**7. Genetics**

Familial clustering, ethnic differences, and regional discrepancies sugges<sup>t</sup> a genetic component to IgAN and IgAV.

The genetic influence of GdIgA1 production and expression during IgAN and IgAV is highlighted by a study from Kiryluk et al [89]. Serum GdIgA1 levels (quantified using HAA lectin based ELISA) from 20 children with IgAV and nephritis, and 14 children with IgAN were compared to 51 age- and ethnicity match pediatric controls. Serum level of GdIgA1 were significantly elevated in the 34 children with IgAV or IgAN compare to controls. It was also elevated in a large fraction of 54 first-degree relatives, compared with 141 unrelated healthy adult controls. A unilineal transmission of the trait was found in17, bilineal transmission in 1, and sporadic occurrence in 5 of 23 families when both parents and the patient were analyzed. There was a significant age-, gender, and householdadjusted heritability of serum GdIgA1 estimated at 76% in pediatric IgAN and at 64% in pediatric IgAV with nephritis.

High heritability of GdIgA1 in IgAN have been previously shown in adults from other ethnic origins: Caucasiens [90], Asians [91], and African Americans [92].

Kiryluk et al. collaborated with many teams around the world to provide insight into why IgAN differs in terms of incidence, presentation and prognosis all over the world, through a huge genome-wide association (GWAS) study to localize five IgAN susceptibility, in 10,775 individuals from Europe, Asia and America [93]. Nevertheless, these studies did not include patients with IgAV. There is only one small genetic study (285 IgAV patients and 1006 healthy controls from Spain genotyped by Illumina HumanCore BeadChips) showing in IgAV, as for IgAN, variations in the loci of the HLA class 2 genes region (HLA-DRB1 position 13 and 11) suggesting the same susceptibilities [94].

#### **8. Discussion and Future Research**

After reporting all those studies, can we say that IgA Nephropathy and IgA Vasculitis are two clinical entities of the same disease?

Clinical studies showed that they differentiate clearly in terms of clinical presentation and age at onset.

Concerning outcome, studies are conflicting, but tend to show that if patients are stratified on age and genetic background, IgAN and IgAV have the same renal prognosis. The presence of clinically speaking extra-renal disease makes the diagnosis of IgAV easy at an early stage, whereas in patients whose disease is limited to the kidney, the diagnosis is inevitably belated and therefore more advanced. It is not said, moreover, that these patients had, some years before, some unnoticed purpuric lesions. Therefore, the real question is: Why do some patients with IgAV have no renal involvement, and why do patients with IgAN have no skin lesions?

Physiopathological mechanisms and their related biomarkers are similar, each time they have been evaluated in the same study, none of which have been identified, to date, as having a strong prognostic value, either in IgAN and IgAV. It is thus most essential to identify early diagnostic and prognostic markers, which could be able to detect patients who will not spontaneously heal and require specific treatment (yet to be defined). Working together to set up new clinical studies appears necessary. It will be crucial for those future trials:

