**3. Conclusion**

Genetics of IS represents a unique challenge. Among the most examined candidate genes in IS are those associated with lipid metabolism. Unfortunately, the results are complex and far from clear-cut. According the literature review in this chapter it can be consluded that genes (polymorphisms) that are the most likely to be associated with IS are: apoE (apo ε2/ε3/ε4) and PON1 gene (p.Gln192Arg). Insufficient or inconsistent data that neither supported nor excluded an association of some genes polymorphisms with IS apoAV (c.1131T>C), LPA (rs3798220), LPL (S447X), LDLR (c.370A>T), OLR1(IIVS4-14A/G, IVS4- 73C/T) and EPHX2 (G860A). For other genes/polymorphisms that were reviewed in this paper, we are reasonably confident that an association with IS can be ruled out.

The reasons for contradictory results in the studies may be limited sample size, heterogeneity of study designs and endpoints, differences in inclusion and exclusion criteria, ethnically different patient populations, selection of control population, different stroke subtypes and age of stroke onset, type of statistical evaluation, covariates, correction for multiple testing etc. One of the limitations of multiple non-reproducible candidate gene studies was the restriction to a single or rather few genetic variants tested for association with disease in examined gene. Further, genetic variants of candidate genes with strong effects at the transcriptional level or others affecting the functionality of the protein may have escaped the test for association with disease risk. Thus, in retrospect, it is not surprising that the candidate gene approach resulted in only limited success in the elucidation of IS stroke genes.

Research in the field of IS should be directed towards facilitation of the characterization of IS pathogenesis at the molecular level and the development of genetic markers' panels for assessment of IS risk. Technological developments such as GWAS, NGS technology, transcription profiling and proteomics will provide huge amounts of genetic information and allow investigators to identify variants in patients with specific stroke subtype and to identify how they exert their effects at the molecular level. The replication in an independent study, in large and well-characterized groups of patients of different ethnic origin, is required to confirm previously obtained results. On the basis of genetic or genomic information the therapeutic outcome or side effects in stroke patients could be predicted, as the effectiveness and safety of applied therapy. Also, this approach may help in stroke prevention by identification of presymptomatic at-risk individuals, resulting in minimizing patients' morbidity and mortality and reducing health care costs associated with stroke.

### **Author details**

594 Lipoproteins – Role in Health and Diseases

Icelandic population [226,227].

associated with IS [230].

elucidation of IS stroke genes.

**3. Conclusion** 

(*ZFHX3*) were observed to be associated with cardioembolic stroke and atrial fibrillation in

Three GWAS were performed in Japanese populations. Kubo et al. [228] found significant association of non-synonymous SNP (1425 GA) in protein kinase C-eta (PRKCH) with lacunar infarction in the pathogenesis of IS. Hata et al. [229] found that SNP in the 5' flanking region of angiotensin receptor like-1 (AGTRL1) gene (rs9943582, - 154G/A) to have a significant association with brain infarction. Also, rs9615362 of cell surface receptor CELSR1 (cadherin epidermal growth factor laminin A seven-pass G-type receptor 1) was

Genetics of IS represents a unique challenge. Among the most examined candidate genes in IS are those associated with lipid metabolism. Unfortunately, the results are complex and far from clear-cut. According the literature review in this chapter it can be consluded that genes (polymorphisms) that are the most likely to be associated with IS are: apoE (apo ε2/ε3/ε4) and PON1 gene (p.Gln192Arg). Insufficient or inconsistent data that neither supported nor excluded an association of some genes polymorphisms with IS apoAV (c.1131T>C), LPA (rs3798220), LPL (S447X), LDLR (c.370A>T), OLR1(IIVS4-14A/G, IVS4- 73C/T) and EPHX2 (G860A). For other genes/polymorphisms that were reviewed in this

The reasons for contradictory results in the studies may be limited sample size, heterogeneity of study designs and endpoints, differences in inclusion and exclusion criteria, ethnically different patient populations, selection of control population, different stroke subtypes and age of stroke onset, type of statistical evaluation, covariates, correction for multiple testing etc. One of the limitations of multiple non-reproducible candidate gene studies was the restriction to a single or rather few genetic variants tested for association with disease in examined gene. Further, genetic variants of candidate genes with strong effects at the transcriptional level or others affecting the functionality of the protein may have escaped the test for association with disease risk. Thus, in retrospect, it is not surprising that the candidate gene approach resulted in only limited success in the

Research in the field of IS should be directed towards facilitation of the characterization of IS pathogenesis at the molecular level and the development of genetic markers' panels for assessment of IS risk. Technological developments such as GWAS, NGS technology, transcription profiling and proteomics will provide huge amounts of genetic information and allow investigators to identify variants in patients with specific stroke subtype and to identify how they exert their effects at the molecular level. The replication in an independent study, in large and well-characterized groups of patients of different ethnic origin, is required to confirm previously obtained results. On the basis of genetic or genomic information the therapeutic outcome or side effects in stroke patients could be predicted, as the effectiveness and safety of applied therapy. Also, this approach may help in stroke

paper, we are reasonably confident that an association with IS can be ruled out.

Sanja Stankovic\* , Milika Asanin and Nada Majkic-Singh *Clinical Center of Serbia, University of Belgrade, Serbia* 

### **4. References**


<sup>\*</sup> Corresponding Author


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