Analysis of the association of allelic variants of apolypoprotein E and interleukin 1 beta genes with multiple sclerosis in ethnic Tatars

Multiple sclerosis (MS) is a multifactorial disease of the central nervous system. The apolipoprotein E (APOE) and interleukin 1 β (IL1B) genes are considered to be candidate genes of MS. The aim of the study was to examine the hypothesis of the importance of APOE and IL1B gene polymorphisms in MS development in ethnic Tatars. DNA samples isolated by phenol-chloroform extraction from peripheral blood of 383 ethnic Tatars (120 MS patients and 263 healthy donors) were studied. 112C/R and 158R/C APOE gene polymorphisms as well as ?511T/C IL1B gene polymorphism were analyzed by polymerase chain reaction (PCR) followed by PCR product digestion by endonuclease. Odds ratio (OR) values were used for evaluation of the relative risk of alleles and(or) genotype combinations. It has been shown that APOE*2/*3 genotype is associated with low risk of the disease development (OR = 0.20) in women. A combined effect of APOE and IL1B allelic variants has been discovered indicating the increased risk of the disease development in the carriers of APOE*4 and IL1B*T/*T alleles (OR = 4.76).     

Role of Kisspeptin and Leptin in the Development of Immune Reactivity during Pregnancy

The effects of kisspeptin, an important regulator of reproductive function, and leptin, a classical metabolic hormone, on the formation of inducible regulatory T cells (iTreg) and T helper cells that produce interleukin 17 (Th17), as well as on the activity of indoleamine 2,3-dioxygenase (IDO) have been studied. Both hormones are actively produced by the placenta and involved in the formation of a new hormonal profile during pregnancy. It was found that kisspeptin at concentrations typical for trimesters I–III of pregnancy stimulates the formation of iTreg and simultaneously inhibit Th17 induction. Regardless of the used concentration, kisspeptin increases the secretion of interleukin-10 (IL-10) and reduces the production of IL-17A in CD4⁺ T lymphocytes in women. At the same time leptin at physiological concentrations typical for pregnancy has the opposite effect, inhibiting the formation of iTreg without affecting the production of IL-10 in cultures of CD4⁺T lymphocytes and simultaneous stimulating the induction of Th17 and production of IL-17A in CD4⁺T lymphocytes. At the concentration corresponding to trimesters II–III of pregnancy both hormones significantly enhance lipopolysaccharide-induced activity of IDO in monocytes.     

Apropas phenomenon of women predominance among carriers of reciprocal translocations during disturbances in reproduction

The predominance of females among reciprocal (rec) translocation carriers, which have problems with reproduction in the anamnesis, is well established and usually accounts for the sterility of male carriers of this type of translocations. However, no careful comparative studies have been performed. Meta-analysis of the data on the examined pairs with reproduction problems shows that, among patients with infertility, the frequency of rec carriers was observed in 0.48% (74/15304) of men and in 0.41% (64/15454) of women; the sex ratio (SR) was 1.17, which does not differ significantly from the population value, 1.06 (p = 0.36). Robertsonian translocations (rob) were observed in 0.58% of men and in 0.11% of women; SR = 5.3 (p = 5 × 10^–13) in this group. Inversions (inv) were more often detected in women than in men, 0.14 and 0.27%, SR = 0.59 (p = 0.020). Among patients with habitual miscarriages, the frequencies of rec carriers were significantly higher than in patients with infertility: in 0.78% (151/19353) of men and in 1.42% (281/19737) of women, GR = 0.55 (p = 10^–9). Carriers of rob were found in 0.33% of men and 0.60% of women, SR = 0.55 (p = 9.7 × 10^–5). The frequency of inv was 0.17 and 0.20%, respectively. The results supports the notion that the predominance of women among fertile carriers of rob is caused by the sterility of male carriers of such rearrangements. However, the predominance of women among fertile carriers of rec cannot be due to this reason. The first reason is because there is no significant prevalence of men over women among infertile carriers of such type translocations. The second reason is because the frequency of rec male carriers among patients with infertility is significantly lower than their frequency among fertile carriers. It is likely that the reason for the observed phenomenon is the inherent oogenesis factors which affect segregation of the aberrant chromosomes.     

Associations between interleukin-10 polymorphisms and susceptibility to juvenile idiopathic arthritis: a systematic review and meta-analysis

Background

Cytokine genes, including interleukin-10 (IL-10), are known to play important roles in the pathogenesis of juvenile idiopathic arthritis (JIA). This study aims to determine whether the IL-10 polymorphisms confer susceptibility to JIA.

Methods

A meta-analysis was performed on the associations between the IL-10-1082 G/A, -592 C/A, and -819 C/T polymorphisms and JIA. A total number of 7 studies involving 1,785 patients and 6,142 controls were considered in the meta-analysis.

Results

Meta-analysis of the IL-10-592 C/A and -819 C/T polymorphisms showed no association with JIA in the study participants, or in Caucasian or Middle Eastern participants. Meta-analysis of the IL-10-1082 A allele in all study participants, Caucasian and Middle Eastern, showed significant associations with RA (overall ORs were 1.17, 1.15, and 1.41, respectively). Meta-analysis of the AA versus GG genotype of the IL-10-1082 G/A polymorphism revealed significant associations with JIA (OR = 3.66, 95% CI = 1.44-9.29, P = 0.006) in participants from Middle Eastern countries. Additionally, meta-analysis of the GG versus AA+GA genotypes of the IL-10 -1082 G/A polymorphism revealed the GG genotype as the protective factor against JIA in the Middle Eastern subgroup (OR = 0.44, 95% CI = 0.20-0.94, P = 0,04). Moreover, meta-analysis of the IL-10 -1082 A allele in 4 studies on Hardy-Weinberg equilibrium showed a significant association with JIA (OR = 1.17, 95% CI = 1.07-1.28, P = 0.0009). No association was found between the IL-10 (-1082, -819, -592) ACC, ATA, and GCC haplotypes and JIA.

Conclusions

These results suggest that the IL-10-1082 G/A polymorphism confers susceptibility to JIA.

     

<Emphasis Type="Italic">SNCA</Emphasis> alleles rs356219 and rs356165 are associated with Parkinson’s disease and increased α-synuclein gene expression in CD45<Superscript>+</Superscript> blood cells

Impaired metabolism of α-synuclein (SNCA) and its aggregation are key molecular events underlying Parkinson’s disease (PD). Emerging data show that there is a connection between PD and the gene locus containing the SNCA gene. Meta-analyses have demonstrated a highly significant PD connection with single nucleotide polymorphisms (SNPs) rs356165 (A/G) and rs356219 (A/G) in the SNCA gene. We conducted SNP genotyping in 260 PD patients (n = 260) and 262 healthy people (n = 262) from northwestern regions of Russia. Linkage disequilibrium was registered between rs356219 and rs356165 alleles (D' = 0.926). It was confirmed that G alleles (rs356165 and rs356219) are associated with increased risk of PD development. For the first time, we have evaluated the relationship between rs356165 and rs356219 and levels of SNCA mRNA and α-synuclein protein in CD45⁺ peripheral blood cells in drug-naïve PD patients (n = 43) and controls (n = 39). Both the level of mRNA SNCA gene and that of α-synuclein protein were increased in carriers of rs356219 and rs356165 compared to carriers with AA genotype in control group (in the group of healthy people) (p = 0.046 and p = 0.039, respectively). Linkage disequilibrium was shown between associated marker alleles. Our data suggest that rs356165 and rs356219 allele variants may affect the PD development by up-regulation of SNCA expression.     

Association of <Emphasis Type="Italic">FGFR2</Emphasis> (rs2981579) gene polymorphism with the risk of mesial occlusion

The molecular-genetic testing of the polymorphic rs2981579 (C>T) locus of the FGFR2 gene as the marker of increased predisposition to the development of mesial occlusion was carried out in 110 patients with mesial occlusion and 103 general-population control subjects from Ukraine. It was shown that polymorphism rs2981579 in gene FGFR2 is associated with mesial occlusion (OR = 1.67, 95% CI = 1.14–2.45, p = 0.009). Compared to CC carriers, TT+CT carriers had a 3.21-fold higher risk of mesial occlusion (95% CI = 1.57–6.57, p = 0.001). We found the protective effect of the homozygous allele C on mesial occlusion development (OR = 0.31, p = 0.001). This is the first published data on FGFR2 polymorphisms rs2981579 (C>T) in patients with mesial occlusion.     

Erratum to: “Apropos phenomenon of female predominance among carriers of reciprocal translocations with reproductive disorders”

Female predominance among carriers of reciprocal translocations (rec) has been commonly explained by male sterility, although appropriate comparative studies had not been carried out. The objectives of this study were comparative analysis of rates of carriers of balanced chromosomal rearrangement among patients with infertility and among patients with recurrent miscarriages and comparative analysis of maleto-female ratio (sex ratio, SR) in the carriers. Metaanalysis of data from 34 publications on prevalence of chromosomal rearrangements in couples with reproductive failures showed that among couples with infertility, a carrier of reciprocal translocation was found in 0.48% (74/15306) of males and in 0.41% (64/15456) of females, SR =1.17, not different statistically from the population value of 1.06 (p = 0.36). Carriers of Robertsonian translocations (rob) were detected in 0.58% of males and in 0.11% of females, SR = 5.3 (p = 5 × 10^–13). Carriers of an inversion (inv) were found at a slightly lower rate among infertile males compared to females, 0.16% vs 0.27%, SR = 0.59 (p = 0.020). Among patients with miscarriages, carriers of rec were detected at a significantly higher rate compared to patients with infertility, in 0.78% (151/19353) of males and in 1.42% (281/19737) of females, SR = 0.55 (p = 1 × 10^–9). Carriers of rob were found in 0.33% of male patients and in 0.6% of female patients, SR = 0.56 (p = 9.7 × 10–5). Rates of male and female carriers of inv were 0.17 and 0.20%, respectively. The data obtained corroborate with the observation of female predominance among fertile carriers of rob due to male sterility. However, female predominance among fertile carriers of rec cannot be explained by the same reason. Firstly, there is no significant male prevalence among infertile carriers, secondly, the rate of rec carriers among infertile males is lower compared to that among fertile patients. This phenomenon might be explained by factors inherent to oogenesis affecting meiotic segregation of rearranged.     

Association between relative bone mass and vitamin D receptor gene polymorphism

The paper reports a search for association between the relative bone tissue mass (percent of total body mass, %BT) and FokI (rs10735810), BsmI (rs1544410), and TaqαI (rs731236) vitamin D receptor gene polymorphisms. The group of apparently healthy young adults born in the central and northern regions of European Russia included 61 men and 60 women aged 16–23 years. No statistical association was detected between the FokI polymorphism and %BT. The carriers of the BsmI *A allele exhibited a higher %BT (p = 0.0172) compared to the subjects bearing the BsmI *G*G allele. The subjects with the *C*C TaqαI genotype were characterized by increased %BT compared to the carriers of the *T allele (p = 0.0018). The data are in good correspondence with the results obtained in the studies involving apparently healthy representatives of Central European and Northern European populations of the corresponding age.     

Usefulness of selected laboratory markers in ulcerative colitis

Introduction

This study aimed to compare the accuracy of selected laboratory markers in assessing disease activity in patients with ulcerative colitis (UC). The analysis included serum IL-2, IL-4, IL-6, IL-10, IL-17, TNF-α, IFN-γ, hsCRP, peripheral regulatory T cells, as well as fecal calprotectin and lactoferrin.

Patients and methods

A group of 45 adults with UC was enrolled in the study. Disease activity was assessed using the Mayo endoscopic index, while for clinical activity scoring, the Clinical Activity Index (CAI) was used. Concentrations of markers investigated were estimated by means of flow cytometry and enzyme-linked immunosorbent assays: the results were correlated with both indices.

Results

The study demonstrated that both fecal markers, i.e. calprotectin (r = 0.880, P<0.001) and lactoferrin (r = 0.799, P<0.001) correlated closely with the Mayo endoscopic score, and might be used to evaluate the severity of UC in the clinical setting. The correlation of these markers with CAI was also significant, with r = 0.831 for calprotectin (P<0.001) and r = 0.672 for lactoferrin (P<0.05). As for the other markers investigated, only IL-6 (r = 0.598, P<0.001), IL-17A (r = 0.587, P<0.005), and TNF-α (r = 0.701, P<0.001) correlated closely with the Mayo endoscopic index. The correlation of the markers with CAI was also significant, though weaker, with r = 0.525 for IL-6 (P<0.001), r = 0.587 for IL-17A (P<0.05), and r = 0.624 for TNF-α (P<0.001).

Discussion

Despite the fact, that UC is generally considered to be an IL-13-driven, Th2-like type of disease, markers of inflammation such as serum interleukin (IL)-6, IL-17, TNF-α, fecal calprotectin and lactoferrin might be useful in assessing disease activity.

     

Association of genes of different functional classes with type 1 diabetes

The genetic structure of susceptibility to type 1 diabetes (T1D) in the population of Tomsk was studied. We had a group of T1D patients (N = 285) and a population sample (N = 300) and we studied 58 SNPs localized in the 47 genes which products are involved in various metabolic pathways and processes as fibrogenesis, endothelial dysfunction, and inflammation. Genotyping was performed by mass spectrometry using the Sequenom MassARRAY system (United States). We compared the group of T1D patients and the population sample and found an association with the predisposition to disease for seven markers: rs3765124 of the ADAMDEC1 gene, genotype AA (p = 0.004), allele A (p = 0.033); rs1007856 of the ITGB5 gene, genotype TT (p = 0.015), allele T (p = 0.036); rs20579 of the LIG1 gene, genotype CC (p = 0.004), allele C (p = 0.002); rs12980602 of the IFNL2 gene, allele C (p = 0.029); rs4986819 of the PARP4 gene, allele C (p = 0.044); rs1143674 of the ITGA4 gene genotype GG (p = 0.002); rs679620 of the MMP3 gene, genotype AA (p = 0.008). Thus, the products of genes associated with T1D belong to different molecular classes: metalloproteases (ADAMDEC1, MMP3), cytokines (IL28A), cell surface receptors (ITGA4), adhesion molecules (ITGB5), DNA ligases (LIG1), and ribosyltransferase enzymes (PARP4). The ADAMDEC1, ITGA4, and ITGB5 genes belong to two biological processes: cell communication and signal transduction. The LIG1 and PARP4 genes regulate the metabolism of nucleic acids, MMP3 is involved in the regulation of protein metabolism, and the IFNL2 is involved in the immune response.     

Targeted imputation of sequence variants and gene expression profiling identifies twelve candidate genes associated with lactation volume,composition and calving interval in dairy cattle

Dairy cattle are an interesting model for gaining insights into the genes responsible for the large variation between and within mammalian species in the protein and fat content of their milk and their milk volume. Large numbers of phenotypes for these traits are available, as well as full genome sequence of key founders of modern dairy cattle populations. In twenty target QTL regions affecting milk production traits, we imputed full genome sequence variant genotypes into a population of 16,721 Holstein and Jersey cattle with excellent phenotypes. Association testing was used to identify variants within each target region, and gene expression data were used to identify possible gene candidates. There was statistical support for imputed sequence variants in or close to BTRC, MGST1, SLC37A1, STAT5A, STAT5B, PAEP, VDR, CSF2RB, MUC1, NCF4, and GHDC associated with milk production, and EPGN for calving interval. Of these candidates, analysis of RNA-Seq data demonstrated that PAEP, VDR, SLC37A1, GHDC, MUC1, CSF2RB, and STAT5A were highly differentially expressed in mammary gland compared to 15 other tissues. For nine of the other target regions, the most significant variants were in non-coding DNA. Genomic predictions in a third dairy breed (Australian Reds) using sequence variants in only these candidate genes were for some traits more accurate than genomic predictions from 632,003 common SNP on the Bovine HD array. The genes identified in this study are interesting candidates for improving milk production in cattle and could be investigated for novel biological mechanisms driving lactation traits in other mammals.     

Acid-base and gas-transfer properties of the blood of newborn infants

The concentration of HCO ₃ ^? , pH, pO₂, sO₂, and pCO₂ were measured in the total umbilical blood of neonates born in January–February (n = 169) and June–July (n = 172). The former group displayed higher values of pH, pO₂, and sO₂, whereas pCO₂ and the concentration of HCO ₃ ^? were higher in the latter group. There was a 70–80% coincidence of the variants in both groups (the regions of statistical transgressions); seasonal factors were responsible for 20–30% of the differences.     

An overlooked phenomenon: Female-biased sex ratio among carriers of Robertsonian translocations detected in consecutive newborn studies

Examination of the sex ratio (SR, male to female ratio) among carriers of Robertsonian translocations (rob) in newborns in the general population has not previously been given due attention, probably because of focusing on the striking female preponderance among fertile women explained by sterility of male carriers. Meta-analysis of published studies on 68,212 newborns showed differences in SR depending on the type of rearrangements: there were similar rates of male and female reciprocal translocation carriers (34♂/33♀, 0.97 and 0.99‰, correspondingly), but female preponderance among carriers of rob, regardless of their parental origin was observed (27♂/41♀, 0.77 and 1.24‰, correspondingly). Similar results were obtained from the prenatal cohort. Collectively, among carriers of rob with known parental origin, there were 66♂ and 97♀ (SR = 0.68), different from the expected ratio of 1: 1, p = 0.0093; for carriers of reciprocal translocations and inversions a typical slight male prevalence was found. Female-biased SR was demonstrated for carriers of the most frequent rob, t(13;14), with 50♂/85♀ (SR = 0.59, p = 0.0016), but not for carriers of other robs (28♂/27♀, SR = 1.04). A mechanism of female-specific rescue of translocation trisomy, due to loss of maternal chromosome, resulting in female preponderance among carriers of balanced translocations, along with reciprocal male preponderance among carriers of unbalanced translocations, could explain the observed phenomenon. Both female-biased SR among carriers of balanced 45,der(13;14),upd(14) with 4♂/12♀ and malebiased SR among carriers of unbalanced 46,+13,der(13;14) with 16♂/2♀, support the proposed hypothesis.     

New susceptibility locus for obesity and dyslipidaemia on chromosome 3q22.3

Background

The muscle Ras (MRAS) gene resides on chromosome 3q22.3 and encodes a member of the membrane-associated Ras small GTPase proteins, which function as signal transducers in multiple processes including cell growth and differentiation. Its role in cardiovascular disease is not fully understood yet. In a preliminary study in heterozygous familial hypercholesterolaemia, we identified a locus linking the early onset of coronary artery disease (CAD) to chromosome 3q.22 and elected to sequence the MRAS gene using the MegaBACE DNA analysis system. In the present study, we investigated the association of seven single-nucleotide polymorphisms (SNPs) at this locus with CAD and its dyslipidaemia-related risk traits in 4,650 Saudi angiographed individuals using TaqMan assays by the Applied Biosystems real-time Prism 7900HT Sequence Detection System.

Results

Among the studied SNPs, rs6782181 (p = 0.017) and rs9818870T (p = 0.009) were associated with CAD following adjustment for sex, age and other confounding risk factors. The rs6782181_GG also conferred risk for obesity (1,764 cases vs. 2,586 controls) [1.16(1.03–1.30); p = 0.017], hypercholesterolaemia (1,686 vs. 2,744) [1.23(1.02–1.47); p = 0.019], hypertriglyceridaemia (1,155 vs. 3,496) [1.29(1.01–1.45); p = 0.043] and low high-density lipoprotein-cholesterol (lHDL-chol) levels (1,935 vs. 2,401) [1.15(1.02–1.30); p = 0.023] after adjustment. Additionally, rs253662_(CT+TT) [1.16(1.01–1.32); p = 0.030] was associated with lHDL-chol levels. Interestingly, rs253662 (p = 0.014) and rs6782181 (p = 0.019) were protective against acquiring high low-density lipoprotein-cholesterol (hLDL-chol) levels (p = 0.014), while rs1720819 showed similar effects against CAD (p < 0.0001). More importantly, a 7-mer haplotype, ACCTGAC (χ² = 7.66; p = 0.0056), constructed from the studied SNPs, its 6-mer derivative CCTGAC (χ² = 6.90; p = 0.0086) and several other shorter derivatives conferred risk for obesity. hLDL-chol was weakly linked to CTAA (χ² = 3.79; p = 0.052) and CCT (χ² = 4.32; p = 0.038), while several other haplotypes were protective against both obesity and hLDL-chol level.

Conclusion

Our results demonstrate that the genomic locus for the MRAS gene confers risk for CAD, obesity and dyslipidaemia and point to the possible involvement of other genes or regulatory elements at this locus, rather than changes in the M-Ras protein function, in these events.

     

The spectrum of mutations in genes associated with resistance to rifampicin,isoniazid, and fluoroquinolones in the clinical strains of <Emphasis Type="Italic">M. tuberculosis</Emphasis> reflects the transmissibility of mutant clones

To study the transmissibility of drug resistant mutant clones, M. tuberculosis samples were isolated from the patients of the clinical department and the polyclinic of the Central TB Research Institute (n = 1455) for 2011–2014. A number of clones were phenotypically resistant to rifampicin (n = 829), isoniazid (n = 968), and fluoroquinolones (n = 220). We have detected 21 resistance-associated variants in eight codons of rpoB, six variants in three codons of katG, three variants in two positions of inhA, four variants in four positions of ahpC, and nine variants in five codons of gyrA, which were represented in the analyzed samples with varied frequencies. Most common mutations were rpoB 531 Ser→Leu (77.93%), katG 315 (Ser→Thr) (94.11%), and gyrA 94 (Asp→Gly) (45.45%). We found that the mutations at position 15 of inhA (C→T) (frequency of 25.72%) are commonly associated with katG 315 (Ser→Thr). This association of two DNA variants may arise due to the double selection by coexposure of M. tuberculosis to isoniazid and ethionamide. The high transmissibility of mutated strains was observed, which may be explained by the minimal influence of the resistance determinants on strain viability. The high transmissibility of resistant variants may also explain the large populational prevalence of drug-resistant TB strains.     

Interleukin-6 and C-reactive protein,successful aging,and mortality: the PolSenior study

Background

In the elderly, chronic low-grade inflammation (inflammaging) is a risk factor for the development of aging-related diseases and frailty. Using data from several thousand Eastern Europeans aged 65 years and older, we investigated whether the serum levels of two proinflammatory factors, interleukin-6 (IL-6) and C-reactive protein (CRP), were associated with physical and cognitive performance, and could predict mortality in successfully aging elderly.

Results

IL-6 and CRP levels systematically increased in an age-dependent manner in the entire study group (IL-6: n?=?3496 individuals, p?<?0.001 and CRP: n?=?3632, p?=?0.003), and in the subgroup of successfully aging individuals who had never been diagnosed with cardiovascular disease, myocardial infarction, stroke, type 2 diabetes, or cancer, and had a Mini Mental State Examination (MMSE) score ≥24 and a Katz Activities of Daily Living (ADL) score ≥5 (IL-6: n?=?1258, p?<?0.001 and CRP: n?=?1312, p?<?0.001). In the subgroup of individuals suffering from aging-related diseases/disability, only IL-6 increased with age (IL-6: n?=?2238, p?<?0.001 and CRP: n?=?2320, p?=?0.249). IL-6 and CRP levels were lower in successfully aging individuals than in the remaining study participants (both p?<?0.001). Higher IL-6 and CRP levels were associated with poorer physical performance (lower ADL score) and poorer cognitive performance (lower MMSE score) (both p?<?0.001). This association remained significant after adjusting for age, gender, BMI, lipids, estimated glomerular filtration rate, and smoking status. Longer survival was associated with lower concentrations of IL-6 and CRP not only in individuals with aging-related diseases/disability (HR?=?1.063 per each pg/mL, 95 % CI: 1.052-1.074, p?<?0.001 and HR?=?1.020 per each mg/L, 95 % CI: 1.015-1.025, p?<?0.001, respectively) but also in the successfully aging subgroup (HR?=?1.163 per each pg/mL, 95 % CI: 1.128-1.199, p?<?0.001 and HR?=?1.074 per each mg/L, 95 % CI: 1.047-1.100, p?<?0.001, respectively). These associations remained significant after adjusting for age, gender, BMI, lipids and smoking status. The Kaplan-Meier survival curves showed similar results (all p?<?0.001).

Conclusions

Both IL-6 and CRP levels were good predictors of physical and cognitive performance and the risk of mortality in both the entire elderly population and in successfully aging individuals.

     

Filtering genetic variants and placing informative <Emphasis Type="Italic">priors</Emphasis> based on putative biological function

High-density genetic marker data, especially sequence data, imply an immense multiple testing burden. This can be ameliorated by filtering genetic variants, exploiting or accounting for correlations between variants, jointly testing variants, and by incorporating informative priors. Priors can be based on biological knowledge or predicted variant function, or even be used to integrate gene expression or other omics data. Based on Genetic Analysis Workshop (GAW) 19 data, this article discusses diversity and usefulness of functional variant scores provided, for example, by PolyPhen2, SIFT, or RegulomeDB annotations. Incorporating functional scores into variant filters or weights and adjusting the significance level for correlations between variants yielded significant associations with blood pressure traits in a large family study of Mexican Americans (GAW19 data set). Marker rs218966 in gene PHF14 and rs9836027 in MAP4 significantly associated with hypertension; additionally, rare variants in SNUPN significantly associated with systolic blood pressure. Variant weights strongly influenced the power of kernel methods and burden tests. Apart from variant weights in test statistics, prior weights may also be used when combining test statistics or to informatively weight p values while controlling false discovery rate (FDR). Indeed, power improved when gene expression data for FDR-controlled informative weighting of association test p values of genes was used. Finally, approaches exploiting variant correlations included identity-by-descent mapping and the optimal strategy for joint testing rare and common variants, which was observed to depend on linkage disequilibrium structure.