Strong Genetic Association Research Articles

Distinct Genetic Backgrounds in Quantitative Traits Preceding Type 2 Diabetes: One Reason for Missing Heritability

Genome-wide association studies (GWAS) have identified variants associated with type 2 diabetes (T2D), but less than five percent of the genetic variance associated with T2D is accounted for in GWAS studies performed using T2D as endpoint. These findings suggest relevance of assessing preceding quantitative traits (QTs) or sub-phenotypes and their respective markers for contributing to the appearance of glycemic thresholds defining T2D. The QTs first appear in gestation and childhood when birth weight and childhood weight gain have an influence on T2D. Changes in fetal growth are associated with metabolic programming for T2D in adulthood. Subsequently gains in body fat leading to obesity, ectopic lipid deposition in liver and muscle, dyslipidemia and hypertension express in the β-cells, hypothalamus, adipocytes, myocytes, liver and kidney, and are associated with worsening insulin resistance and β-cell failure preceding overt T2D. Obesity, an increasingly common trait is associated with gene variants that regulate energy balance but have no association with T2D with few exceptions. For instance, FTO gene variants are associated with early onset of obesity and have also been associated with T2D and hypertension suggesting pleiotropism. Non-alcoholic fatty liver disease (NAFLD) has an independent genetic background and is considered as a new addition to the metabolic syndrome. Association of NAFLD with dyslipidemia, Review Article British Journal of Medicine & Medical Research, 4(2): 590-620, 2014 591 cardiovascular disease and hepatic insulin resistance contributes to progression to T2D. The classic dyslipidemia encountered in insulin resistant states consisting of increased triglyceride, low high-density lipoprotein cholesterol (HDL-C) and molding of triglyceridecontaining lipoproteins to form atherogenic LDL particles and dysfunctional HDL particles, has strong environmental and genetic association. In addition evidence is accumulating to show that the abnormal lipoproteins have a direct effect on β-cells leading to failure and possible acceleration of diabetes onset. Consequently known variants affecting either the dyslipidemia or β-cell function have a compound effect on T2D. Like other preceding traits the genetic background for commonly encountered hypertension is independent of diabetes although it remains a predictive trait. However, increasing evidence supports a role for the renin-angiotensin system in causing oxidative stress and insulin resistance. Finally when glucose intolerance has progressed to overt T2D, reversibility is usually no longer possible; therefore recognition of preceding prediabetic glycemic thresholds and both their genetic and environmental associations may facilitate and serve as signals for prevention. Thus a better understanding of the sequential expression of the respective QTs and genetic variation affecting their metabolic effects leading to T2D could initiate more effective prevention strategies.

Association between IL28B Polymorphisms and Spontaneous Clearance of Hepatitis B Virus Infection

Background/AimsSingle-nucleotide polymorphisms (SNPs) near the interleukin 28B gene (IL28B; interferon [IFN]-λ-3) are associated with outcomes of chronic hepatitis C virus (HCV) and hepatitis B virus (HBV) infection treated with peginterferon (PEG-IFN) alpha-based antiviral therapy. In this study, we investigated the influence of IL28B polymorphisms on spontaneous clearance of HBV infection in a large Korean cohort.MethodsBetween January 2007 and June 2010, a total of 208 patients with chronic HBV infection and newly diagnosed HBV-related hepatocellular carcinoma were recruited as the CC group [HBsAg(+) for >6 months, anti-HBc(+), and anti-HBs(-)]. In addition, 351 organ donors were stratified into the UE group [n = 106; HBsAg(-), anti-HBc(-), and anti-HBs(-)] or the SC group [n = 245; HBsAg(-), anti-HBc(+), and anti-HBs(+)]. The SNaPshot ddNTP Primer Extension Kit (Applied Biosystems, Foster City, CA) was used for SNP detection. Direct full sequencing of the IL28B coding region was attempted.ResultsRegardless of group, rs12979860 CC was most frequently identified (85.0% in UE, 85.9% in SC, and 93.5% in CC, respectively), whereas rs12979860 TT was not identified in any group. Similarly, rs12980275 AA and rs8099917 TT were most frequently identified (≥85%) regardless of group, whereas rs12980275 GG was identified in only one subject in the SC group. In addition, rs8099917 GG was not identified. The prevalences of CC in rs12979860, AA in rs12980275, and TT in rs8099917 were significantly higher in the CC group when compared with the UE and SC group (all P<0.05). Among 19 novel SNPs in the IL28B coding region, the proportions of 6 SNPs were significantly different among the UE, SC, and CC groups (all P<0.05).ConclusionsThe SNP upstream of IL28B that has the strongest genetic association with HCV recovery has an inverse influence on HBV recovery. Additional studies are needed to understand the mechanisms of this SNP in HBV infection.

AB1125 Juvenile idiopathic arthritis enthesitis-related arthritis (ERA) subtype: Do boys and girls have a different clinical fenotype and course?

BackgroundEnthesitis-related arthritis (ERA) is a subtype of juvenile idiopathic arthritis (JIA) according to the International League of Associations for Rheumatology (ILAR) classification. Its frequency varies widely on different populations. It...

SP0077 Vasculitis: Year in Review

A major achievement in nosology has been the development of novel classification criteria for Behçet disease (BD), called “International criteria for Behçet’s disease” (ICBD) (1). Data on 2556 patients with...

AB0194 HLA DRB1 alleles in incomplete lupus erithematosus

BackgroundSystemic lupus erythematous (SLE) represents a heterogeneous group of patients. Some of them are diagnosed with SLE with mild articular and cutaneous symptoms, while others present with severe organ damage....

Rheumatoid Arthritis in Latin Americans Enriched for Amerindian Ancestry Is Associated With Loci in Chromosomes 1, 12, and 13, and the HLA Class II Region

To identify susceptibility loci for rheumatoid arthritis (RA) in Latin American individuals with admixed European and Amerindian genetic ancestry. Genotyping was performed in 1,475 patients with RA and 1,213 control subjects, using a customized BeadArray containing 196,524 markers covering loci previously associated with various autoimmune diseases. Principal components analysis (EigenSoft package) and Structure software were used to identify outliers and define the population substructure. REAP software was used to define cryptic relatedness and duplicates, and genetic association analyses were conducted using Plink statistical software. A strong genetic association between RA and the major histocompatibility complex region was observed, localized within BTNL2/DRA-DQB1- DQA2 (P = 7.6 × 10(-10) ), with 3 independent effects. We identified an association in the PLCH2-HES5-TNFRSF14-MMEL1 region of chromosome 1 (P = 9.77 × 10(-6) ), which was previously reported in Europeans, Asians, and Native Canadians. We identified one novel putative association in ENOX1 on chromosome 13 (P = 3.24 × 10(-7) ). Previously reported associations were observed in the current study, including PTPN22, SPRED2, STAT4, IRF5, CCL21, and IL2RA, although the significance was relatively moderate. Adjustment for Amerindian ancestry improved the association of a novel locus in chromosome 12 at C12orf30 (NAA25) (P = 3.9 × 10(-6) ). Associations with the HLA region, SPRED2, and PTPN22 improved in individuals positive for anti-cyclic citrullinated peptide antibodies. Our data define, for the first time, the contribution of Amerindian ancestry to the genetic architecture of RA in an admixed Latin American population by confirming the role of the HLA region and supporting the association with a locus in chromosome 1. In addition, we provide data for novel putative loci in chromosomes 12 and 13.

Imputation of variants from the 1000 Genomes Project modestly improves known associations and can identify low-frequency variant-phenotype associations undetected by HapMap based imputation.

Genome-wide association (GWA) studies have been limited by the reliance on common variants present on microarrays or imputable from the HapMap Project data. More recently, the completion of the 1000 Genomes Project has provided variant and haplotype information for several million variants derived from sequencing over 1,000 individuals. To help understand the extent to which more variants (including low frequency (1% ≤ MAF <5%) and rare variants (<1%)) can enhance previously identified associations and identify novel loci, we selected 93 quantitative circulating factors where data was available from the InCHIANTI population study. These phenotypes included cytokines, binding proteins, hormones, vitamins and ions. We selected these phenotypes because many have known strong genetic associations and are potentially important to help understand disease processes. We performed a genome-wide scan for these 93 phenotypes in InCHIANTI. We identified 21 signals and 33 signals that reached P<5×10−8 based on HapMap and 1000 Genomes imputation, respectively, and 9 and 11 that reached a stricter, likely conservative, threshold of P<5×10−11 respectively. Imputation of 1000 Genomes genotype data modestly improved the strength of known associations. Of 20 associations detected at P<5×10−8 in both analyses (17 of which represent well replicated signals in the NHGRI catalogue), six were captured by the same index SNP, five were nominally more strongly associated in 1000 Genomes imputed data and one was nominally more strongly associated in HapMap imputed data. We also detected an association between a low frequency variant and phenotype that was previously missed by HapMap based imputation approaches. An association between rs112635299 and alpha-1 globulin near the SERPINA gene represented the known association between rs28929474 (MAF = 0.007) and alpha1-antitrypsin that predisposes to emphysema (P = 2.5×10−12). Our data provide important proof of principle that 1000 Genomes imputation will detect novel, low frequency-large effect associations.

The peptide motif of the single dominantly expressed class I molecule of the chicken MHC can explain the response to a molecular defined vaccine of infectious bursal disease virus (IBDV)

In contrast to typical mammals, the chicken MHC (the BF-BL region of the B locus) has strong genetic associations with resistance and susceptibility to infectious pathogens as well as responses to vaccines. We have shown that the chicken MHC encodes a single dominantly expressed class I molecule whose peptide-binding motifs can determine resistance to viral pathogens, such as Rous sarcoma virus and Marek’s disease virus. In this report, we examine the response to a molecular defined vaccine, fp-IBD1, which consists of a fowlpox virus vector carrying the VP2 gene of infectious bursal disease virus (IBDV) fused with β-galactosidase. We vaccinated parental lines and two backcross families with fp-IBD1, challenged with the virulent IBDV strain F52/70, and measured damage to the bursa. We found that the MHC haplotype B15 from line 15I confers no protection, whereas B2 from line 61 and B12 from line C determine protection, although another locus from line 61 was also important. Using our peptide motifs, we found that many more peptides from VP2 were predicted to bind to the dominantly expressed class I molecule BF2*1201 than BF2*1501. Moreover, most of the peptides predicted to bind BF2*1201 did in fact bind, while none bound BF2*1501. Using peptide vaccination, we identified one B12 peptide that conferred protection to challenge, as assessed by bursal damage and viremia. Thus, we show the strong genetic association of the chicken MHC to a T cell vaccine can be explained by peptide presentation by the single dominantly expressed class I molecule.

Functionally Relevant Microsatellite Markers From Chickpea Transcription Factor Genes for Efficient Genotyping Applications and Trait Association Mapping

We developed 1108 transcription factor gene-derived microsatellite (TFGMS) and 161 transcription factor functional domain-associated microsatellite (TFFDMS) markers from 707 TFs of chickpea. The robust amplification efficiency (96.5%) and high intra-specific polymorphic potential (34%) detected by markers suggest their immense utilities in efficient large-scale genotyping applications, including construction of both physical and functional transcript maps and understanding population structure. Candidate gene-based association analysis revealed strong genetic association of TFFDMS markers with three major seed and pod traits. Further, TFGMS markers in the 5′ untranslated regions of TF genes showing differential expression during seed development had higher trait association potential. The significance of TFFDMS markers was demonstrated by correlating their allelic variation with amino acid sequence expansion/contraction in the functional domain and alteration of secondary protein structure encoded by genes. The seed weight-associated markers were validated through traditional bi-parental genetic mapping. The determination of gene-specific linkage disequilibrium (LD) patterns in desi and kabuli based on single nucleotide polymorphism-microsatellite marker haplotypes revealed extended LD decay, enhanced LD resolution and trait association potential of genes. The evolutionary history of a strong seed-size/weight-associated TF based on natural variation and haplotype sharing among desi, kabuli and wild unravelled useful information having implication for seed-size trait evolution during chickpea domestication.

Genetic variants associated with methotrexate efficacy and toxicity in early rheumatoid arthritis: results from the treatment of early aggressive rheumatoid arthritis trial

Methotrexate (MTX) has emerged as first-line therapy for early moderate to severe rheumatoid arthritis (RA), but individual variation in treatment response remains unexplained. We tested the associations between 863 known pharmacogenetic variants and MTX response in 471 TEAR Trial participants with early RA. Efficacy and toxicity were modeled using multiple regression, adjusted for demographic and clinical covariates. Penalized regression models were used to test joint associations of markers and/or covariates with the outcomes. The strongest genetic associations with efficacy were in CHST11 (five markers with P <0.003), encoding carbohydrate (chondroitin 4) sulfotransferase 11. Top markers associated with MTX toxicity were in the cytochrome p450 genes CYP20A1 and CYP39A1, solute carrier genes SLC22A2 and SLC7A7, and the mitochondrial aldehyde dehydrogenase gene ALDH2. The selected markers explained a consistently higher proportion of variation in toxicity than efficacy. These findings could inform future development of personalized therapeutic approaches.

Systems Genetics Implicates Cytoskeletal Genes in Oocyte Control of Cloned Embryo Quality

Cloning by somatic cell nuclear transfer is an important technology, but remains limited due to poor rates of success. Identifying genes supporting clone development would enhance our understanding of basic embryology, improve applications of the technology, support greater understanding of establishing pluripotent stem cells, and provide new insight into clinically important determinants of oocyte quality. For the first time, a systems genetics approach was taken to discover genes contributing to the ability of an oocyte to support early cloned embryo development. This identified a primary locus on mouse chromosome 17 and potential loci on chromosomes 1 and 4. A combination of oocyte transcriptome profiling data, expression correlation analysis, and functional and network analyses yielded a short list of likely candidate genes in two categories. The major category-including two genes with the strongest genetic associations with the traits (Epb4.1l3 and Dlgap1)-encodes proteins associated with the subcortical cytoskeleton and other cytoskeletal elements such as the spindle. The second category encodes chromatin and transcription regulators (Runx1t1, Smchd1, and Chd7). Smchd1 promotes X chromosome inactivation, whereas Chd7 regulates expression of pluripotency genes. Runx1t1 has not been associated with these processes, but acts as a transcriptional repressor. The finding that cytoskeleton-associated proteins may be key determinants of early clone development highlights potential roles for cytoplasmic components of the oocyte in supporting nuclear reprogramming. The transcriptional regulators identified may contribute to the overall process as downstream effectors.

Association of ZAP70 and PTPN6, but Not BANK1 or CLEC2D, with Inflammatory Bowel Disease in the Tunisian Population

Inflammatory bowel diseases (IBDs), consisting of ulcerative colitis (UC) and Crohn's disease (CD), are complex disorders with multiple genes contributing to disease pathogenesis. We aimed to identify the associations of genetic variations in the ZAP70, PTPN6, BANK1, and CLEC2D genes encoding for intracellular signaling molecules with IBDs. One hundred seven patients (39 CD and 68 UC) with IBD and 162 healthy control subjects from the Southern Tunisia were recruited. We genotyped 4 single-nucleotide polymorphisms (SNPs) in ZAP70 (rs1020396, rs11686881, rs13420683, and rs17695937), 2 SNPs in PTPN6 (rs7310161 and rs759052), 3 SNPs in BANK1 (rs10516487, rs17266594, and rs3733197), and 1 SNP in CLEC2D (rs3764021). ZAP70 displayed a strong genetic association with CD for rs13420683 [allele C, p=0.003, P(corr)=0.006, odds ratio (OR)=2.25 (1.32; 3.85); genotype CC, p=0.016, P(corr)=0.048, OR=2.57 (1.22; 5.41)]. However, in UC, a weak association with PTPN6 was observed [TT (p=0.01; P(corr)=0.03; OR=2.11 (1.18; 3.76)]. No significant association in the BANK1 and CLEC2D genes was observed. These results suggest the involvement of the ZAP70 and PTPN6 genes in the genetic component conferring a general susceptibility to CD and UC, respectively. This work provides motivation for studies aiming to replicate these findings in larger populations.

Psoriasis Epidemiology: The Interplay of Genes and the Environment

Psoriasis is a common chronic dermatological disease whose prevalence varies among different populations worldwide. In epidemiological studies, the factors that potentially account for this variability include climate, genetic susceptibility, and environmental antigen exposure. In this issue, Parisi et al. performed a systematic review to explore the global prevalence and incidence of psoriasis.

HLA-DRB1* Allele Frequencies in Pediatric, Adolescent and Adult-Onset Multiple Sclerosis Patients, in a Hellenic Sample. Evidence for New and Established Associations

Studies in many populations consistently have showed that the human leukocyte antigens (HLA) and especially the DRB1*15 allele has by far the strongest genetic association with multiple sclerosis (MS). The aim of this study was to investigate the role of HLA-DRB1* alleles in MS risk/resistance and onset. A sample of 165 Hellenic MS patients (18 with pediatric-, 24 with adolescent- and 123 with adult-onset MS) and 107 healthy volunteers were examined with molecular techniques. Comparisons were made according to the Benjamini-Yekutieli method for p value correction. Both adult-onset MS patients and early-onset MS patients (age at onset below 20 years-old) had a significantly higher frequency of the DRB1*15 allele and a significantly lower frequency of the DRB1*11 allele compared to controls. For the early-onset vs. healthy group comparison, subgroup analyses revealed that both the pediatric- and the adolescent-onset MS groups contributed to the aforementioned DRB1*15 significant difference, while the DRB1*11 difference was ascribed solely to the adolescent-MS onset vs. healthy group comparison. Within MS patients comparisons revealed that early-onset MS patients had a tendency for higher DRB1*03 allele and a lower DRB1*16 allele frequency frequencies compared to adult-onset MS patients, although both non-significant. Notably, pediatric-onset MS patients showed complete absence of the DRB1*16 allele, along with a non-significant tendency for higher DRB1*15 allele frequency relative to the adult-onset group. Finally, the adolescent-onset MS group was presented with a lower DRB1*11 allele frequencies compared both to the pediatric- and the adult-onset MS group. Our findings confirm previous studies on the role of HLA-DRB1* in MS. New findings that need to be confirmed by further studies are the pathogenetic role of DRB1*03 for early-onset MS and the putative protective role of the DRB1*16 allele in the pediatric-onset MS.

A multiplex assay to rapidly exclude HLA-DQ2.5 and HLA-DQ8 expression in patients at risk for celiac disease

Celiac disease (CD) is an inflammatory disorder of the small intestine induced by gluten ingestion. CD has a strong genetic association with human leukocyte antigen (HLA)-DQ2.5 and HLA-DQ8. The absence of HLA-DQ2.5 and HLA-DQ8 has a strong negative predictive value for CD. Genetic screening of HLA-DQ2.5 and HLA-DQ8 in patients at risk is of great value. We designed, developed, and validated a multiplex assay based on multiplex ligation-dependent probe amplification (MLPA) technology, allowing the simultaneous detection of DQA1*05-DQB1*02, encoding HLA-DQ2.5, and DQA1*03-DQB1*03:02, encoding HLA-DQ8. The amplified products were separated and identified using capillary electrophoresis. When compared with a polymerase chain reaction followed by single-strand conformation polymorphism/ heteroduplex analysis, one discrepancy was found. Sequencing analysis showed that the developed MLPA assay result was correct. Furthermore, we demonstrated that the MLPA method is able to distinguish between the heterozygote and homozygote expression of HLA-DQ2.5 or HLA-DQ8. This study shows that it is possible to rapidly and accurately screen for the absence of HLA-DQ2.5 and HLA-DQ8 using MLPA, excluding patients at risk for CD for further serological or histological follow-up. In addition, MLPA might be an accurate tool to screen for other specific HLA types in the context of disease association in a diagnostic laboratory setting.

The role of the palatine tonsils in the pathogenesis and treatment of psoriasis

Psoriasis is a common chronic skin disease with strong genetic associations and environmental triggers. Patients with psoriasis develop sore throats much more frequently than nonpsoriatic individuals and it is well documented that streptococcal throat infections can trigger the onset of psoriasis, and such infections cause exacerbation of chronic psoriasis. It is now generally accepted that psoriatic lesions are caused by abnormal reactivity of specific T lymphocytes in the skin. However, it has been shown in recent years that activation of specific immunity is always preceded by activation of nonspecific innate immune mechanisms, and that abnormalities in the innate immune system can cause dysregulation in specific immune responses. Here we explore the possible immune mechanisms that are involved in the link between infection of the tonsils and this inflammatory skin disease. Moreover, we survey the literature and discuss the suitability of tonsillectomy as a treatment for psoriasis.

Association of ankylosing spondylitis with HLA-B27 and ERAP1: Pathogenic role of antigenic peptide

Ankylosing spondylitis (AS) is a form of seronegative inflammatory arthritis whose strong genetic association with the human leucocyte antigen (HLA)-B27 has been known for almost 4 decades. However, its mechanism remains poorly understood. Recently, with the development of genetics, further more genes have been robustly associated with the disease. Genome-wide association studies identified the association between AS and ERAP1 (endoplasmic reticulum associated aminopeptidase 1). And ERAP1 has shown the potential in trimming antigenic peptides to optimal length for binding to HLA-B27 in the ER (endoplasmic reticulum). However, the length of the peptides are strictly restricted in the process of peptide transporting, processing and presentation. A hypothesis is proposed that the abnormal mechanism of AS may related to the trimming of N-terminal sequences from antigenic precursors in the ER and the length of the antigenic peptides that are presented to the T-cell receptors.

Hypomethylation of the IL17RC Promoter Associates with Age-Related Macular Degeneration

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the elderly population worldwide. Although recent studies have demonstrated strong genetic associations between AMD and SNPs in a number of genes, other modes of regulation are also likely to play a role in the etiology of this disease. We identified a significantly decreased level of methylation on the IL17RC promoter in AMD patients. Furthermore, we showed that hypomethylation of the IL17RC promoter in AMD patients led to an elevated expression of its protein and messenger RNA in peripheral blood as well as in the affected retina and choroid, suggesting that the DNA methylation pattern and expression of IL17RC may potentially serve as a biomarker for the diagnosis of AMD and likely plays a role in disease pathogenesis.

Protein-Protein Interaction Analysis Highlights Additional Loci of Interest for Multiple Sclerosis

Genetic factors play an important role in determining the risk of multiple sclerosis (MS). The strongest genetic association in MS is located within the major histocompatibility complex class II region (MHC), but more than 50 MS loci of modest effect located outside the MHC have now been identified. However, the relative candidate genes that underlie these associations and their functions are largely unknown. We conducted a protein-protein interaction (PPI) analysis of gene products coded in loci recently reported to be MS associated at the genome-wide significance level and in loci suggestive of MS association. Our aim was to identify which suggestive regions are more likely to be truly associated, which genes are mostly implicated in the PPI network and their expression profile. From three recent independent association studies, SNPs were considered and divided into significant and suggestive depending on the strength of the statistical association. Using the Disease Association Protein-Protein Link Evaluator tool we found that direct interactions among genetic products were significantly higher than expected by chance when considering both significant regions alone (p<0.0002) and significant plus suggestive (p<0.007). The number of genes involved in the network was 43. Of these, 23 were located within suggestive regions and many of them directly interacted with proteins coded within significant regions. These included genes such as SYK, IL-6, CSF2RB, FCLR3, EIF4EBP2 and CHST12. Using the gene portal BioGPS, we tested the expression of these genes in 24 different tissues and found the highest values among immune-related cells as compared to non-immune tissues (p<0.001). A gene ontology analysis confirmed the immune-related functions of these genes. In conclusion, loci currently suggestive of MS association interact with and have similar expression profiles and function as those significantly associated, highlighting the fact that more common variants remain to be found to be associated to MS.

Pseudoexfoliation syndrome, a systemic disorder with ocular manifestations

Pseudoexfoliation syndrome (PXS) is a systemic condition with eye manifestations. In the eye, pseudoexfoliation material deposits on various structures of the anterior segment. The nature of this material is mostly fibrillar with fibers made up of microfibrils and coated with amorphous material. The composition of these fibrils is diverse and includes basement membrane components as well as enzymes involved in extracellular matrix maintenance. Pseudoexfoliation is the most common cause of secondary open-angle glaucoma (pseudoexfoliation glaucoma, PXG) worldwide. The goal of this review is to summarize our knowledge on the genetics of this systemic disorder and its resultant ocular manifestations. PXS familial aggregation suggests genetic inheritance. PXS has been strongly associated with single nucleotide polymorphisms (SNPs) of the lysyl oxidase-like 1 (LOXL1) gene on chromosome 15q24.1. Two of these SNPs confer a higher than 99% population attributable risk for PXS and PXG in the Nordic population; however, they carry different risks in different populations. The high risk haplotypes also vary among different populations. LOXL1 is one of group of the enzymes involved in the cross-linking of collagen and elastin in the extracellular matrix. Its function in connective tissue maintenance has been confirmed in mice; however, its actual role in PXS remains unclear. Contactin-associated protein-like 2 also has a strong genetic association with PXS in a German cohort and is an attractive candidate molecule. It encodes for a protein involved in potassium channel trafficking. Other candidate genes linked to PXS include lysosomal trafficking regulator, clusterin, adenosine receptors, matrix metalloproteinase-1 (MMP1), and glutathione transferase. These genes may be modifying genes for development of PXS and PXG.