Bioinformatics workshop and conferences organized in Pakistan.

<p>Bioinformatics workshop and conferences organized in Pakistan.</p

Bioinformatics research and degree awarding public and private institutes in Pakistan.

<p>Bioinformatics research and degree awarding public and private institutes in Pakistan.</p

Decreased serum PON1 arylesterase activity in familial hypercholesterolemia patients with a mutated LDLR gene

<div><p>Abstract Paraoxonase 1 (PON1) is a serum enzyme associated with high density lipoprotein (HDL) regulation through its paraoxonase and arylesterase activity. PON1 inhibits the oxidation of HDL and low density lipoprotein (LDL), and is involved in the pathogenesis of a variety of diseases including atherosclerosis. Conversely, mutations in the low density lipoprotein receptor (LDLR) result in failure of receptor mediated endocytosis of LDL leading to its elevated plasma levels and onset of familial hypercholesterolemia (FH). In the current study we investigated the role of PON1 polymorphisms rs662; c.575A > G (p.Gln192Arg) and rs854560; c.163T > A (p.Leu55Met) in a large family having FH patients harboring a functional mutation in LDLR. Genotypes were revealed by RFLP, followed by confirmation through Sanger sequencing. PON1 activity was measure by spectrophotometry. Our results show significantly reduced serum paraoxonase and arylesterase activities in FH patients compared with the healthy individuals of the family (p < 0.05). PON1 QQ192 genotype showed a significantly higher association with FH (p=0.0002). PON1 Q192 isoform was associated with reduced serum paraoxonase activity by in silico analysis and PON1 R192 exhibited higher serum paraoxonase and arylesterase activity than the other polymorphs. Our results highlight that the combination of LDLR mutations and PON1 MMQQ genotypes may lead to severe cardiac events.</p></div

Association between gene score and outcome in the Pakistani samples.

<p>Logistic regression was performed for each group. (A) Islamabad study, outcome is MI, and (B) Lahore study, outcome is CHD. Error bars represent 95% confidence intervals.</p

Association between gene score and CHD in NPHSII.

<p>Logistic regression (age adjusted) was performed for each group. Error bars represent 95% confidence intervals.</p

Reclassification of NPHSII participants with the addition of the gene scores to the Framingham conventional risk factor score.

<p>NRI = net reclassification index.</p><p>Reclassification of NPHSII participants with the addition of the gene scores to the Framingham conventional risk factor score.</p

SNPs included in the gene scores.

<p>SNPs marked with an asterisk (*) are included in both the 19 and 13 SNP gene score.</p><p>⁺rs599839 was genotyped instead of rs646776, r² = 0.95 in Europeans</p><p>⁺⁺For rs7412, the protective SNP is included in the gene score</p><p>SNPs included in the gene scores.</p

<i>KIF1A</i> novel frameshift variant p.(Ser887Profs*64) exhibits clinical heterogeneity in a Pakistani family with hereditary sensory and autonomic neuropathy type IIC

Background: Hereditary sensory and autonomic neuropathies (HSANs) are rare heterogeneous group of neurological disorders caused by peripheral nerve deterioration. The HSANs sub-clinical classes have clinical and genetic overlap which often lead to misdiagnosis. In the present study a Pakistani family with five affected members suffering from severe neuropathy were genetically analyzed to identify the disease causative element in the family. Methods: Genome wide high-density single nucleotide polymorphism (SNP) microarray analysis was carried out followed by whole exome sequencing of the affected proband and another affected sibling. Shared homozygous regions in all severely affected members were identified through homozygosity mapping approach. Results: The largest homozygous region of 14.1 Mb shared by the five severely affected members of the family was identified on chromosome 2. Subsequent exome sequencing identified a novel single nucleotide deletion c.2658del; p.(Ser887Profs*64) in KIF1A. Segregation analysis revealed that this mutation was homozygous in all five affected individuals of the family with severe clinical manifestation, while members of the family that were heterozygous carriers shared abnormal skin features (scaly skin) only with the homozygous affected members. Conclusions: A novel frameshift mutation p.(Ser887Profs*64) in KIF1A is the potential cause of severe HSANIIC in a Pakistani family along with incomplete penetrance in mutation carriers. We demonstrate that using a combination of different techniques not only strengthens the gene finding approach but also helps in proper sub-clinical characterization along with identification of mutated alleles exhibiting incomplete penetrance leading to intrafamilial clinical variability in HSAN group of inherited diseases.</p

Comparison of risk allele frequencies between the control groups from the Pakistani studies and between the combined total of the Pakistani control groups and NPHSII.

<p>Comparisons were performed using tests of proportion. RAF = Risk Allele Frequency, CI = Confidence Interval.</p><p>Comparison of risk allele frequencies between the control groups from the Pakistani studies and between the combined total of the Pakistani control groups and NPHSII.</p

Characteristics of the Pakistani sample sets.

<p>Categorical variables were compared using a χ² test while continuous variables were compared using Welch’s t-tests.</p><p>* Log transformed data. Geometric mean and approximate SD are given.</p><p>Characteristics of the Pakistani sample sets.</p