Halplotypes of the ovine ADRB3 gene (ADRB3) and their association with post-weaning growth in New Zealand Suffolk sheep

The β₃-adrenergic receptor (ADRB3) regulates thermogenesis and lipolysis in brown and white adipose tissue. Previously, sixteen ovine ADRB3 haplotypes have been defined. In this study, the relationship between these ADRB3 haplotypes and variation in post-weaning growth was investigated in 797 New Zealand Suffolk lambs from 38 sire lines and eight studs, using PCR-SSCP and General Linear Mixed-effects Models. Seven haplotypes were found in these sheep and they comprised five previously reported intron sequences and four previously reported 3′UT sequences. The frequencies of the various diplotypes ranged from 0.1 to 17.6 % and individual haplotypes from 0.8 to 32.5 %. The presence of haplotype A-b was associated with a decreased weaning-weight (P = 0.001). Sheep with the B-c/F-e diplotype had a higher mean weaning-weight than those with A-b/B-c or A-b/E-e (P < 0.05). The presence of C-a was found to be associated with increased post-weaning growth (P = 0.008), while the presence of B-c was associated with decreased post-weaning growth (P = 0.005). Sheep with A-b/C-a had higher mean post-weaning growth than those with A-b/A-b, A-b/B-c, B-c/B-c, B-c/E-e or B-c/F-e (P < 0.05). Sheep with B-c/B-c had lower mean post-weaning growth than those with A-b/C-a or B-c/C-a (P < 0.05). Additive effects for the different forms of the B-c haplotypes on post-weaning growth were identified. The effects of the ovine ADRB3 haplotypes on weaning-weight and post-weaning growth confirm that they could be used as a candidate gene-marker for improving sheep growth.     

Genetic and functional analysis of common MRC1 exon 7 polymorphisms in leprosy susceptibility

The chromosomal region 10p13 has been linked to paucibacillary leprosy in two independent studies. The MRC1 gene, encoding the human mannose receptor (MR), is located in the 10p13 region and non-synonymous SNPs in exon 7 of the gene have been suggested as leprosy susceptibility factors. We determined that G396S is the only non-synonymous exon 7-encoded polymorphism in 396 unrelated Vietnamese subjects. This SNP was genotyped in 490 simplex and 90 multiplex leprosy families comprising 704 patients (47% paucibacillary; 53% multibacillary). We observed significant under-transmission of the serine allele of the G396S polymorphism with leprosy per se (P = 0.036) and multibacillary leprosy (P = 0.034). In a sample of 384 Brazilian leprosy cases (51% paucibacillary; 49% multibacillary) and 399 healthy controls, we observed significant association of the glycine allele of the G396S polymorphism with leprosy per se (P = 0.016) and multibacillary leprosy (P = 0.023). In addition, we observed a significant association of exon 7 encoded amino acid haplotypes with leprosy per se (P = 0.012) and multibacillary leprosy (P = 0.004). Next, we tested HEK293 cells over-expressing MR constructs (293-MR) with three exon 7 haplotypes of MRC1 for their ability to bind and internalize ovalbumin and zymosan, two classical MR ligands. No difference in uptake was measured between the variants. In addition, 293-MR failed to bind and internalize viable Mycobacterium leprae and BCG. We propose that the MR–M. leprae interaction is modulated by an accessory host molecule of unknown identity.     

Angiotensinogen T174M and M235T Variants and Hypertension in the Hani and Yi Minority Groups of China

A case–control study of 538 individuals investigated whether the angiotensinogen gene (AGT) might be implicated in the pathogenesis of essential hypertension in the Hani and Yi populations of China. Genotypes for two diallelic DNA polymorphisms observed at amino acid residues 174 (T174M) and 235 (M235T) within the coding sequence were determined. M235T and T174M genotyping with PCR-RFLP was performed in 267 normotensive subjects and 271 hypertensive subjects. No significant difference was found between normotensives and hypertensives in genotype distribution and allele frequency for either M235T or T174M in the Hani or the Yi populations (P > 0.05). Relative to carriers of the 235T/235T and 174T/174T combination, the others had a significantly elevated risk of hypertension (OR = 1.62, 95% CI 1.02–2.59; P = 0.043) in the Hani population. The AGT M235T and T174M variants in combination may play a role in the genetic predisposition to develop essential hypertension in the Hani minority of China.     

Association of four insulin resistance genes with type 2 diabetes mellitus and hypertension in the Chinese Han population

Insulin resistance plays an important role in the development of type 2 diabetes mellitus (T2DM) and hypertension. The purpose of the present study was to evaluate the association between four insulin resistance genes (ADIPOQ, LEPR, RETN, and TRIB3) and both T2DM and hypertension. A total of 768 Han Chinese subjects were recruited into this study, including 188 cases who had T2DM alone, 223 cases who had hypertension alone, 181 cases with both T2DM and hypertension, and 176 control subjects with neither T2DM nor hypertension. Twenty-three tag SNPs in four insulin resistance genes were genotyped and analyzed for association with T2DM and hypertension. One intron SNP (rs13306519) in LEPR and one 3′UTR SNP (rs1063537) in ADIPOQ demonstrated a significant association with T2DM (P = 0.024 and 0.014 respectively). Another intron SNP (rs12037879) in LEPR and a promoter region SNP (rs266729) in ADIPOQ were significantly associated with hypertension (P = 0.041 and 0.042, respectively). These associations survived the permutation test (P = 0.023, 0.018, 0.026, and 0.035, respectively). These associations were still found to be significant in the additive model after adjusting for potential confounding factors including age, sex, BMI, HDL, LDL, total cholesterol, and triglyceride levels (P = 0.024, 0.016, 0.04, and 0.043, respectively). No other gene variants were found to be significantly associated with T2DM or hypertension (P > 0.05). None of the studied gene variants were found to be significantly associated with T2DM+ hypertension (P > 0.05). A significant interaction was observed between two SNPs rs13306519 in LEPR and rs266729 in ADIPOQ for T2DM (P_int = 0.012, OR_int = 2.67) and hypertension (P_int = 0.0041, OR_int = 2.23). These findings suggest that variants in ADIPOQ and LEPR are risk factors for T2DM and hypertension in the Chinese population and that variants in RETN and TRIB3 are not major risk factors for these diseases.     

Molecular Cloning, Genomic Organization, and Expression of a Testicular Isoform of Hormone-Sensitive Lipase

By catalyzing the rate-limiting step in adipose tissue lipolysis, hormone-sensitive lipase (HSL) is an important regulator of energy homeostasis. The role and importance of HSL in tissues other than adipose are poorly understood. We report here the cloning and expression of a testicular isoform, designated HSL_tes. Due to an addition of amino acids at the NH₂-termini, rat and human HSL_tesconsist of 1068 and 1076 amino acids, respectively, compared to the 768 and 775 amino acids, respectively, of the adipocyte isoform (HSL_adi). A novel exon of 1.2 kb, encoding the human testis-specific amino acids, was isolated and mapped to the HSL gene, 16 kb upstream of the exons encoding HSL_adi. The transcribed mRNA of 3.9 kb was specifically expressed in testis. No significant similarity with other known proteins was found for the testis-specific sequence. The amino acid composition differs from the HSL_adisequence, with a notable hydrophilic character and a high content of prolines and glutamines. COS cells, transfected by the 3.9-kb human testis cDNA, expressed a protein of the expected molecular mass (M_r≈ 120,000) that exhibited catalytic activity similar to that of HSL_adi. Immunocytochemistry localized HSL to elongating spermatids and spermatozoa; HSL was not detected in interstitial cells.     

Association, interaction, and replication analysis of genes encoding serotonin transporter and 5-HT3 receptor subunits A and B in alcohol dependence

On the basis of the converging evidence showing regulation of drinking behavior by 5-HT_3AB receptors and the serotonin transporter, we hypothesized that the interactive effects of genetic variations in the genes HTR3A, HTR3B, and SLC6A4 confer greater susceptibility to alcohol dependence (AD) than do their effects individually. We examined the associations of AD with 22 SNPs across HTR3A, HTR3B, and two functional variants in SLC6A4 in 500 AD and 280 healthy control individuals of European descent. We found that the alleles of the low-frequency SNPs rs33940208:T in HTR3A and rs2276305:A in HTR3B were inversely and nominally significantly associated with AD with odds ratio (OR) and 95 % confidence interval of 0.212 and 0.073, 0.616 (P = 0.004) and 0.261 and 0.088, 0.777 (P = 0.016), respectively. Further, our gene-by-gene interaction analysis revealed that two four-variant models that differed by only one SNP carried a risk for AD (empirical P < 1 × 10^?6 for prediction accuracy of the two models based on 10⁶ permutations). Subsequent analysis of these two interaction models revealed an OR of 2.71 and 2.80, respectively, for AD (P < 0.001) in carriers of genotype combinations 5′-HTTLPR:LL/LS(SLC6A4)–rs1042173:TT/TG(SLC6A4)–rs1176744:AC(HTR3B)–rs3782025:AG(HTR3B) and 5′-HTTLPR:LL/LS(SLC6A4)–rs10160548:GT/TT(HTR3A)–rs1176744:AC(HTR3B)–rs3782025:AG(HTR3B). Combining all five genotypes resulted in an OR of 3.095 (P = 2.0 × 10^?4) for AD. Inspired by these findings, we conducted the analysis in an independent sample, OZ-ALC-GWAS (N = 6699), obtained from the NIH dbGAP database, which confirmed the findings, not only for all three risk genotype combinations (Z = 4.384, P = 1.0 × 10^?5; Z = 3.155, P = 1.6 × 10^?3; and Z = 3.389, P = 7.0 × 10^?4, respectively), but also protective effects for rs33940208:T (χ ² = 3.316, P = 0.0686) and rs2276305:A (χ ² = 7.224, P = 0.007). These findings reveal significant interactive effects among variants in SLC6A4–HTR3A–HTR3B affecting AD. Further studies are needed to confirm these findings and characterize the molecular mechanisms underlying these effects.     

Association of HSL gene E1-c.276C>T and E8-c.51C>T mutation with economical traits of Chinese Simmental cattle

Hormone-sensitive lipase (HSL) is responsible for the decomposition of triglycerides in adipose tissue to release free fatty acids, and it is a key rate-limiting enzyme in the regulation of adipose tissue deposition and decomposition. The objective of this study was to evaluate the association between novel SNPs in the coding region of bovine HSL gene and carcass and meat quality traits of Chinese Simmental-cross steers. Two novel SNPs were genotyped and the 47 traits of carcass and meat quality traits were measured in the population studied. Statistical analysis revealed that the SNPs of HSL gene were associated with the carcass and meat quality traits. The individuals with TT genotypes of E1-276C>T showed significant higher dressing percentage, net meat rate, hind legs circumference, fat coverage rate, mesenteric fat and kidney fat (p < 0.05). E8-51C>T (P17S) also showed a significant association with the pH of beef and fatty acids content in Chinese Simmental cattle (p < 0.01). Our findings indicated that polymorphisms in HSL might be one of important genetic factors that influence carcass yield and meat quality in beef cattle, and it may be a useful marker for meat quality traits in future marker-assisted selection programs in beef cattle breeding and production.     

Identification of rare genetic variants in novel loci associated with Paget’s disease of bone

In genome-wide association studies, single nucleotide polymorphisms located in five novel loci were associated with PDB. We aimed at identifying rare genetic variants of candidate genes located in these loci and search for genetic association with PDB in the French-Canadian population. Exons, promoter and exon–intron junctions from patients with familial PDB and healthy individuals were sequenced in candidate genes, located within novel loci associated with PDB in our population. Rare variant was defined by a minor allele frequency <0.05 or absent from dbSNP (NCBI). We sequenced seven genes in 1p13 locus, three genes in 7q33, three genes in 8q22, and five genes in 15q24 locus. We identified 126 rare variants in at least one patient with PDB of whom 55 were located in 1p13 locus, 32 in 7q33, 10 in 8q22 and 29 in 15q24 locus. We located 71 of these 126 rare variants in an intron, 30 in an exon and 9 in an untranslated region. 60 % of these variants were located in functionally relevant gene regions. Among the 12 missense rare variants in PDB, two (rs62620995 in TM7SF4; rs62641691 in CD276) were predicted to be damaging by in silico analysis tools. Rs62620995, which altered a conserved amino acid (p.Leu397Phe) in the TM7SF4 gene, encoding the DC-STAMP protein involved in osteoclastogenesis through RANK signaling pathway, was found to have a marginal association with PDB (p = 0.09). Rs35500845, located in the CTHRC1 gene, which encodes a regulator of collagen matrix deposition, was also associated with PDB in the French-Canadian population (p = 0.046).     

The novel human MRC1 gene polymorphisms are associated with susceptibility to pulmonary tuberculosis in Chinese Uygur and Kazak populations

The MRC1 gene, encoding the human mannose receptor (MR), is a member of the C-type lectin receptors family. MR can recognize and bind to Mycobacterium tuberculosis by the extracellular structure, and play a role in antigen-presenting and maintaining a stable internal environment. This study aimed to investigate potential associations of SNPs in exon 7 of the MRC1 gene with pulmonary tuberculosis (TB). G1186A, G1195A, T1212C, C1221G, C1303T and C1323T were genotyped using PCR and DNA sequencing in 595 Chinese Uygur and 513 Kazak subjects. In the Uygur, the frequency of allele G (P = 0.031, OR = 1.29, 95 % CI = 1.02–1.62) and AA genotype (P = 0.033, OR = 1.64, 95 % CI = 1.04–2.60) for G1186A was lower in the pulmonary TB than healthy control and were significantly correlated with pulmonary TB. After adjustment for age and gender, G1186A was found to be additive models in association with pulmonary TB (P = 0.04, OR = 1.27, 95 % CI = 1.01–1.60). By calculating linkage disequilibrium, the frequency of haplotype GGTCCT (P = 0.032, OR = 0.75, 95 % CI = 0.57–0.97) and GGTCCC (P = 0.044, OR = 0.57, 95 % CI = 0.33–0.99) was significantly associated with pulmonary TB. No association was found between other SNPs and pulmonary TB. In the Kazak, all SNPs were not associated with pulmonary TB. Our results suggest that genetic factors play an important role in susceptibility to pulmonary TB at the individual level, and provide an experimental basis to clarify the pathogenesis of pulmonary TB.     

Analysis on DNA sequence of KiSS-1 gene and its association with litter size in goats

Three pairs of primers were designed to clone the goat KiSS-1 and scan polymorphisms and four pairs to detect polymorphisms in sexual precocious and sexual late-maturing goat breeds. A 4118 bp DNA fragment was obtained, which contains an ORF of 408 bp and encodes 135 amino acids, having a high homology with other mammals. The protein was predicted containing a signal peptide of 17 amino acids. There are two mutations (G3433A [A86T] and C3688A) in exon 3, three mutations (G296C, G454T and T505A) in intron 1 and a 18 bp deletion (?)/insertion (+) (1960–1977) in intron 2 and no mutations in exon 2. The genotype distribution didn’t show obvious difference between sexual precocious and sexual late-maturing goat breeds and no consistency within the sexual late-maturing breeds. For the 296 locus, the Jining Grey goats with genotype CC had 0.80 (P < 0.01) or 0.77 (P < 0.01) kids more than those with genotype GG or GC, respectively. No significant difference (P > 0.05) was found in litter size between GG and GC. For the 1960–1977 locus, the Jining Grey goat does with genotype ?/? had 0.77 (P < 0.01) or 0.73 (P < 0.01) kids more than those with +/+ or +/?, respectively. No significant difference (P > 0.05) was found in litter size between +/+ and +/? genotypes. For the other four loci, no significant difference (P > 0.05) was found in litter size between different genotypes in Jining Grey goats. The present study preliminarily indicated an association between allele C of the 296 locus and allele (?) of the 1960–1977 locus in KiSS-1 and high litter size in Jining Grey goats.     

Regulation of Visceral and Subcutaneous Adipocyte Lipolysis by Acute AICAR‐induced AMPK Activation

This study investigated the role of adenosine monophosphate–activated protein kinase (AMPK) in the regulation of lipolysis in visceral (VC) and subcutaneous (SC) rat adipocytes and the molecular mechanisms involved in this process. VC (epididymal and retroperitoneal) and SC (inguinal) adipocytes were isolated from male Wistar rats (160–180 g). Adipocytes were incubated either in the absence or in the presence of the AMPK agonist 5‐aminoimidazole‐4‐carboxamide‐1‐β‐d‐ribofuranoside (AICAR, 0–500 µmol/l). AMPK and acetyl‐CoA carboxylase (ACC) phosphorylation, basal and epinephrine‐stimulated (100 nmol/l) glycerol release, and hormone‐sensitive lipase (HSL) phosphorylation and activity were determined. AICAR‐induced (500 µmol/l) AMPK activation inhibited basal glycerol release by ～42, 41, and 44% in epididymal, retroperitoneal, and inguinal adipocytes, respectively. Epinephrine‐stimulated glycerol release was almost completely prevented by AICAR treatment in adipocytes from all fat depots. The AMPK inhibitor compound C (20 µmol/l) prevented AICAR‐induced phosphorylation of AMPK and significantly increased basal (～1.3‐, 1.4‐, and 1.7‐fold) and epinephrine‐stimulated (～1.3‐, 1.2‐, 1.4‐fold) glycerol release in epididymal, retroperitoneal, and inguinal adipocytes, respectively. AICAR increased phosphorylation of HSL_Ser565 and inhibited epinephrine‐induced phosphorylation of HSL_Ser563 and HSL_Ser660. This was also accompanied by a 73% reduction in epinephrine‐stimulated HSL activity. Compound C prevented the phosphorylation of HSL_Ser565 induced by AICAR and partially prevented the inhibitory effect of this drug on basal and epinephrine‐stimulated lipolysis in adipocytes in VC and SC fat depots. In summary, despite different fat depots eliciting distinct rates of lipolysis, acute AICAR‐induced AMPK activation suppressed HSL phosphorylation/activation and exerted similar antilipolytic effects on both VC and SC adipocytes.     

Monoamine oxidase A gene polymorphisms and enzyme activity associated with risk of gout in Taiwan aborigines

Taiwanese aborigines have a high prevalence of hyperuricemia and gout. Uric acid levels and urate excretion have correlated with dopamine-induced glomerular filtration response. MAOs represent one of the major renal dopamine metabolic pathways. We aimed to identify the monoamine oxidase A (MAOA, Xp11.3) gene variants and MAO-A enzyme activity associated with gout risk. This study was to investigate the association between gout and the MAOA single-nucleotide polymorphisms (SNPs) rs5953210, rs2283725, and rs1137070 as well as between gout and the COMT SNPs rs4680 Val158Met for 374 gout cases and 604 controls. MAO-A activity was also measured. All three MAOA SNPs were significantly associated with gout. A synonymous MAOA SNP, rs1137070 Asp470Asp, located in exon 14, was associated with the risk of having gout (P = 4.0 × 10^?5, adjusted odds ratio 1.46, 95% confidence intervals [CI]: 1.11–1.91). We also showed that, when compared to individuals with the MAOA GAT haplotype, carriers of the AGC haplotype had a 1.67-fold (95% CI: 1.28–2.17) higher risk of gout. Moreover, we found that MAOA enzyme activity correlated positively with hyperuricemia and gout (P for trend = 2.00 × 10^?3 vs. normal control). We also found that MAOA enzyme activity by rs1137070 allele was associated with hyperuricemia and gout (P for trend = 1.53 × 10^?6 vs. wild-type allele). Thus, our results show that some MAOA alleles, which have a higher enzyme activity, predispose to the development of gout.     

Association of Genetic Variants of MTHFR,ENPP1, and ADIPOQ with Myocardial Infarction in Egyptian Patients

The study aimed to investigate the association between MTHFR C677T, ENPP1 K121Q, and ADIPOQ 45 T/G gene polymorphisms and incidence of myocardial infarction (MI) in Egyptian patients. The study included 60 unrelated patients suffering from their first MI and 60 unrelated controls. Patients were recruited from Kasr-El Eini hospital, Cairo University. The previously mentioned polymorphisms were determined in all participants by PCR–RFLP. There was no significant difference in the distribution of genotypes and alleles of MTHFR C677T between groups. In contrast, significant difference was found in the distributions of genotypes and alleles of ENPP1 K121Q and ADIPOQ 45 T/G between MI patients and controls (P = 0.01, P = 0.004, P = 0.009, P = 0.001, respectively). Univariate analysis revealed that 121Q ENPP1 and 45 G ADIPOQ alleles were associated with the increased risk of MI (OR = 3; 95 % CI = 1.45–6.2; P = 0.004 and OR = 5.8; 95 % CI = 1.92–17.54; P = 0.001, respectively). The mutant homozygous genotypes of MTHFR, ENPP1, and ADIPOQ were more prevalent in diabetic hypertensive MI patients than it was among non-diabetic normotensive MI patients. Regarding the coagulation profile, INR (P = 0.009) and PC % (P = 0.022) were significantly different among the three genotypes of MTHFR C677T. The 677 T, 121 Q, and 45G variants were associated with MI in Egyptian patients; however, more studies are needed to determine the possible protective effect for these polymorphisms in our population.     

Analysis of coding variants identified from exome sequencing resources for association with diabetic and non-diabetic nephropathy in African Americans

Prior studies have identified common genetic variants influencing diabetic and non-diabetic nephropathy, diseases which disproportionately affect African Americans. Recently, exome sequencing techniques have facilitated identification of coding variants on a genome-wide basis in large samples. Exonic variants in known or suspected end-stage kidney disease (ESKD) or nephropathy genes can be tested for their ability to identify association either singly or in combination with known associated common variants. Coding variants in genes with prior evidence for association with ESKD or nephropathy were identified in the NHLBI-ESP GO database and genotyped in 5,045 African Americans (3,324 cases with type 2 diabetes associated nephropathy [T2D-ESKD] or non-T2D ESKD, and 1,721 controls) and 1,465 European Americans (568 T2D-ESKD cases and 897 controls). Logistic regression analyses were performed to assess association, with admixture and APOL1 risk status incorporated as covariates. Ten of 31 SNPs were associated in African Americans; four replicated in European Americans. In African Americans, SNPs in OR2L8, OR2AK2, C6orf167 (MMS22L), LIMK2, APOL3, APOL2, and APOL1 were nominally associated (P = 1.8 × 10^?4–0.044). Haplotype analysis of common and coding variants increased evidence of association at the OR2L13 and APOL1 loci (P = 6.2 × 10^?5 and 4.6 × 10^?5, respectively). SNPs replicating in European Americans were in OR2AK2, LIMK2, and APOL2 (P = 0.0010-0.037). Meta-analyses highlighted four SNPs associated in T2D-ESKD and all-cause ESKD. Results from this study suggest a role for coding variants in the development of diabetic, non-diabetic, and/or all-cause ESKD in African Americans and/or European Americans.     

Associations between interferon regulatory factor 5 polymorphisms and rheumatoid arthritis: a meta-analysis

The aim of this study was to determine whether interferon regulatory factor 5 (IRF5) polymorphisms confers susceptibility to rheumatoid arthritis (RA) in populations with different ethnicities. We searched the literature using the Pubmed and Embase databases and conducted meta-analyses on associations between the four IRF5 polymorphisms (rs2004640, rs729302, rs752637, and rs2280714) and RA susceptibility, using fixed and random effects models. A total of 12 comparison studies were considered in this meta-analysis, which in total involved 7,916 RA patients and 6,452 controls, and eight European, three Asian, and one Argentinean population. Meta-analysis showed an association between the minor allele of rs2004640 and RA in all subjects (odds ratio [OR] = 0.928, 95 % confidence interval [CI] = 0.865–0.996, P = 0.037). After stratification by ethnicity, analysis indicated that the minor allele was significantly associated with RA in Europeans (OR = 0.889, 95 % CI = 0.839–0.941, P = 5.03 × 10^?6), but not in Asians (OR = 1.057, 95 % CI = 0.978–1.144, P = 0.164). A direct comparison between anti-citrullinated peptide antibody-positive and -negative patients revealed no difference of the frequency of the rs2004640 minor allele (OR = 1.047, 95 % CI = 0.813–1.348, P = 0.724). Meta-analysis identified a significant association between RA and the minor allele of the rs729302 polymorphism in the overall population (OR = 0.896, 95 % CI = 0.826–0.972, P = 0.009) and in Asians (OR = 0.862, 95 % CI = 0.795–0.935, P = 3.50 × 10^?5), but not in Europeans (OR = 0.951, 95 % CI = 0.877–1.031, P = 0.225). Meta-analysis showed an association between the minor allele of rs752637 and RA in Europeans (OR = 0.858, 95 % CI = 0.789–0.932, P = 3.03 × 10^?5), but not in Asians (OR = 1.035, 95 % CI = 0.918–1.168, P = 0.572). No association was found between the rs2280714 polymorphism and RA susceptibility. This meta-analysis confirms that the IRF5 rs2004640, rs729302 and rs752637 polymorphisms are associated with RA susceptibility in different ethnic groups, especially in Europeans and Asians, but further study of this association is required in other ethnic groups.     

Hormone-sensitive lipase deficiency affects the expression of SR-BI,LDLr, and ABCA1 receptors/transporters involved in cellular cholesterol uptake and efflux and disturbs fertility in mouse testis

Hormone-sensitive lipase (HSL) hydrolyse acylglycerols, cholesteryl and retinyl esters. HSL is a key lipase in mice testis, as HSL deficiency results in male sterility. The present work study the effects of the deficiency and lack of HSL on the localization and expression of SR-BI, LDLr, and ABCA1 receptors/transporters involved in uptake and efflux of cholesterol in mice testis, to determine the impact of HSL gene dosage on testis morphology, lipid homeostasis and fertility. The results of this work show that the lack of HSL in mice alters testis morphology and spermatogenesis, decreasing sperm counts, sperm motility and increasing the amount of Leydig cells and lipid droplets. They also show that there are differences in the localization of HSL, SR-BI, LDLr and ABCA1 in HSL^+/+, HSL^+/− and HSL^−/− mice. The deficiency or lack of HSL has effects on protein and mRNA expression of genes involved in lipid metabolisms in mouse testis. HSL^−/− testis have augmented expression of SR-BI, LDLr, ABCA1 and LXRβ, a critical sterol sensor that regulate multiple genes involved in lipid metabolism; whereas LDLr expression decreased in HSL^+/− mice. Plin2, Abca1 and Ldlr mRNA levels increased; and LXRα (Nr1h3) and LXRβ (Nr1h2) decreased in testis from HSL^−/− compared with HSL^+/+; with no differences in Scarb1. Together these data suggest that HSL deficiency or lack in mice testis induces lipid homeostasis alterations that affect the cellular localization and expression of key receptors/transporter involved in cellular cholesterol uptake and efflux (SR-BI, LDRr, ABCA1); alters normal cellular function and impact fertility.     

Potential Contribution of Dopaminergic Gene Variants in ADHD Core Traits and Co-Morbidity: A Study on Eastern Indian Probands

Association of dopaminergic genes, mainly receptors and transporters, with Attention Deficit Hyperactivity Disorder (ADHD) has been investigated throughout the world due to the importance of dopamine (DA) in various physiological functions including attention, cognition and motor activity, traits. However, till date, etiology of ADHD remains unknown. We explored association of functional variants in the DA receptor 2 (rs1799732 and rs6278), receptor 4 (exon 3 VNTR and rs914655), and transporter (rs28363170 and rs3836790) with hyperactivity, cognitive deficit, and co-morbid disorders in eastern Indian probands. Diagnostic and Statistical Manual for Mental Disorders-IV was followed for recruitment of nuclear families with ADHD probands (N = 160) and ethnically matched controls (N = 160). Cognitive deficit and hyperactive traits were measured using Conner’s parents/teachers rating scale. Peripheral blood was collected after obtaining informed written consent and used for genomic DNA isolation. Genetic polymorphisms were analyzed by PCR-based methods followed by population- as well as family-based statistical analyses. Association between genotypes and cognitive/hyperactivity traits and co-morbidities was analyzed by the Multifactor dimensionality reduction (MDR) software. Case–control analysis showed statistically significant difference for rs6278 and rs28363170 (P = 0.004 and 1.332e?007 respectively) while family-based analysis exhibited preferential paternal transmission of rs28363170 ‘9R’ allele (P = 0.04). MDR analyses revealed independent effects of rs1799732, rs6278, rs914655, and rs3836790 in ADHD. Significant independent effects of different sites on cognitive/hyperactivity traits and co-morbid disorders were also noticed. It can be summarized from the present investigation that these gene variants may influence cognitive/hyperactive traits, thereby affecting the disease etiology and associated co-morbid features.