor β3, angiotensinogen, aldosterone synthase, angiotensin II receptor type 1 and angiotensin II receptor type 2, that are related to RAAS and essential hypertension (EH) was evaluated and explored in northern Chinese Han individuals. A case-control study including 1090 EH cases and 700 controls was performed. Eight single-nucleotide polymorphisms (SNPs), rs699, rs4762, rs5707, rs5186, rs4994, rs1799998, rs5193 and rs5194, located in the six genes were genotyped with TaqMan real-time PCR method. Statistical analysis software (SPSS 17.0) was used for descriptive statistics and association analyses. Among the six genes related to RAAS, the frequencies of rs4994 (ADRB3) and rs5194 (AGTR2) were found to be significantly different between the EH cases and controls (P < 0.05). Logistic regression analyses adjusted for covariates showed rs4994 to be closely associated with EH under the recessive (P = 0.019, odds ratio (OR) = 0.373, 95% confidence interval (CI) 0.163-0.851) and homozygous (P = 0.028, OR = 0.394, 95% CI 0.172-0.903) models. The association was also significantly close in the male subset (P < 0.05). Significant association was also observed between rs1799998 (CYP11B2) and EH (P < 0.05) in the dominant, additive and allelic models. These data demonstrated that ADRB3 rs4994 and CYP11B2 rs1799998 were significantly closely associated with EH in northern Han Chinese individuals. The CC of rs4994 and CC or C allele of rs1799998 might be protective genetic factors of hypertension.

Mitochondrial DNA haplogroup D4b is a protective factor for ischemic stroke in Chinese Han population.

Mitochondrial DNA (mtDNA) haplogroups affect the assembly and stability of the mitochondrial respiratory chain, which is potentially related to susceptibility to ischemic stroke (IS). However, the role of mtDNA in IS has not been comprehensively studied. The purpose of this study was to explore whether mtDNA polymorphisms and haplogroups are involved in the etiology of IS in the Chinese Han population. We recruited 200 patients with IS and 200 matched controls and genotyped them for 18 mtDNA single nucleotide polymorphisms defining the major Eastern Asian haplogroups by SNaPshot minisequencing. We also sequenced the hypervariable segment I (HVS-I), position 16051-16400. The prevalence of haplogroup D4b was significantly lower in IS patients than in healthy controls (0 and 8 %, respectively, corrected P = 2 × 10(-5), odds ratio = 0.028, 95 % confidence interval = 0.002-0.468).The positive association between haplogroup D4b and IS may be related to the protective effect of haplogroup D4b against oxidative damage, which decreases the risk of IS. Our study provides the first evidence that haplogroup D4b is a potential genetic protective factor for IS in the Chinese Han population.

Maternal predictors of anxiety risk in young males with fragile X.

Children with fragile X syndrome (FXS) demonstrate high rates of anxiety disorders, with 65-83% meeting diagnostic criteria. The severity of anxiety symptoms in FXS has been shown to be partially predicted by elevated negative affect across early childhood [Tonnsen et al. (2013a); J Abnorm Child Psychol 41:267-280]. This association suggests that biologically driven vulnerability emerges early in development, as is reported in non-clinical populations. However, anxiety emergence is likely moderated by multifaceted genetic, biological and environmental risk and protective factors. Mothers with the FMR1 premutation have been shown to exhibit elevated parenting stress and internalizing symptoms, which have each been associated with child behavior problems [Bailey et al. (2008a); Am J Med Genet Part A 146A:2060-2069 and Bailey et al. (2008b) Am J Med Genet Part A 146A:720-729]. Despite these findings, it is unclear whether maternal factors directly relate to anxiety vulnerability in high-risk children with FXS, a question essential to informing targeted, family-sensitive treatment. The present study examines how maternal protective and risk factors relate to child inhibition reflected in (1) child anxiety symptoms, (2) child trajectories of negative affect, and (3) the association between child anxiety and negative affect. Primary predictors include maternal parenting stress, indicators of mental health risk (anxiety and depressive symptoms), and maternal optimism. We also examine genetic correlates in mothers (CGG repeats, activation ratio, mRNA). Our findings suggest that behavioral inhibition in young children with FXS is associated with higher parenting stress and lower optimism, and higher parenting stress is associated with lower maternal X-activation ratio. These findings underscore the need for family-sensitive treatment strategies for anxiety disorders in children with FXS.

Gene polymorphisms in CCR5, CCR2, SDF1 and RANTES among Chinese Han population with HIV-1 infection

Chemokines and chemokine receptors are crucial for immune response in HIV-1 infection. Although many studies have been done to investigate the relationship between chemokines and chemokine receptor gene polymorphisms and host’s susceptibility to HIV-1 infection, the conclusions are under debate. In the present study, a cohort of 287 HIV-1 seropositive patients, 388 ethnically age-matched healthy controls and 49 intravenous drug users (IDUs) HIV-1 exposed seronegative individuals (HESN) from Chinese Han population were enrolled in order to determine the influence of host genetic factors on HIV-1 infection. Seven polymorphisms on four known chemokines/chemokine receptor genes (CCR5Δ32, CCR5 m303, CCR5 59029A/G, CCR2 64I, RANTES −403A/G, RANTES −28C/G and SDF1 3′-A) were screened. CCR5Δ32 and CCR5 m303 were absent or infrequent in Chinese Han population, which may not be hosts’ genetic protective factors for HIV-1 infection. Our results showed the CCR5 59029A/G, CCR2 64I and SDF1 3′-A were not associated with host’s resistance to HIV-1 infection. The frequency of RANTES −403A allele was significantly lower in HIV-1 patients than in healthy blood donors (p=0.0005) and HESN group (p=0.035), which implied the association between A allele and reduced HIV-1 infection risk. Different genetic models were assessed to investigate this association (AA vs. GG+AG, OR=0.38 95% CI, 0.22–0.65 p=0.0004; A vs. G, OR=0.66 95% CI, 0.52–0.84 p=0.0006), which supported this association, either. The genotype and allele distribution of RANTES −28 between HIV-1 patients and healthy controls (genotype profile: p=0.072; allele profile: p=0.027) or HIV-1 seronegative group (genotype profile: p=0.036; allele profile: p=0.383) were both at the marginal level of significance, which were not observed after Bonferroni correction. All these results suggest the RANTES −403A may be associated with reduced susceptibility to HIV-1 infection, while the RANTES −28 locus not. By lack of the patients’ clinical information, whether these polymorphisms affect AIDS disease progression and their role in different HIV-1 infection routes could not performed in present study and needs to be assessed in ongoing studies.

Decreased CALM expression reduces Aβ42 to total Aβ ratio through clathrin-mediated endocytosis of γ-secretase

A body of evidence suggests that aberrant metabolism of amyloid-β peptide (Aβ) underlies the aetiology of Alzheimer disease (AD). Recently, a single-nucleotide polymorphism in phosphatidylinositol binding clathrin assembly protein (PICALM/CALM) gene, which encodes a protein implicated in the clathrin-mediated endocytosis, was identified as a genetic protective factor for AD, although its mechanistic details have little been explored. Here we show that loss of CALM leads to the selective decrease in the production ratio of the pathogenic Aβ species, Aβ42. Active form of γ-secretase is constitutively endocytosed via the clathrin-mediated pathway in a CALM dependent manner. Alteration in the rate of clathrin-mediated endocytosis of γ-secretase causes a shift in its steady-state localization, which consequently impacts on the production ratio of Aβ42. Our study identifies CALM as an endogenous modulator of γ-secretase activity by regulating its endocytosis and also as an excellent target for Aβ42-lowering AD therapeutics.

The importance of longitudinal cohort studies in understanding risk and protective factors for dementia

As readers of this journal will be well aware, the last decade has witnessed a transformation in our understanding of the pathophysiology of dementias, perhaps most especially Alzheimer's disease (AD), as well as a much greater understanding of the undoubtedly complex and multifactorial etiology of the AD process. An increasing number of genetic risk and protective factors have been identified, as well as potentially modifiable risk factors, including vascular factors such as hypertension and exercise, education, lifestyle, and nutrition. In parallel, there has been considerable progress in developing and validating biomarkers for AD and other dementias. These have transformed the landscape for research, allowing in vivo patient stratification according to pathology, and now have fed through to inform our clinical diagnostic criteria. Particular examples include imaging biomarkers such as characteristic atrophy patterns on magnetic resonance imaging (MRI), hypoperfusion/hypometabolism on functional brain imaging, increased cortical amyloid uptake on positron emission tomography (PET), as well as CSF alterations in tau and β-amyloid. Several changes in blood have also been shown, including altered inflammatory markers, which may prove to be important biomarkers in the future.

Protective Effect of CCR5 Delta-32 Allele Against HIV-1 in Mexican Women

C-C chemokine receptor type 5 (CCR5) is known for its role as a co-receptor for HIV-1 infection. Some individuals possess a 32 bp deletion, known as Delta-32 allele which has been reported to confer resistance to HIV-1 infection. In order to estimate the distribution of Delta-32 allele of CCR5 gene, 1034 mestizo individuals from the Northwest of Mexico, including 385 HIV-1-infected individuals, 472 healthy controls and 177 uninfected female sex workers; were examined by allele-specific PCR. There was no statistically significant difference in the frequency of Delta-32 allele between HIV-1 positive and healthy individuals (OR= 1.1, p= 0.6). However, we found a significantly reduced prevalence of CCR5 Delta-32 heterozygous genotype in female patients (OR= 0.084, 95% CI= 0.011 - 0.630, p= 0.002), as well as in allele frequency, compared to male patients. Furthermore, we observed an inverse relationship between allele frequency and the risk of HIV-1 transmission and AIDS progression among female healthy controls, sex workers and HIV-1 infected groups. Our findings support previous data showing Delta-32 as a genetic protective factor against HIV-1 infection in Mexican women, as well as in women from other populations.

Genetic risk and protective factors of TNFSF15 gene variants detected using single nucleotide polymorphisms in Hungarians with psoriasis and psoriatic arthritis

The aim of this study was to examine the role of single nucleotide polymorphisms (SNPs) and haplotypes of the tumor necrosis factor ligand superfamily member 15 (TNFSF15) gene in Hungarians with psoriasis and psoriatic arthritis. A case-control study was performed, and five TNFSF15 SNPs (rs3810936, rs6478108, rs6478109, rs7848647, rs7869487) were genotyped in 319 patients with psoriasis, 105 of whom also have psoriatic arthritis, and in 200 healthy individuals. Three haplotypes (A, B, C) based on these five SNPs were also analyzed. Our findings suggest that the rs6478109 SNP may be a genetic risk factor in psoriasis (p=0.0046), while haplotype C may be protective (p=0.0250). These results suggest that certain variants of the TNFSF15 gene contribute to the pathogenesis of the immune-mediated, multifactorial skin disease psoriasis, and that this difference is more readily apparent when groups of patients with and without psoriatic arthritis are examined separately.

Genetics of healthy aging and longevity

Longevity and healthy aging are among the most complex phenotypes studied to date. The heritability of age at death in adulthood is approximately 25 %. Studies of exceptionally long-lived individuals show that heritability is greatest at the oldest ages. Linkage studies of exceptionally long-lived families now support a longevity locus on chromosome 3; other putative longevity loci differ between studies. Candidate gene studies have identified variants at APOE and FOXO3A associated with longevity; other genes show inconsistent results. Genome-wide association scans (GWAS) of centenarians vs. younger controls reveal only APOE as achieving genome-wide significance (GWS); however, analyses of combinations of SNPs or genes represented among associations that do not reach GWS have identified pathways and signatures that converge upon genes and biological processes related to aging. The impact of these SNPs, which may exert joint effects, may be obscured by gene-environment interactions or inter-ethnic differences. GWAS and whole genome sequencing data both show that the risk alleles defined by GWAS of common complex diseases are, perhaps surprisingly, found in long-lived individuals, who may tolerate them by means of protective genetic factors. Such protective factors may ‘buffer’ the effects of specific risk alleles. Rare alleles are also likely to contribute to healthy aging and longevity. Epigenetics is quickly emerging as a critical aspect of aging and longevity. Centenarians delay age-related methylation changes, and they can pass this methylation preservation ability on to their offspring. Non-genetic factors, particularly lifestyle, clearly affect the development of age-related diseases and affect health and lifespan in the general population. To fully understand the desirable phenotypes of healthy aging and longevity, it will be necessary to examine whole genome data from large numbers of healthy long-lived individuals to look simultaneously at both common and rare alleles, with impeccable control for population stratification and consideration of non-genetic factors such as environment.

Relationship between single nucleotide polymorphisms and its haplotype of X-ray repair cross complementing group 1 and susceptibility of pancreatic carcinoma

The aim of this study was to evaluate the effects of XRCCl gene polymorphisms and its haplotype on the susceptibility of pancreatic carcinoma. Peripheral blood DNA was extracted from 210 pancreatic carcinoma patients and 213 control subjects. SNaPshot technique was used for genotyping seven SNP sites of the XRCCl gene (rs3213403, rs25487, rs1799782, rs731420, rs1001581, rs12611088, and rs3213282). Logistic regression model was performed to analyze the relationship of different genotypes or haplotype and the susceptibility of pancreatic carcinoma. The frequency for allele A at site rs25487 in the case group was significantly higher than that in the control group (P < 0.05). The frequency of GG, GA and AA genotype between the case group and control group had statistically significant differences (P < 0.05). Compared with GG genotype, the risk of pancreatic carcinoma in the subjects carrying mutated allele A (GA+AA) was increased by 0.648 times (P < 0.05). Among them the pancreatic carcinoma risk of individuals carrying A allele was increased by 0.552 times compared with the individuals carrying G allele. The frequency of allele and genotype at site rs1799782 in the case group and control group had a significant difference (P < 0.05). Compared with the CC genotype, the risk of pancreatic carcinoma in the subjects carrying mutated allele T (CT+TT) was increased by 0.683 times. Among them the pancreatic carcinoma risk of individuals carrying T allele was increased by 0.549 times compared with the individuals carrying C allele. Significant differences were observed in linkage disequilibrium between any two of the seven SNPs (P < 0.05), the frequency of H4-AGCCCGC, H6-GGCCCGG or H7-AGCCTAG haplotypes was significantly lower in the case group than that in the control group (P < 0.05). The single nucleotide polymorphisms of rs25487 and rs1799782 for XRCC1 gene may be correlated with the occurrence of pancreatic carcinoma. The haplotypes of H4-AGCCCGC, H6-GGCCCGG and H7-AGCCTAG might be a potential genetic protective factor for the occurrence of pancreatic carcinoma.

Epigenomic strategies at the interface of genetic and environmental risk factors for autism

Autism spectrum disorders (ASD) have been increasing in prevalence over the last two decades, primarily because of increased awareness and diagnosis. However, autism is clearly a complex human genetic disorder that involves interactions between genes and environment. Epigenetic mechanisms, such as DNA methylation, act at the interface of genetic and environmental risk and protective factors. Advancements in genome-wide sequencing has broadened the view of the human methylome and revealed the organization of the human genome into large-scale methylation domains that footprint over neurologically important genes involved in embryonic development. Future integrative epigenomic analyses of genetic risk factors with environmental exposures and methylome analyses are expected to be important for understanding the complex etiology of ASD.

Current State of Care for Diabetic Retinopathy in India

In this article we review the current state of care of diabetic retinopathy in India. We discuss the magnitude of the problem; diabetes, and diabetic retinopathy in India. We highlight the causes of vision loss in diabetic retinopathy. The current level of awareness among general population and physicians is a concern. Current screening strategies practiced in India and the situational analysis of ophthalmologists in India are also reviewed. We review the current management of diabetic macular edema and proliferative diabetic retinopathy. To know the current practice pattern among retinal surgeons in India, a survey was done and the results of the survey are presented. There are few studies in the Indian population which have found some genetic risk and protective factors and a summary of these studies are also presented in this article.

Cumulative socioeconomic status risk, allostatic load, and adjustment: a prospective latent profile analysis with contextual and genetic protective factors.

The health disparities literature has identified a common pattern among middle-aged African Americans that includes high rates of chronic disease along with low rates of psychiatric disorders despite exposure to high levels of cumulative socioeconomic status (SES) risk. The current study was designed to test hypotheses about the developmental precursors to this pattern. Hypotheses were tested with a representative sample of 443 African American youths living in the rural South. Cumulative SES risk and protective processes were assessed at ages 11-13 years; psychological adjustment was assessed at ages 14-18 years; genotyping at the 5-HTTLPR was conducted at age 16 years; and allostatic load (AL) was assessed at age 19 years. A latent profile analysis identified 5 profiles that evinced distinct patterns of SES risk, AL, and psychological adjustment, with 2 relatively large profiles designated as focal profiles: a physical health vulnerability profile characterized by high SES risk/high AL/low adjustment problems, and a resilient profile characterized by high SES risk/low AL/low adjustment problems. The physical health vulnerability profile mirrored the pattern found in the adult health disparities literature. Multinomial logistic regression analyses indicated that carrying an s allele at the 5-HTTLPR and receiving less peer support distinguished the physical health vulnerability profile from the resilient profile. Protective parenting and planful self-regulation distinguished both focal profiles from the other 3 profiles. The results suggest the public health importance of preventive interventions that enhance coping and reduce the effects of stress across childhood and adolescence.

An analysis of the association between the vitamin D pathway and serum 25-hydroxyvitamin D levels in a healthy Chinese population

Vitamin D deficiency has been recognized as a major public health issue worldwide. Recent studies have indicated that genetic factors might play an important role in determining serum 25-hydroxyvitamin D [25(OH)D] levels in Caucasians and African Americans. However, the genes that contribute to the variation in serum 25(OH)D levels in Chinese are unknown. In this study, we screened 15 key genes within the vitamin D metabolic pathway using 96 single-nucleotide polymorphism (SNP) markers in a group of 2897 unrelated healthy Chinese subjects. Significant confounding factors that may influence the variability in serum 25(OH)D levels were used as covariates for association analyses. An association test for quantitative traits was performed to evaluate the association between candidate genes and serum 25(OH)D levels. In the present study, variants and/or haplotypes in GC, CYP2R1, and DHCR7/NADSYN1 were identified as being associated with 25(OH)D levels. Participants with three or four risk alleles of the two variants (GC-rs4588 and CYP2R1-rs10766197) had an increased chance of presenting with a 25(OH)D concentration lower than 20 ng/mL (odds ratio 2.121, 95% confidence interval 1.586-2.836, p = 6.1 × 10(-8) ) compared with those lacking the risk alleles. Each additional copy of a risk allele was significantly associated with a 0.12-fold decrease in the log-25(OH)D concentration (p = 3.7 × 10(-12) ). Haplotype TGA of GC rs705117-rs2282679-rs1491710, haplotype GAGTAC of GC rs842999-rs705120-rs222040-rs4588-rs7041-rs10488854, haplotype CA of GC rs1155563-rs222029, and haplotype AAGA of CYP2R1 rs7936142-rs12794714-rs2060793-rs16930609 were genetic risk factors toward a lower 25(OH)D concentration. In contrast, haplotype TGGGCCC of DHCR7/NADSYN1 rs1790349-rs7122671-rs1790329-rs11606033-rs2276360-rs1629220-rs2282618 were genetic protective factors. The results suggest that the GC, CYP2R1, and DHCR7/NADSYN1 genes might contribute to variability in the serum 25(OH)D levels in a healthy Chinese population in Shanghai. These markers could be used as tools in Mendelian randomization analyses of vitamin D, and they could potentially be drug targets in the Chinese population in Shanghai.